A comprehensive review on phytochemistry and pharmacology of genus Kopsia: monoterpene alkaloids - major secondary metabolites.

Kopsia belongs to the family Apocynaceae, which was originally classified as a genus in 1823. Kopsia consists of medicinal plants that can be traditionally used to treat rheumatoid arthritis, pharyngitis, tonsillitis, and dropsy. More than one hundred and twenty-five publications have been documented relating to the phytochemical and pharmacological results, but a systematic review is not available. The goal of this study is to compile almost all of the secondary metabolites from the plants of genus Kopsia, as well as the coverage of their pharmacological research. The document findings were conducted via reliable sources, including Web of Science, Sci-Finder, Science Direct, PubMed, Google Scholar, and publishers, while four words "Kopsia", "monoterpene alkaloids", "Phytochemistry" and "Pharmacology" are key factors to search for references. Most Kopsia secondary metabolites were collected. A total of four hundred and seventy-two, including four hundred and sixty-six monoterpene alkaloids, five triterpenoids, and one sterol, were summarized, along with their resource. Kopsia monoterpene alkaloids presented in various skeletons, but aspidofractinines, eburnamines, and chanofruticosinates are the three major backbones. Mersinines and pauciflorines are new chemical classes of monoterpene alkaloids. With the rich content of monoterpene alkaloids, Kopsia constituents were also the main objects in pharmacological studies since the plant extracts and isolated compounds were proposed for anti-microbial, anti-inflammatory, anti-allergic, anti-diabetic, anti-manic, anti-nociceptive, acetylcholinesterase (AChE) inhibitory, cardiovascular, and vasorelaxant activities, especially cytotoxicity. This journal is © The Royal Society of Chemistry.

Introduction

Natural products are chemical substances created by living organisms and found in nature. In the medicinal chemistry field, this concept is usually limited to secondary metabolites.[1] The pharmacological studies on potential bioactive agents tend to find that lead molecules for drug development could arise from natural resources.

Kopsia belongs to the subfamily Rauvolfioideae of the family Apocynaceae.[2] This genus, containing about 30 species, is widely distributed in Southeast Asia, China, Australia, and some islands of the Western Pacific.[3,4]Kopsia plants are recognized as a fertile reservoir of novel and bioactive secondary metabolite type alkaloids. Therefore, they have been traditionally used in each country. Chinese folk medicine deals with the use of parts of K. officinalis Tsiang & P. T. Li to treat rheumatoid arthritis, pharyngitis, tonsillitis, and dropsy.[4] In Malaysia, the roots of four species, K. larutensis King & Gamble, K. macrophylla Hook.f., K. singapurensis Ridl., and K. paucifora Hook.f., were applied as a poultice to ulcerate noses in tertiary syphilis.[2,5]Kopsia constituents are also well-known in pharmacological discoveries, in which they have a wide spectrum of pharmacological effects such as anticancer and anti-manic activities.[6,7]

Recently, the search for bioactive molecules from the genus Kopsia has drawn lots of interest to natural product chemists and pharmacists.[8-13] Although there have been a variety of experimental studies, an overview of phytochemical and pharmacological assessments is not available now. The current review provides notes on basic knowledge about phytochemical research and sheds light on the pivotal role of Kopsia constituents in pharmacological examinations. More than one hundred twenty-five relevant publications have been used, as well as the data collection is from the 1950s to now.

Phytochemistry

Since the 1950s, a large number of phytochemical studies on Kopsia plants have been published. To some extent, this current paper provides basic knowledge about the isolation processes of Kopsia secondary metabolites. The results related to experimental reports are primarily based on chromatographic approaches, such as silica gel chromatography or HPLC procedure (high performance chromatography column), whereas the NMR structural elucidation of isolated compounds is due to the most utilization of spectral methods, such as 1D/2D-NMR, mass spectroscopy (MS), ultraviolet-visible (UV-Vis), optical rotation (OR), infrared (IR), circular dichroism (CD) and comparisons with previous literature. Among recorded thirty species, nineteen plants, including K. arborea, K. dasyrachis, K. deverrei, K. flavida, K. fruticosa, K. grandifolia, K. griffithii, K. hainanensis, K. jasminiflora, K. lancibracteolata, K. lapidilecta, K. larutensis, K. macrophylla, K. officinalis, K. pauciflora, K. profunda, K. singapurensis, K. teoi, and K. terengganensis, have been most widely utilized for phytochemical investigations. More than four hundred seventy metabolites were collected and tabulated in Table 1 and Fig. 1–9. Significantly, four hundred sixty-six isolated compounds have been categorized as monoterpene alkaloids, in which they have induced a diversity of chemical skeletons, including aspidofractinines 1–204, chanofruticosinates 205–241, aspidospermines 242–248, danuphyllines 249–252, eburnamines 253–301, akuammilines 302–322, sarpagines 323–326, aspidophyllines 327–331, strychnos 332–356, stemmadenine 357, mersinines 358–378, pauciflorines 379–390, skytanthines 391–400, rhazinilams 401–409, lundurines 410–426, aspidospermas 427–431, catharinensines 432–436, leuconoxines 437–442, pericines 443–446, alstonines 447–449, quebrachamines 450–452, arbophyllinines 453–454, arboflorines 455–456, andrasinines 457–458, corynantheines 459–460, carbolines 461–462, arbophyllidine 463, mersicarpine 464, azepane-fused tetrahydro-β-carboline 465, and andranginine 466. In each group, the name of the compound was alphabetically ordered in an arrangement. The similar chemical classes will be placed close to each other.

Monoterpene alkaloids and non-alkaloidal constituents from the genus Kopsia

No.	Compounds	Species	References
Aspidofractinines
1	Arbolodinine A	K. arborea stem bark	8
2	Aspidofractinine	K. arborea stem bark, K. hainanensis twig and leaf, K. officinalis stem	9–11
3	(2β,5β)-Aspidofractinin-16-ol	K. hainanensis twig and leaf, K. officinalis leaf	9, 12 and 13
4	Aspidofractinine-1,3-dicarboxylic acid	K. officinalis stem	11
5	N-Carbomethoxy-11-hydroxy-12-methoxykopsinaline	K. griffithii leaf, K. officinalis twig, leaf and fruit	14–16
6	N-Carbomethoxy-11-methoxy-12-hydroxykopsinaline	K. officinalis fruit	14
7	N(1)-Carbomethoxy-11, 12-dimethoxykopsinaline	K. griffithii leaf, K. officinalis fruit	14, 15 and 17
8	N-Carbomethoxy-12-methoxykopsinaline	K. officinalis fruit	14
9	N-Carbomethoxy-5,22-dioxokopsane	K. dasyrachis stem, K. pauciflora stem	18 and 19
10	Dasyrachine	K. arborea stem bark, K. dasyrachis stem	10 and 18
11	Decarbomethoxykopsine (demethoxycarbonylkopsin)	K. fruticosa leaf, K. officinalis leaf and twig	16 and 20
12	Decarbomethoxyisokopsine	K. fruticosa leaf	20
13	Decarbomethoxykopsifine	K. arborea twig, K. dasyrachis stem, K. officinalis stem, K. pauciflora stem and stem bark	11, 18, 19, 21 and 22
14	N(1)-Decarbomethoxykopsamine	K. arborea stem bark, K. hainanensis stem and leaf, K. pauciflora leaf, K. singapurensis leaf	7, 10, 22 and 23
15	N a-Demethoxycarbonyl-12-methoxykopsine	K. jasminiflora stem bark, K. officinalis leaf and twig	16, 24 and 25
16	10-Demethoxykopsidasinine	K. jasminiflora	26
17	5,22-Dioxokopsane	K. hainanensis stem bark and twig, K. macrophylla bark, K. officinalis root, stem, twig and fruit, K. pauciflora stem bark	11, 12, 14, 16, 19 and 27–29
18	11,12-Dimethoxykopsamine	K. dasyrachis leaf	30
19	11,12-Dimethoxykopsinaline	K. pauciflora stem bark	22
20	16-epi-Kopsinine	K. fruticosa stem bark, K. officinalis stem, K. singapurensis leaf	11, 31 and 32
21	16-epi-Kopsinilam	K. jasminiflora stem bark	24
22	16-epi-17α-Hydroxy-Δ14,15-kopsinine	K. teoi stem bark and leaf	33
23	14,15-β-Epoxykopsingine	K. teoi leaf	34
24	N(1)-Formylkopsininic acid	K. singapurensis root	35 and 36
25	N(1)-Formylkopsininic acid-N(4)-oxide	K. singapurensis root	35 and 36
26	Fruticosamine	K. fruticosa leaf, K. jasminiflora leaf	20 and 37–41
27	Fruticosiamine A	K. fruticosa leaf	41
28	Fruticosine	K. jasminiflora leaf, K. fruticosa leaf, K. officinalis twig	20 and 37–42
29	11-Hydroxykopsilongine	K. officinalis fruit and leaf	13 and 25
30	11-Hydroxykopsingine	K. teoi leaf	34
31	5β-Hydroxykopsinine	K. jasminiflora stem bark	24
32	15-Hydroxykopsamine	K. singapurensis root	35 and 36
33	15α-Hydroxykopsinine	K. arborea stem bark; K. fruticosa leaf and stem bark, K. singapurensis bark	10, 31 and 36
34	17α-Hydroxykopsinine	K. teoi stem bark	43
35	17α-Hydroxy-Δ14,15-kopsinine	K. singapurensis stem bark and leaf; K. teoi stem and stem bark	23, 32, 34 and 44–48
36	Jasminiflorine	K. jasminiflora leaf	40
37	Kopsamidine A	K. arborea stem bark	10
38	Kopsamidine B	K. arborea stem bark	10
39	Kopsamine	K. arborea twig and stem bark, K. dasyrachis stem and leaf, K. officinalis stem, root, leaf and fruit, K. griffithii leaf, K. pauciflora stem and stem bark, K. singapurensis leaf and root, K. teoi stem bark	10, 13–15, 17–19, 21, 25, 30, 36, 43, 49 and 50
40	Kopsamine N-oxide	K. arborea stem bark; K. dasyrachis stem and leaf, K. officinalis fruit, K. griffithii leaf, K. pauciflora stem, K. singapurensis root	10, 14, 15, 17–19, 30, 36, 49 and 51
41	Kopsanone	K. arborea stem bark; K. fruticosa stem bark, K. jasminiflora stem bark, K. hainanensis stem bark, K. pauciflora stem and stem bark, K. officinalis fruit	10, 14, 19, 22, 24, 29 and 31
42	Kopsaporine	K. singapurensis stem bark, K. teoi stem and stem bark	32, 34, 44 and 45
43	Kopsiafrutine A	K. fruticosa aerial part	52
44	Kopsiafrutine B	K. fruticosa aerial part	52
45	Kopsiafrutine C	K. fruticosa aerial part	52
46	Kopsiafrutine D	K. fruticosa aerial part	52
47	Kopsiafrutine E	K. fruticosa aerial part	52
48	Kopsiahainanin A	K. hainanensis twig and leaf	53
49	Kopsiahainanin B	K. hainanensis twig and leaf	53
50	Kopsiahainanin C	K. hainanensis twig and leaf	53
51	Kopsiahainanin D	K. hainanensis twig and leaf	53
52	Kopsiahainanin E	K. hainanensis twig and leaf	53
53	Kopsiahainanin F	K. hainanensis twig and leaf	53
54	Kopsiahainin A	K. hainanensis twig and leaf	54
55	Kopsiahainin B	K. hainanensis twig and leaf	54
56	Kopsiahainin C	K. hainanensis twig and leaf	54
57	Kopsiahainin D	K. hainanensis twig and leaf	54
58	Kopsiahainin E	K. hainanensis twig and leaf	54
59	Kopsiaofficine A	K. officinalis aerial part	55
60	Kopsiaofficine B	K. officinalis aerial part	55
61	Kopsiaofficine C	K. officinalis aerial part	55
62	Kopsiarborines A	K. arborea aerial part	56
63	Kopsidarine	K. singapurensis leaf	48
64	Kopsidasine	K. dasyrachis leaf	57
65	Kopsidasine-N-oxide	K. dasyrachis leaf	57
66	Kopsidasinine	K. dasyrachis leaf	57
67	Kopsidine A	K. singapurensis leaf, K. teoi leaf and stem bark	34, 43, 45, 48 and 58
68	Kopsidine B	K. teoi leaf	34, 45 and 58
69	Kopsidine C	K. singapurensis leaf, K. teoi leaf	34, 48 and 58
70	Kopsidine C N-oxide	K. singapurensis leaf	48
71	Kopsidine D	K. singapurensis leaf, K. teoi leaf	32, 34 and 58
72	Kopsidine E	K. arborea bark	59
73	Kopsifine	K. arborea stem bark, K. dasyrachis stem, K. hainanensis twig, K. officinalis stem, K. pauciflora stem and stem bark, K. singapurensis root	10–12, 18, 22, 49 and 60
74	Kopsiflorine	K. arborea stem bark; K. dasyrachis stem, K. hainanensis stem and leaf, K. officinalis leaf	7, 10, 12, 13, 18 and 61
75	Kopsiflorine N(4)-oxide	K. dasyrachis stem	18
76	Kopsifoline A	K. fruticosa leaf and aerial part, K. singapurensis leaf	31, 36, 52, 62 and 63
77	Kopsifoline B	K. fruticosa leaf	31, 62 and 63
78	Kopsifoline C	K. fruticosa leaf	31, 62 and 63
79	Kopsifoline D	K. fruticosa leaf	31 and 63
80	Kopsifoline E	K. fruticosa leaf	31 and 63
81	Kopsifoline F	K. fruticosa leaf	31 and 63
82	Kopsifoline G	K. hainanensis stem	64
83	Kopsihainin B	K. hainanensis stem	65
84	Kopsihainin C	K. hainanensis stem	65
85	Kopsihainin D	K. hainanensis twig	12
86	Kopsihainin E	K. hainanensis twig	12
87	Kopsihainin F	K. hainanensis twig	12
88	Kopsijasminine	K. teoi stem bark	43
89	Kopsijasmine	K. jasminiflora leaf	40
90	Kopsilarutensinine	K. larutensis stem bark and leaf	66
91	Kopsilongine	K. arborea twig and stem bark, K. dasyrachis stem, K. griffithii leaf and stem bark, K. officinalis leaf, K. pauciflora stem	10, 13, 15, 17–19, 21, 22 and 32
		K. singapurensis leaf
92	Kopsilongine-N-oxide	K. singapurensis leaf	32
93	Kopsiloscine A	K. singapurensis leaf	32
94	Kopsiloscine B	K. singapurensis leaf	32
95	Kopsiloscine C	K. singapurensis leaf and stem bark	32 and 48
96	Kopsiloscine D	K. singapurensis leaf	32
97	Kopsiloscine E	K. singapurensis leaf	32
98	Kopsiloscine F	K. singapurensis leaf	32
99	Kopsiloscine G	K. singapurensis stem bark and leaf	23 and 48
100	Kopsiloscine H	K. singapurensis stem bark	23
101	Kopsiloscine I	K. hainanensis stem and leaf, K. singapurensis stem bark	7 and 23
102	Kopsiloscine J	K. singapurensis leaf	23
103	Kopsimaline A	K. singapurensis leaf	23
104	Kopsimaline B	K. singapurensis leaf	23
105	Kopsimaline C	K. singapurensis leaf	23
106	Kopsimaline D	K. singapurensis leaf	23
107	Kopsimaline E	K. singapurensis leaf	23
108	Kopsimaline F	K. singapurensis leaf	48
109	Kopsinarine	K. dasyrachis stem, K. hainanensis twig	12 and 18
110	Kopsine	K. dasyrachis stem, K. fruticosa leaf	18, 20, 38, 39, 41 and 67
111	Kopsinganol	K. singapurensis stem bark, K. teoi stem, stem bark and leaf	32, 34, 43, 45, 47 and 48
112	Kopsingine	K. singapurensis leaf and stem bark, K. teoi stem, stem bark and leaf	32–34, 44, 45 and 48
113	Kopsinginine	K. teoi stem and stem bark	34, 43–45 and 47
114	Kopsinginol	K. teoi stem and stem bark	34, 45 and 47
115	Kopsinidine A	K. arborea stem bark	10
116	Kopsinidine B	K. arborea stem bark	10
117	Kopsininic acid (kopsinic acid)	K. hainanensis stem bark, K. jasminiflora stem bark, K. officinalis stem, twig and leaf, K. singapurensis bark and leaf	11, 13, 16, 24, 29 and 36
118	Kopsinicine	K. singapurensis leaf	23
119	Kopsinidine A	K. arborea stem bark, K. officinalis leaf	10 and 25
120	Kopsinidine B	K. arborea stem bark, K. officinalis leaf	10 and 25
121	Kopsinidine C	K. officinalis leaf and twig	16
122	Kopsinidine D	K. officinalis leaf and twig	16
123	Kopsinidine E	K. officinalis leaf and twig	16
124	Kopsinilam	K. hainanensis stem bark and twig, K. jasminiflora stem bark, K. officinalis stem, twig, leaf and fruit	11, 12, 14, 16, 24 and 29
125	Kopisininate	K. hainanensis stem and leaf	7
126	Kopsinine	K. arborea twig and stem bark, K. dasyrachis stem, K. fruticosa stem bark, K. jasminiflora stem bark, K. grandifolia stem bark, K. griffithii leaf and stem bark, K. hainanensis leaf, stem, stem bark and twig, K. larutensis stem, stem bark and leaf, K. officinalis root, stem, twig, leaf and fruit, K. singapurensis stem bark and leaf, K. pauciflora stem, stem bark and leaf, K. teoi stem bark	7, 9–11, 13–19, 21–25, 28, 29, 32, 36, 42, 43, 48, 50, 51, 64–66 and 68–72
127	Kopsinine-N(4)-oxide	K. dasyrachis stem, K. griffithii stem bark, K. hainanensis stem and leaf, K. officinalis fruit and leaf, K. pauciflora stem, K. singapurensis bark	7, 13, 15, 18, 25 and 36
128	Kopsinine methochloride	K. officinalis leaf and twig	16
129	Kopsinine B	K. officinalis leaf and twig	16
130	Kopsinine F	K. hainanensis stem and leaf	7
131	Kopsinitarine A	K. singapurensis leaf, K. teoi leaf	34, 48, 73 and 74
132	Kopsinitarine B	K. singapurensis leaf, K. teoi leaf	34, 48, 73 and 74
133	Kopsinitarine C	K. teoi leaf	34, 73 and 74
134	Kopsinitarine D	K. teoi leaf	34 and 74
135	Kopsinitarine E	K. teoi stem bark	43
136	Kopsinol	K. teoi stem and stem bark	34, 45 and 47
137	(−)-Kopsinoline	K. hainanensis stem bark, K. officinalis stem, twig and leaf	11, 16 and 29
138	Kopsiofficine A	K. officinalis stem	11
139	Kopsiofficine B	K. officinalis stem	11
140	Kopsiofficine C	K. officinalis stem	11
141	Kopsiofficine D	K. officinalis stem	11
142	Kopsiofficine E	K. officinalis stem	11
143	Kopsiofficine F	K. officinalis stem	11
144	Kopsiofficine L	K. officinalis stem	75
145	Kopsofinone	K. singapurensis leaf	23
146	Kopsonoline	K. teoi stem bark	43
147	Kopsorinine	K. fruticosa leaf and stem bark	31
148	Lahadinine A	K. pauciflora leaf	76
149	Lahadinine B	K. pauciflora leaf	76
150	Mersingine A	K. singapurensis leaf, K. teoi leaf	34, 49 and 74
151	Mersingine B	K. teoi leaf	34 and 74
152	N(1)-Methoxycarbonyl-11,12-dimethoxykopsinaline	K. arborea stem bark, K. pauciflora stem	10, 19 and 51
153	N(1)-Methoxycarbonyl-11,12-methoxylenedioxykopsinaline	K. officinalis leaf, twig, stem and root, K. pauciflora stem and leaf	11, 16, 42, 51, 69 and 76
154	N(1)-Methoxycarbonyl-11,12-methylenedioxy-Δ16,17-kopsinine	K. profunda stem	4
155	N(1)-Methoxycarbonyl-12-methoxy-Δ16,17-kopsinine	K. griffithii leaf, K. pauciflora stem, K. profunda stem and leaf, K. teoi stem bark	4, 17, 19, 43, 51 and 77
156	N(1)-Methoxycarbonyl-12-methoxykopsinaline	K. officinalis root, stem, twig, leaf and fruit, K. pauciflora stem	11, 16, 25, 51 and 69
157	N(1)-Methoxycarbonyl-11,12-methylenedioxy-Δ16,17-kopsinine N(4) oxide	K. profunda stem and leaf	77
158	N(1)-Methoxycarbonyl-12-hydroxy-Δ16,17-kopsinine	K. pauciflora stem, K. profunda stem and leaf	19 and 77
159	N(1)-Methoxycarbonyl-12-methoxy-Δ16,17-kopsinine N(4) oxide	K. profunda stem and leaf	77
160	11-Methoxykopsingine	K. teoi leaf	34
161	11-Methoxykopsilongine	K. dasyrachis stem, K. officinalis stem and leaf	11, 13 and 18
162	11-Methoxykopsilongine N(4)-oxide	K. dasyrachis stem	18
163	11-Methoxy-12-hydroxy-kopsinol	K. teoi leaf	34
164	12-Methoxykopsidasinine	K. griffithii leaf	17
165	(−)-12-Methoxykopsinaline	K. officinalis leaf and twig	13, 16, 42 and 69
166	12-Methoxykopsine	K. arborea leaf, K. jasminiflora stem bark, K. officinalis root and stem, K. pauciflora leaf	11, 22, 24 and 78
167	12-Methoxy-10-demethoxykopsidasinine	K. griffithii leaf, K. pauciflora stem	15, 51
168	12-Methoxypleiocarpine	K. dasyrachis stem and leaf, K. hainanensis stem and leaf, K. griffithii leaf, K. pauciflora stem	7, 15, 17–19 and 30
169	(−)-Methylenedioxy-11,12-kopsinaline	K. arborea twig	7
170	N(4)-Methylkopsininate	K. officinalis leaf and twig	16
171	11,12-Methylenedioxykopsaporine	K. singapurensis bark, K. teoi stem, stem bark and leaf	33, 34 and 79
172	(−)-11,12-Methylenedioxykopsinaline	K. dasyrachis stem, K. officinalis root, stem, leaf, twig and fruit	11, 16, 18, 25 and 69
173	11,12-Methylenedioxykopsinaline N(4)-oxide	K. griffithii stem bark, K. officinalis stem, twig and leaf	11, 15 and 16
174	11,12-Methylenedioxykopsine	K. arborea stem bark, K. dasyrachis stem, K. officinalis stem, K. pauciflora stem bark	10, 11, 18 and 22
175	Nitaphylline	K. teoi leaf	34, 46 and 80
176	5-Oxokopsinic acid	K. jasminiflora stem bark, K. officinalis twig and leaf	16 and 24
177	Paucidactine A	K. pauciflora stem bark	19
178	Paucidactine B	K. arborea stem bark, K. pauciflora stem bark	10 and 19
179	Paucidactine C	K. arborea stem bark, K. pauciflora stem bark	10 and 19
180	Paucidactine D	K. pauciflora stem bark	19
181	Paucidactine E	K. pauciflora stem bark	19
182	Paucidactinine	K. pauciflora stem bark	19
183	Paucidisine	K. pauciflora stem bark	19
184	Paucidirinine	K. pauciflora stem bark	19
185	Paucidirisine	K. pauciflora stem bark	19
186	Pauciduridine	K. officinalis stem, K. pauciflora stem bark	11 and 19
187	Paucifinine	K. pauciflora leaf and stem bark	22 and 76
188	Paucifinine-N-oxide	K. pauciflora leaf	76
189	Pleiocarpine	K. arborea stem bark, K. dasyrachis stem and leaf, K. griffithii leaf, K. officinalis fruit, K. pauciflora stem,	10, 14, 15, 17–19, 25 and 30
190	Pleiocarpine N-oxide	K. pauciflora stem	19
191	Pseudokopsinine	K. pauciflora leaf and stem bark	22
192	5,6-Secokopsinine	K. jasminiflora stem bark	24
193	Singaporentine A	K. singapurensis leaf	36
194	Singapurensine A	K. singapurensis bark	79
195	Singapurensine B	K. singapurensis bark	79
196	Singapurensine C	K. singapurensis bark	79
197	Singapurensine D	K. singapurensis bark	79
198	Venacarpine A	K. fruticosa leaf, K. singapurensis bark	31 and 36
199	Venacarpine B	K. fruticosa leaf	31
200	Venalstonidine	K. arborea stem bark	10
201	(−)-Venalstonine	K. arborea stem bark, K. fruticosa stem bark, K. lapidilecta stem and bark, K. singapurensis bark	10, 31, 36 and 81
202	Yunnanoffine A	K. officinalis leaf	25
203	Yunnanoffine B	K. officinalis leaf	25
204	Yunnanoffine D	K. officinalis leaf	25
Chanofruticosinates
205	Chanofruticosinic acid	K. officinalis leaf and twig	16
206	N 1-Decarbomethoxy chanofruticosinic acid	K. hainanensis stem and leaf	7
207	11,12-Dimethoxydanuphylline	K. fruticosa aerial part	3
208	Flavisiamine A (prunifoline D)	K. arborea leaf, K. flavida leaf	82–84
209	Flavisiamine B	K. flavida leaf	83
210	Flavisiamine C	K. arborea leaf, K. flavida leaf	83 and 84
211	Flavisiamine D (prunifoline E)	K. arborea leaf and stem bark, K. flavida leaf	10 and 82–84
212	Flavisiamine E	K. flavida leaf	41
213	Flavisiamine F	K. flavida leaf	41
214	12-Hydroxylprunifoline A	K. lancibracteolata stem	85
215	12-Hydroxylprunifoline C	K. lancibracteolata stem	85
216	Kopreasin A	K. arborea leaf	84
217	Kopsia A (methyl chanofruticosinate)	K. dasyrachis leaf, K. hainanensis stem and leaf, K. officinalis leaf, twig, and stem, K. pauciflora leaf	7, 13, 16, 22, 25, 30, 75 and 86
218	Kopsia B (des-N-(methoxycarbonyl)chanofruticosin-methyleste)	K. officinalis leaf	86
219	Kopsia C (6,7-methylendioxychanofruticosin-methylester or methyl 11,12-methylenedioxychanofruticosinate)	K. arborea leaf and stem bark, K. dasyrachis leaf, K. officinalis stem and leaf, twig and leaf, K. pauciflora stem bark and leaf	10, 16, 22, 30, 75, 84, 86 and 87
220	Kopsihainanine A	K. hainanensis leaf and stem	6
221	Kopsihainanine B	K. hainanensis leaf and stem	6
222	12-Methoxychanofruticosinic acid	K. officinalis leaf and twig	16
223	Methyl chanofruticosinate N(4)-oxide	K. hainanensis stem and leaf	7
224	Methyl 11,12-dimethoxychanofruticosinate	K. arborea leaf, K. flavida leaf, K. officinalis leaf	13, 22, 25, 82, 88 and 89
225	Methyl N1-decarbomethoxychanofruticosinate	K. arborea leaf and stem bark, K. dasyrachis leaf, K. flavida leaf, K. fruticosa leaf, K. hainanensis stem and leaf, K. officinalis twig, leaf and stem, K. pauciflora leaf	7, 10, 16, 25, 30, 41, 42, 65, 75, 82–84 and 87
226	Methyl N1-decarbomethoxy chanofruticosinate N(4)-oxide	K. hainanensis stem and leaf	7
227	Methyl 12-methoxy-N1-decarbomethoxychanofruticosinate	K. arborea leaf, K. flavida leaf	83, 84, 88 and 89
228	Methyl 12-methoxychanofruticosinate	K. arborea leaf and stem bark, K. flavida leaf, K. officinalis stem, twig and leaf, K. pauciflora leaf	10, 16, 22, 75, 82, 84, 88 and 89
229	Methyl 11,12-methylenedioxy-N1-decarbomethoxychanofruticosinate	K. arborea stem bark and leaf, K. dasyrachis leaf, K. flavida leaf, K. officinalis leaf, twig and stem, K. pauciflora leaf and stem bark	10, 16, 22, 25, 30, 42, 75, 82–84 and 87–89
230	Methyl 11,12-methylenedioxy-N1-decarbomethoxy-Δ14,15-chanofruticosinate	K. arborea stem bark and leaf, K. flavida leaf, K. hainanensis stem and leaf	7, 10, 82–84 and 87
231	Methyl (2β,11β,12β,19α)-6,7-didehydro-8,21-dioxo-11,21-cycloaspidospermidine-2-carboxylate	K. officinalis leaf	13
232	Methyl 3-oxo-12-methoxy-N1-decarbomethoxy-14,15-didehydrochanofruticosinate	K. flavida leaf	89
233	Methyl 3-oxo-11,12-methylenedioxy-N1-decarbomethoxy-14,15-didehydrochanofruticosinate	K. flavida leaf	89
234	Δ1,2-Methyldemethoxycarbonylchanofruticosinate	K. officinalis leaf	25
235	11,12-Methylenedioxychanofruticosinic acid	K. officinalis leaf and twig	16
236	3-Oxo-11,12-dimethoxy-N1-decarbomethoxy-14,15-didehydrochanofruticosinate	K. fruticosa aerial part	3
237	N(4)-Oxide prunifoline D	K. lancibracteolata stem	85
238	Prunifoline A	K. arborea leaf	82
239	Prunifoline B	K. arborea leaf	82 and 84
240	Prunifoline C	K. arborea leaf, K. fruticosa leaf	41 and 82
241	Prunifoline F	K. arborea leaf	82
Aspidospermines
242	Aspidospermine	K. pauciflora leaf	22
243	(+)-1,2-Dehydroaspidospermine	K. pauciflora leaf	22
244	Eburenine	K. arborea aerial part	90
245	Kopsiofficine G	K. officinalis stem	11
246	Kopsiyunnanine G	K. arborea aerial part	90
247	Vincadifformine	K. arborea twig and stem bark, K. officinalis stem and fruit	10, 11, 14 and 21
248	Vincadifformine N(4)-oxide	K. officinalis stem	11
Danuphyllines
249	Danuphylline	K. dasyrachis leaf	30 and 91
250	Danuphylline B	K. arborea leaf	78
251	11,12-De(methylenedioxy)danuphylline	K. officinalis leaf	13
252	Kopsihainin A	K. hainanensis stem	65
Eburnamines
253	(−)-Demethylnorpleiomutine	K. dasyrachis stem, K. pauciflora stem	18 and 19
254	(+)-Eburnamenine	K. pauciflora stem and stem bark	19 and 22
255	(−)-Eburnamenine	K. arborea aerial part, K. hainanensis twig, stem bark and leaf, K. larutensis bark, K. officinalis fruit	9, 14, 29, 90 and 70
256	(+)-Eburnamine	K. hainanensis stem bark	29
257	(−)-Eburnamine	K. arborea aerial part, K. griffithii stem bark, K. hainanensis twig and leaf, K. larutensis leaf, stem and stem bark, K. officinalis root and stem, K. pauciflora stem and stem bark, K. singapurensis stem bark, K. terengganensis bark	5, 9, 15, 19, 22, 23, 50, 51, 66, 68, 70, 90 and 92
258	(−)-Eburnaminol	K. larutensis stem bark, K. terengganensis bark	68 and 92
259	(+)-Eburnamonine	K. arborea aerial part, K. dasyrachis stem, K. griffithii leaf, K. larutensis leaf and stem bark, K. officinalis leaf and twig, K. pauciflora stem	5, 13, 15, 17–19, 42, 51, 68, 70, 90 and 93
260	(+)-Eburnamonine N(4)-oxide	K. larutensis leaf and stem	5 and 70
261	(−)-Eburnamonine	K. jasminiflora stem bark	24
262	(−)-O-Ethyleburnamine	K. arborea aerial part, K. larutensis stem	70 and 90
263	(+)-Ethylisoeburnamine	K. arborea aerial part	90
264	16α-Hydroxy-19-oxoeburnamine	K. officinalis leaf	25
265	16β-Hydroxy-19-oxoeburnamine	K. officinalis leaf	25
266	(+)-19(R)-Hydroxyeburnamine	K. dasyrachis stem	18 and 93
267	19-Hydroxy-(−)-eburnamonine	K. arborea twig, K. larutensis leaf, K. officinalis twig	5, 7 and 42
268	(−)-19(R)-Hydroxyisoeburnamine	K. dasyrachis stem, K. pauciflora stem and stem bark	19, 22 and 93
269	(+)-(19R)-19-Hydroxyeburnamine	K. officinalis leaf, K. pauciflora stem and stem bark	13, 19 and 22
270	(−)-19(R)-Hydroxyeburnamenine	K. pauciflora stem	19
271	(−)-(19R)-19-Hydroxyisoeburnamine	K. dasyrachis stem, K. officinalis leaf	13 and 18
272	(−)-19(R)-Hydroxy-O-ethylisoeburnamine	K. pauciflora stem	19
273	19(S)-Hydroxy-Δ14-vicamone	K. jasminiflora stem bark	24
274	(+)-Isoeburnamine	K. arborea aerial part, K. dasyrachis stem, K. hainanensis stem bark, K. larutensis leaf, stem and stem bark, K. teoi stem bark and leaf, K. officinalis leaf, K. pauciflora stem and stem bark, K. terengganensis bark	5, 13, 18, 19, 22, 33, 29, 51, 68, 70, 90, 92 and 93
275	(−)-Isoeburnamine	K. officinalis root	28 and 69
276	16-Isoeburnamine ((+)-methylisoeburnamine)	K. arborea aerial part, K. officinalis stem	75 and 90
277	(+)-Kopsoffine	K. hainanensis, K. officinalis root	28 and 29
278	Kopsiofficine H	K. officinalis stem	75
279	Kopsiofficine I	K. officinalis stem	75
280	Kopsiofficine J	K. officinalis stem	75
281	Kopsiofficine K	K. officinalis stem	75
282	Kopsoffinol	K. dasyrachis stem, K. pauciflora stem	19 and 93
283	(+)-Larutensine	K. larutensis stem bark	68
284	Larutenine	K. larutensis leaf and stem, K. officinalis leaf, K. pauciflora leaf, K. terengganensis bark	5, 13, 22, 70 and 92
285	Larutenine A	K. pauciflora stem, stem bark and leaf	19 and 22
286	Larutenine B	K. pauciflora stem and stem bark	19 and 22
287	Melohenine B	K. hainanensis twig and leaf	9
288	(−)-Methyleburnamine	K. arborea aerial part	90
289	(−)-Norpleiomutine	K. dasyrachis stem, K. macrophylla bark, K. pauciflora stem and stem bark	18, 19, 22, 27 and 51
290	(+)-O-Methyleburnamine	K. officinalis stem	75
291	(−)-O-Methylisoeburnamine (O-methylvincanol)	K. hainanensis twig and leaf, K. officinalis stem	9 and 75
292	(+)-19-Oxoeburnamine	K. pauciflora stem and stem bark	19, 22 and 51
293	19-Oxo-(−)-eburnamonine	K. jasminiflora stem bark, K. officinalis twig	24 and 42
294	(−)-19-Oxoisoeburnamine	K. pauciflora stem	19
295	O-Methyl-16-epi-vincanol	K. hainanensis twig and leaf	9
296	20-Oxo-eburnamenine	K. officinalis root, leaf and stem	25, 50 and 75
297	Phutdonginin	K. arborea twig	21
298	Terengganensine A	K. terengganensis bark	92
299	Terengganensine B	K. terengganensis bark	92
300	Δ14-Vicamone	K. jasminiflora stem bark	24
301	Yunnanoffine C	K. officinalis leaf	25
Akuammilines
302	Akuammidine	K. arborea stem bark, K. singapurensis root, stem bark and leaf	10, 23, 32, 48 and 49
303	Akuammiline	K. macrophylla bark, K. teoi stem and stem bark	27, 34, 43, 45 and 47
304	Akuammiline N(4)-oxide	K. griffithii stem bark	15
305	ψ-Akuammigine	K. fruticosa stem bark	31
306	Deacetylakuammiline (rhazimol)	K. deverrei stem bark, K. griffithii leaf and stem bark, K. macrophylla bark, K. singapurensis stem bark, K. teoi stem and stem bark	15, 17, 23, 27, 34, 45, 47 and 94
307	Dregamine	K. macrophylla bark	27
308	16-epi-akuammiline	K. singapurensis leaf, stem bark and root, K. teoi stem bark	23, 32, 36, 43 and 48
309	16-epi-deacetylakuammiline	K. deverrei stem bark, K. griffithii stem bark, K. fruticosa stem bark, K. singapurensis bark, stem bark and leaf, K. teoi stem and stem bark	15, 23, 31, 32, 34, 36, 43, 48 and 94
310	16-epi-deacetylakuammiline-N(4)-oxide	K. griffithii stem bark, K. singapurensis bark	15 and 36
311	16-Hydroxymethyl-pleiocarpamine	K. deverrei stem bark, K. fruticosa stem bark, K. singapurensis stem bark and bark, K. teoi stem bark	23, 31, 43, 36 and 94
312	N-Methylpleiocarpamine	K. singapurensis root	36
313	5-Methoxystrictamine	K. hainanensis twig and leaf	9
314	Rhazimal	K. arborea stem bark	10
315	Rhazinaline N(4)-oxide	K. griffithii stem bark	15
316	Rhazinoline	K. arborea stem bark	10
317	Picralinal	K. hainanensis twig and leaf	9
318	Picramicine	K. fruticosa stem bark, K. singapurensis stem bark	23 and 31
319	Pleiocarpamine	K. dasyrachis stem, K. deverrei stem bark, K. fruticosa stem bark, K. singapurensis bark, K. teoi stem bark	18, 31, 36, 43 and 94
320	Pleiocarpamine methochloride	K. officinalis leaf and twig	16
321	Pleiomalicine	K. hainanensis twig and leaf	9
322	Singaporentinidine	K. singapurensis root	35 and 36
Sarpagines
323	10-Hydroxy-vincadiffine	K. hainanensis twig and leaf	9
324	Perivine	K. officinalis root and stem	50
325	Tabernaemontanine	K. macrophylla bark	27
326	Vincadiffine	K. hainanensis twig and leaf	9
Aspidophyllines
327	Aspidodasycarpine	K. singapurensis root and stem bark, K. teoi stem and stem bark	23, 32, 34, 36, 43, 48 and 49
328	Aspidophylline A	K. singapurensis stem bark	32
329	Aspidophylline B	K. singapurensis stem bark	48
330	Lonicerine	K. fruticosa stem bark, K. singapurensis bark and stem bark, K. teoi stem, stem bark and leaf	23, 31–34, 36, 43 and 48
331	Vincophylline	K. singapurensis leaf	32
Strychnoses
332	Akuammicine	K. pauciflora leaf	22
333	Arbolodinine B	K. arborea stem bark	8
334	Arbolodinine C	K. arborea stem bark	8
335	(E)-Condylocarpine	K. arborea aerial part, K. pauciflora leaf	22 and 95
336	(E)-Condylocarpine N-oxide	K. arborea aerial part	95
337	14α-Hydroxycondylocarpine	K. deverri stem bark, K. singapurensis stem bark	23 and 94
338	14α-Hydroxy-N(4)-methylcondylocarpine	K. singapurensis root	35 and 36
339	14(S)-Hydroxy-19(R)-methoxytubotaiwine	K. jasminiflora stem bark	24
340	Isocondylocarpine	K. arborea aerial part	95
341	Isocondylocarpine N-oxide	K. arborea aerial part	95
342	Kopsiyunnanine A	K. arborea aerial part, K. officinalis aerial part	96 and 97
343	Kopsiyunnanine I	K. arborea aerial part	98 and 99
344	Kopsiyunnanine J1	K. arborea aerial part	99 and 100
345	Kopsiyunnanine J2	K. arborea aerial part	99 and 100
346	Kopsiyunnanine L	K. arborea aerial part	101 and 102
347	Kopsiyunnanine M	K. arborea aerial part	101 and 102
348	Kopsiyunnanine F1	K. arborea aerial part	95
349	Kopsiyunnanine F2	K. arborea aerial part	95
350	Kopsiyunnanine F3	K. arborea aerial part	95
351	Leuconicine B	K. arborea aerial part	98
352	19(R)-Methoxytubotaiwine	K. arborea aerial part and stem bark, K. jasminiflora stem bark	10, 24 and 95
353	19(S)-Methoxytubotaiwine	K. arborea aerial part and stem bark, K. hainanensis twig	10, 12 and 95
354	Mossambine	K. singapurensis stem bark	23
355	Precondylocarpine	K. pauciflora leaf	22
356	Tubotaiwine	K. arborea aerial part, K. hainanensis stem and stem bark	29, 64 and 95
Stemmadenine
357	Stemmadenine	K. pauciflora leaf	22
Mersinines
358	Mersidasine A	K. singapurensis leaf	103
359	Mersidasine B	K. singapurensis leaf	103
360	Mersidasine C	K. singapurensis leaf	103
361	Mersidasine D	K. singapurensis leaf	103
362	Mersidasine E	K. singapurensis leaf	103
363	Mersidasine F	K. singapurensis leaf	103
364	Mersidasine G	K. singapurensis leaf	103
365	Mersifoline A	K. singapurensis leaf	103
366	Mersifoline B	K. singapurensis leaf	103
367	Mersifoline C	K. singapurensis leaf	103
368	Mersilongine	K. singapurensis leaf	23 and 104
369	Mersiloscine	K. singapurensis leaf	103 and 105
370	Mersiloscine A	K. singapurensis leaf	103
371	Mersiloscine B	K. singapurensis leaf	103
372	Mersinaline	K. singapurensis leaf	23 and 106
373	Mersinine A	K. fruticosa leaf, K. singapurensis leaf	103 and 105, 107
374	Mersinine B	K. singapurensis leaf	103 and 105
375	Mersinine C	K. singapurensis leaf	103
376	Mersiphyllines A	K. singapurensis leaf	108
377	Mersiphyllines B	K. singapurensis leaf	108
378	Mersirachine	K. singapurensis leaf	23 and 106
Pauciflorines
379	11,12-Demethoxy-16-deoxypauciflorine	K. officinalis stem and leaf	109
380	20-Deoxykopsijasminilam	K. jasminiflora leaf	40
381	Kopsiarborines C	K. arborea aerial part	56
382	Kopsijasminilam	K. jasminiflora leaf	40
383	Δ14-Kopsijasminilam	K. jasminiflora leaf	40
384	Kopsioffine A	K. officinalis stem and leaf	109
385	Kopsioffine B	K. officinalis stem and leaf	109
386	Kopsioffine C	K. officinalis stem and leaf	109
387	Pauciflorine A	K. pauciflora leaf	110
388	Pauciflorine B	K. pauciflora leaf	110
389	Pauciflorine C	K. pauciflora leaf	22
390	Paucifoline	K. pauciflora leaf	22
Skytanthines
391	Kinabalurine A (kinabalurine)	K. pauciflora leaf	111 and 112
392	Kinabalurine B	K. pauciflora leaf	112
393	Kinabalurine C	K. pauciflora leaf	112
394	Kinabalurine D	K. pauciflora leaf	112
395	Kinabalurine E	K. pauciflora leaf	112
396	Kinabalurine F	K. pauciflora leaf	112
397	Kinabalurine G	K. dasyrachis leaf	30
398	Kopsilactone	K. macrophylla bark	27
399	Kopsirachine	K. dasyrachis leaf	30 and 113
400	Kopsone	K. macrophylla bark	27
Rhazinilams
401	5,21-Dihydrorhazinilam	K. arborea stem bark, K. singapurensis stem bark and leaf	10, 23 and 48
402	Kopsiyunnanine C1	K. arborea aerial part, K. officinalis aerial part	96 and 114
403	Kopsiyunnanine C2	K. arborea aerial part, K. officinalis aerial part	96 and 114
404	Kopsiyunnanine C3	K. arborea aerial part, K. officinalis aerial part	96 and 114
405	Leuconolam	K. griffithii leaf and stem bark, K. hainanensis twigs, stems and leaves, K. officinalis leaf, K. pauciflora leaf, K. singapurensis stem bark	7, 9, 12, 15, 17, 22, 23, 25 and 32
406	O-Methylleuconolam	K. arborea stem bark, K. hainanensis twig, K. officinalis stem	10, 12 and 87
407	Rhazinal	K. dasyrachis stem	32
408	Rhazinicine	K. arborea stem bark, K. dasyrachis stem, K. singapurensis root	10, 18, 49 and 60
409	Rhazinilam	K. arborea aerial part and stem bark, K. officinalis leaves and twigs, K. pauciflora leaves and stem bark, K. singapurensis leaf, bark and stem bark, K. teoi stem, stem bark and leaf	16, 13, 22, 23, 25, 32–34, 36, 45, 47, 48 and 114
Lundurines
410	Epilapidilectinol	K. lapidilecta stem and bark	81
411	Grandilodine A	K. grandifolia stem bark	72
412	Grandilodine B	K. grandifolia stem bark	72
413	Grandilodine C	K. grandifolia leaf	72
414	Isolapidilectine A	K. grandifolia leaf, K. lapidilecta stem and bark	72 and 81
415	Lapidilectam	K. grandifolia stem bark, K. lapidilecta stem and bark	72 and 81
416	Lapidilectine A	K. grandifolia stem bark, K. lapidilecta bark, stem and leaf	72 and 115
417	Lapidilectine B	K. grandifolia stem bark, K. lapidilecta bark, stem and leaf	72 and 115
418	Lapidilectinol	K. lapidilecta stem and bark	81
419	Lundurine A	K. tenuis leaf	71
420	Lundurine B	K. tenuis leaf	71
421	Lundurine C	K. tenuis leaf	71
422	Lundurine D	K. tenuis leaf	71
423	Tenuisine A	K. tenuis leaf	116 and 117
424	Tenuisine B	K. tenuis leaf	71, 116 and 117
425	Tenuisine C	K. tenuis leaf	71, 116 and 117
426	Tenuiphylline	K. tenuis leaf	71 and 117
Aspidospermas
427	Buchtienine	K. griffithii leaf and stem bark	15 and 17
428	Corynantheol	K. hainanensis twig and leaf	9
429	19,20-Dihydroisositsirikine	K. officinalis stem	75
430	Dihydrocorynantheol	K. hainanensis twig and leaf	9
431	16(R)-19,20-E-Isositsirikine	K. griffithii leaf, K. pauciflora leaf	15, 17 and 22
Catharinensines
432	Catharinensine	K. pauciflora leaf	22
433	Kopsirensine A	K. pauciflora leaf	22
434	Kopsirensine B	K. pauciflora leaf	22
435	Kopsirensine C	K. pauciflora leaf	22
436	Kopsiyunnanine B	K. arborea aerial part, K. officinalis aerial part	96 and 97
Leuconoxines
437	Arboloscine	K. arborea stem bark	10 and 118
438	Arboloscine A	K. pauciflora leaf	22
439	Leuconodine D	K. officinalis stem	75
440	Leuconodine F (6-oxoleuconoxine)	K. griffithii leaf, K. pauciflora leaf	22 and 43
441	Leuconoxine	K. arborea stem bark, K. griffithii leaf and stem bark, K. pauciflora stem, stem bark and leaf, K. singapurensis stem bark, K. teoi stem bark	15, 17, 19, 22, 23 and 43
442	Melodinine E	K. arborea twig	21
Pericines
443	Pericidine	K. arborea stem bark	10 and 118
444	Pericine	K. arborea stem bark	10
445	Pericine N-oxide	K. arborea stem bark	10
446	Valparicine	K. arborea stem bark	119 and 120
Alstonines
447	Oxayohimban-16-carboxy acid	K. officinalis stem	75
448	(−)-Tetrahydroalstonine	K. arborea stem bark, K. dasyrachis stem, K. griffithii leaf, K. officinalis root, twigs and leaves, K. larutensis stem bark and leaf, K. pauciflora stem, stem bark and leaf, K. singapurensis stem bark; K. teoi stem bark	10, 15, 17–19, 23, 25, 32, 42, 43, 66 and 69
449	Tetrahydroalstonine pseudoindoxyl	K. pauciflora leaf	22
Quebrachamines
450	Kopsiyunnanine D	K. arborea aerial part	114
451	Kopsiyunnanine H	K. arborea aerial part	90
452	(−)-Quebrachamine	K. arborea aerial part, K. hainanensis twig and leaf, K. officinalis root, K. pauciflora leaf	9, 22, 69 and 114
Arbophyllinines
453	Arbophyllinine A	K. arborea bark	59
454	Arbophyllinine B	K. arborea bark	59
Arboflorines
455	Arboflorine	K. arborea stem bark	10
456	Kopsiyunnanine E	K. arborea aerial part, K. officinalis aerial part	96, 99 and 121
Andrasinines
457	Andransinine	K. pauciflora leaf	22
458	Andransinine A	K. pauciflora leaf	22
Corynantheines
459	Arboricine	K. arborea leaf and stem bark	10 and 120
460	Arboricinine	K. arborea leaf and stem bark	10 and 120
Carbolines
461	Harmane	K. griffithii leaf and stem	15 and 17
462	Harmicine	K. griffithii leaf	15 and 17
Arbophyllidine
463	Arbophyllidine	K. arborea stem bark	59
Mersicarpine
464	Mersicarpine	K. arborea stem bark, K. pauciflora leaf, K. singapurensis stem bark	10, 22 and 23
Azepane-fused tetrahydro-β-carboline
465	Kopsiyunnanine K	K. arborea aerial part	102
Andranginine
466	Andranginine	K. arborea aerial part	102
Triterpenoids and sterols
467	β-Amyrin	K. singapurensis leaf and bark	122
468	β-Amyrin acetate	K. singapurensis leaf and bark	122
469	β-Amyrone	K. singapurensis leaf and bark	122
470	Lupeol	K. singapurensis leaf and bark	122
471	Lupeol acetate	K. singapurensis leaf and bark	122
472	Stigmasterol	K. singapurensis leaf and bark	122

Aspidofractinines

Aspidofractinines are the largest phytochemical class of isolated alkaloids from the genus Kopsia. As shown in Table 1, more than two hundred aspidofractinines have been isolated to date, and they derive from various parts of K. arborea, K. dasyrachis, K. fruticosa, K. grandifolia, K. griffithii, K. hainanensis, K. hainanensis, K. jasminiflora, K. larutensis, K. macrophylla, K. officinalis, K. pauciflora, K. profunda, K. singapurensis, and K. teoi.[4,7-59,61-79,81] From Fig. 1, Kopsia aspidofractinines 1–204 occurred in both monomer and dimer forms, but they did not bind to sugar units. Aspidofractinines 1–204 have been generally associated with the esterification at nitrogen N-1 and carbon C-16, carbonylation at carbon C-5, expoxydation at carbons C-11 and C-12, and hydroxylation, or methoxylation at carbons C-11, C-12, C-16, C-17, and C-18. It was found that 5,22-dioxokopsane (17), kopsamine (39), kopsamine N-oxide (40), kopsanone (41), kopsifine (73), kopsilongine (91), kopsininic acid (117), kopsinilam (124), kopsinine (126), kopsinine-N(4)-oxide (127), pleiocarpine (189), and (−)-venalstonine (201) might be seen as characteristic metabolites in the group of Kopsia aspidofractinines. For instance, compound 126 was recorded to appear in K. arborea twig and stem bark, K. dasyrachis stem, K. fruticosa stem bark, K. jasminiflora stem bark, K. grandifolia stem bark, K. griffithii leaf and stem bark, K. hainanensis leaf, stem, stem bark and twig, K. larutensis stem, stem bark and leaf, K. officinalis root, stem, twig, leaf and fruit, K. singapurensis stem bark and leaf, K. pauciflora stem, stem bark and leaf, and K. teoi stem bark, whereas its N(4)-oxide (127) presented in K. dasyrachis stem, K. griffithii stem bark, K. hainanensis stem and leaf, K. officinalis fruit and leaf, K. pauciflora stem, and K. singapurensis bark.[5-7,9-11,13-19,21-25,28,29,32,36,42,43,48,51,65,66,68-72]

Fig. 1

Aspidofractinines from genus Kopsia.

Taking phytochemical studies into account, a new bisindole alkaloid arbolodinine A (1) was isolated from K. arborea stem bark.[8] Based on NMR, MS, and ECD data, compound 1 was a product by the combination of two apidofractinine units, and its biosynthetic pathway was structurally formulated from precursor 126. Aspidofractinine (2) can be found in K. arborea stem bark, K. hainanensis twigs and leaves, and K. officinalis stem,[9-11] but aspidofractinine-1,3-dicarboxylic acid (4) was only detected in K. officinalis stem.[11] (2β,5β)-Aspidofractinin-16-ol (3) was a new 16-alcohol derivative found in K. officinalis leaves for the first time, and then was detected in K. hainanensis twigs and leaves.[9,12,13] Compounds 5–9 have shared the same feature of carbomethoxylation at nitrogen N-1,[14-19] in which N-carbomethoxy-11-hydroxy-12-methoxykopsinaline (5) and N-carbomethoxy-11-methoxy-12-hydroxykopsinaline (6) were two new metabolites in nature.[14-16] Dasyrachine (10) containing isokopsine skeleton was one of the new metabolites present in the 95% EtOH extract of K. dasyrachis stem.[18] In contrast to compounds 5–9, the next compounds decarbomethoxykopsine (11), decarbomethoxyisokopsine (12), decarbomethoxykopsifine (13), N(1)-decarbomethoxykopsamine (14), Na-demethoxycarbonyl-12-methoxykopsine (15), and 10-demethoxykopsidasinine (16) are associated with the decarbomethoxylation at nitrogen N-1.[10,11,16,18-26] Among them, compounds 13, 15, and 16 were new in nature. 11,12-Dimethoxykopsamine (18) was a known metabolite found in K. dasyrachis leaves, but 11,12-dimethoxykopsinaline (19) was a new one in the stem bark of K. pauciflora stem bark.[22,30] Similarly, 16-epi-kopsinine (20), 16-epi-kopsinilam (21), 16-epi-17α-hydroxy-Δ14,15-kopsinine (22), 14,15-β-epoxykopsingine (23), N(1)-formylkopsininic acid (24), N(1)-formylkopsininic acid-N(4)-oxide (25), fruticosamine (26), fruticosiamine A (27), and fruticosine (28) were new aspidofractinines, and found in genus Kopsia for the first time.[11,20,24,31-37,39-42] The known metabolite 11-hydroxykopsilongine (29) has been detected in both the fruit and leaf of K. officinalis,[13,25] while 11-hydroxykopsingine (30), 5β-hydroxykopsinine (31), and 15-hydroxykopsamine (32) were first isolated from polar extracts of K. teoi leaf, K. jasminiflora stem bark, and K. singapurensis root, respectively.[24,34,35] Two known compounds 33 and 34 were products of 15α and 17α-hydroxylation of kopsinine, respectively (Fig. 1). In the meantime, the structure of the new metabolite 35 is closely related to kopsinine by 17α-OH and olefinic double bond at carbons C-14 and C-15.[44] For a long time, Ruangrungsi et al. (1987) successfully isolated two new aspidofractinines, named jasminiflorine (36) and kopsijasmine (89), from the MeOH extract of K. jasminiflora leaves, whereas kopsamidines A–B (37–38) were separated from the acidic EtOH extract of K. arborea stem bark.[10,40]

To search for bioactive metabolites from Kopsia plants, Long et al. (2018) isolated five new aspidofractinines kopsiafrutines A–E (43–47) from the 80% EtOH extract of K. fruticosa aerial part.[52] Eleven new analogs, kopsiahainanins A–F (48–53) and kopsiahainins A–E (54–58) were among the new compounds found in the 80% EtOH extract of K. hainanensis twigs and leaves.[53,54] In another approach, chromatographic separation of the 95% EtOH extract of K. officinalis aerial part can lead to the isolation of three new metabolites (59–61), which named kopsiaofficines A–C.[55] From K. arborea aerial part, the new compound kopsiarborines A (62) was isolated.[56] Three new metabolites, kopsidasine (64), kopsidasine-N-oxide (65), and kopsidasinine (66) were separated from K. dasyrachis leaves and structurally confirmed by the NMR analysis and Hofmann reaction.[57] Thirteen previously undescribed metabolites kopsidines A–D (67–69 and 71), kopsinitarines B–D (132–134), mersingines A–B (150–151), 11-methoxykopsingine (160), 11-methoxy-12-hydroxy-kopsinol (163), 11,12-methylenedioxykopsaporine (171), and nitaphylline (175) have further been observed in K. teoi leaf, while its stem bark also contained seven other new compounds kopsinganol (111), kopsinginine (113), kopsinginol (114), kopsinol (136), kopsinitarine E (135), kopsinol (136), and kopsonoline (146).[33,34,43-45,73,74,80] Kopsidarine (63), kopsidine C N-oxide (70), and singaporentine A (193) were three new compounds existed in K. singapurensis leaf, whereas its bark encompassed four new others singapurensines A–D (194–197)[36,48,58,79] In two years 2007 and 2008, primarily based on CC approach, Subramaniam et al. successfully isolated nineteen new aspidofractinines, including kopsilongine-N-oxide (92), kopsiloscines A–J (93–102), kopsinalines A–F (103–108), kopsinicine (118), and kopsofinone (145) from K. singapurensis leaf or stem bark (Table 1 and Fig. 1).[23,32,48] Kopsiflorine (74) is now available in the genus Kopsia, but its N(4)-oxide (75) and kopsinarine (109) were new in nature and were found in K. dasyrachis stem.[18] Six indole alkaloidal constituents kopsifolines A–F (76–81) with unprecedented hexacyclic carbon skeleton were detected in the acidic EtOH extract of K. fruticosa leaves.[62,63] Kopsifoline G (82) and kopsihainins B–F (83–87) were purified as new alkaloids from the stem or twig extracts of K. hainanensis.[12,64,65] Among the isolated compounds, kopsijasminine (88) and kopsilarutensinine (90) were also identified to be two new aspidofractinines derived from the stem bark of K. teoi and K. larutensis, respectively.[43,66] The earliest report by Guggisberg et al. (1963) identified that kopsine (110) was a new and major component of K. fruticosa leaves, and it was then isolated frequently.[18,20,38,39,41,67] In a phytochemical research on the acidic EtOH extract of K. arborea stem bark, five new aspidofractinines, kopsinidines A–B (115–116), kopsinidines A–B (119–120), and paucidactine C (179) were isolated.[10]

Phytochemical analysis aided by NMR structural elucidation on the CHCl3 and n-BuOH extracts of K. officinalis leaf and twig has resulted in the isolation of eight new compounds kopsinidines C–E (121–123), N(1)-methoxycarbonyl-11,12-methoxylenedioxykopsinaline (153), N(1)-methoxycarbonyl-12-methoxykopsinaline (156), N(4)-methylkopsininate (170), (−)-11,12-methylenedioxykopsinaline (172), and 5-oxokopsinic acid (176), in addition to seven known compounds kopsinilam (124), kopsinine (126), kopsinine methochloride (128), kopsinine B (129), (−)-kopsinoline (137), (−)-12-methoxykopsinaline (165), and 11,12-methylenedioxykopsinaline N(4)-oxide (173).[16] Among the isolates from K. hainanensis stem and leaves, the new compound kopisininate (125) itself displayed an interesting feature since it contained a carboxylate group (δC 181.6 ppm in CD3OD).[7] Besides known compounds, the application of NMR and MS tools would take a good advance in the natural product chemistry field, by which the chemical structures of seven new aspidofractinines kopsiofficines A–F and L (138–144) from K. officinalis stem and three new analogs yunnanoffines A–C (202–204) from K. officinalis leaf have been determined.[11,25,75] Aspidofractinines were further observed in other Kopsia plants. For instance, apart from known compounds, five new derivatives N(1)-methoxycarbonyl-11,12-methylenedioxy-Δ16,17-kopsinine (154), N(1)-methoxycarbonyl-12-methoxy-Δ16,17-kopsinine (155), N(1)-methoxycarbonyl-11,12-methylenedioxy-Δ16,17-kopsinine N(4) oxide (157), N(1)-methoxycarbonyl-12-hydroxy-Δ16,17-kopsinine (158), and N(1)-methoxycarbonyl-12-methoxy-Δ16,17-kopsinine N(4) oxide (159) were characteristics of K. profunda,[4,77] or lahadinines A–B (145–146), 12-methoxy-10-demethoxykopsidasinine (167), paucidactines D–E (180–181), paucidactinine (182), paucidisine (183), paucidirinine (184), paucidirisine (185), pauciduridine (186), paucifinine (187), and paucifinine-N-oxide (188) were new metabolites isolated from the parts of K. pauciflora.[19,51,76]

Chanofruticosinates, aspidospermines, and danuphyllines

In general, Kopsia chanofruticosinate derivatives 205–241 have established a similarity in the chemical structural skeleton with aspidofractinines (Table 1 and Fig. 2). However, fragment C-2–C-16–C-17–C-20 in aspidofractinines was replaced by a carbon bridge between C-6 and C-20 in chanofruticosinates. To date, these phytochemicals occurred in K. arborea, K. dasyrachis, K. fruticosa, K. flavida, K. hainanensis, K. lancibracteolata, K. officinalis, and K. pauciflora.[3,6,7,10,13,16,22,25,30,41,42,65,75,82-89] From Table 1, kopsia A (217), kopsia C (219), methyl 11,12-dimethoxychanofruticosinate (224), methyl N1-decarbomethoxychanofruticosinate (225), methyl 12-methoxychanofruticosinate (228), methyl 11,12-methylenedioxy-N1-decarbomethoxychanofruticosinate (229), and methyl 11,12-methylenedioxy-N1-decarbomethoxy-Δ14,15-chanofruticosinate (230) were major components in the group of Kopsia chanofruticosinates. Analyzing chemical composition further, the rich alkaloid fraction of K. officinalis leaf and twig have also contained five new derivatives, chanofruticosinic acid (205), kopsias A–C (217–219), 12-methoxychanofruticosinic acid (222), and methyl (2β,11β,12β,19α)-6,7-didehydro-8,21-dioxo-11,21-cycloaspidospermidine-2-carboxylate (231).[13,16,86] According to the phytochemical report of Chen and partners, N1-decarbomethoxy chanofruticosinic acid (206), kopsihainanines A–B (220–221), methyl chanofruticosinate N(4)-oxide (223), and methyl N1-decarbomethoxy chanofruticosinate N(4)-oxide (226) were previously unrecorded compounds and found in K. hainanensis stem and leaf for the first time.[6,7] The application of HPLC chromatographic procedure to the 70% EtOH extract of K. fruticosa aerial part has resulted in the isolation of two new substances, 11,12-dimethoxydanuphylline (207) and 3-oxo-11,12-dimethoxy-N1-decarbomethoxy-14,15-didehydrochanofruticosinate (236).[3] The MeOH extract of K. flavida leaf consisted of serial new alkaloids type chanofruticosinates flavisiamines A–F (208–213).[41,83] Besides known compounds, the chromatographic isolation of the alcoholic extracts of K. arborea leaves has allowed to identify the appearance of seven new methyl chanofruticosinate alkaloids, kopreasin A (216), and prunifolines A–F (208, 211, and 238–241).[82,84] Finally, three new derivatives 12-hydroxylprunifoline A (214), 12-hydroxylprunifoline A (215), and N(4)-oxide prunifoline D (3) were purified from the 70% EtOH extract of K. lancibracteolata stem.[85]

Fig. 2

Chanofruticosinates, aspidospermines and danuphyllines from genus Kopsia.

Regarding aspidospermines, the acidic EtOH extract of K. pauciflora leaf contained aspidospermine (242), and its (+)-1,2-dehydro derivatives (243).[22] A phytochemical report conducted by Wu et al. (2010) revealed that the MeOH extract of K. arborea aerial part was characterized by the presence of the new aspidospermine kopsiyunnanine G (246), and known compound eburenine (244).[90] Similarly, new compound kopsiofficine G (245), together with two known ones, vincadifformine (247) and vincadifformine N(4)-oxide (248) represented for K. officinalis stem.[11]

Only four indole alkaloids danuphyllines 249–252 were found in Kopsia plants, in which danuphylline (249), danuphylline B (250), 11,12-de(methylenedioxy)danuphylline (251), and kopsihainin A (252) were separated from K. dasyrachis leaf, K. arborea leaf, K. officinalis leaf, and K. hainanensis stem, respectively (Table 1 and Fig. 2).[13,30,65,78,91] All these isolates were new in nature. Similar to aspidofractinine derivatives, chanofruticosinates, aspidospermines, and danuphyllines were unique chemical classes found in the family Apocynaceae. Especially, danuphylline derivatives were only detected in Kopsia, thereby they can be used as chemical markers to recognize this genus.

Eburnamines

As can be seen from Table 1 and Fig. 3, eburnamines are also a crucial phytochemical class of the genus Kopsia. Forty-nine compounds 253–301 were isolated to date, and they were mainly derived from K. arborea, K. dasyrachis, K. griffithii, K. hainanensis, K. hainanensis, K. jasminiflora, K. larutensis, K. macrophylla, K. officinalis, K. pauciflora, K. singapurensis, K. teoi, and K. terengganensis.[5,9,13-15,17-19,21-25,27-29,33,42,50,51,66,68-70,75,90,92,93]Kopsia eburnamines appeared in both monomer and dimer forms, but not to have connected with sugar units. (−)-Eburnamenine (255), (−)-eburnamine (257), (+)-eburnamonine (259), (+)-isoeburnamine (274), and larutenine (284) were isolated frequently, e.g., compound 274 was detected in K. arborea aerial part, K. dasyrachis stem, K. hainanensis stem bark, K. larutensis leaf, stem and stem bark, K. teoi stem bark and leaf, K. officinalis leaf, K. pauciflora stem and stem bark, and K. terengganensis bark.[5,13,18,19,22,29,33,51,68,70,90,92,93]

Fig. 3

Eburnamines from genus Kopsia.

(−)-Demethylnorpleiomutine (253), (−)-eburnaminol (258), (−)-O-ethyleburnamine (262), 19-hydroxy-(−)-eburnamonine (267), (−)-19(R)-hydroxyisoeburnamine (268), (+)-(19R)-19-hydroxyeburnamine (269), (−)-(19R)-19-hydroxyisoeburnamine (271), (+)-kopsoffine (277), kopsoffinol (282), (−)-norpleiomutine (289), (−)-O-methylisoeburnamine (291), and 19-oxo-(−)-eburnamonine (293) were found in two or three Kopsia plants (Table 1). (+)-Eburnamenine (254), (+)-eburnamine (256), (−)-eburnamonine (261), (+)-ethylisoeburnamine (263), 16α-hydroxy-19-oxoeburnamine (264), 16β-hydroxy-19-oxoeburnamine (265), melohenine B (287), (−)-methyleburnamine (288), (+)-O-methyleburnamine (290), and O-methyl-16-epi-vincanol (295), and Δ14-vicamone (300) have never been observed in genus Kopsia before. Especially, (−)-eburnaminol (258), (+)-eburnamonine N(4)-oxide (260), (+)-19(R)-hydroxyeburnamine (266), (−)-19(R)-hydroxyisoeburnamine (268), (−)-19(R)-hydroxyeburnamenine (270), (−)-(19R)-19-hydroxyisoeburnamine (271), (−)-19(R)-hydroxy-O-ethylisoeburnamine (272), (−)-isoeburnamine (275), kopsiofficines H–K (278–281), (+)-larutensine (283), larutenine (284), larutenines A–B (285–286), (−)-norpleiomutine (289), (+)-19-oxoeburnamine (292), (−)-19-oxoisoeburnamine (294), 20-oxo-eburnamenine (296), phutdonginin (297), terengganensines A–B (298–299), and yunnanoffine C (301) were new in literature and isolated from genus Kopsia for the first time. Eburnamines is now abundant in genus Kopsia, but this chemical class was only found in the family Apocynaceae.

Akuammilines, sarpagines, and aspidophyllines

A total of twenty-one akuammilines 302–322 have been outlined in Table 1 and Fig. 4. K. arborea, K. dasyrachis, K. deverrei, K. fruticosa, K. griffithii, K. hainanensis, K. macrophylla, K. officinalis, K. singapurensis, and K. teoi were main resource of these phyto-constituents.[9,10,15-17,23,27,31,32,34-36,43,45,47-49,94] Previous studies revealed that deacetylakuammiline (306), 16-epi-deacetylakuammiline (309), 16-hydroxymethyl-pleiocarpamine (311), and pleiocarpamine (319) were likely to be major akuammilines in genus Kopsia.

Fig. 4

Akuammilines, sarpagines and aspidophyllines from genus Kopsia.

The first compound akuammidine (302) was originated from K. arborea stem bark, K. singapurensis root, stem bark, and leaves, while akuammiline (303) presented in the aerial part of K. macrophylla and K. teoi.[10,23,27,32,34,43,45,47-49] Akuammiline N(4)-oxide (304) and 16-epi-deacetylakuammiline-N(4)-oxide (310) were reported to be two new derivatives, which were separated from the rich alkaloidal fraction of K. griffithii stem bark.[15] ψ-Akuammigine (305), dregamine (307), N-methylpleiocarpamine (312), 5-methoxystrictamine (313), rhazimal (314), rhazinaline N(4)-oxide (315), picralinal (317), pleiocarpamine methochloride (320), and pleiomalicine (321) were isolated from genus Kopsia for the first time.[9,10,15,16,27,31,36] Lastly, two new metabolites, rhazinoline (316) and singaporentinidine (322), were purified from the extracts of K. arborea stem bark, K. singapurensis root, respectively.[10,35]

A list of four alkaloidal sarpagines 323–326 has been updated in Table 1 and Fig. 4.[9,27,50] Vincadiffine (326) was a well-known metabolite, but its 10-hydroxy derivative (323) was a new compound in the literature, and both of them were isolated from the MeOH extract of K. hainanensis.[9] Perivine (324) and tabernaemontanine (325) were two known sarpagines derived from K. officinalis root and stem and K. macrophylla bark, respectively.[27,50]

Resemble sarpagines, aspidophylline derivatives are not available in genus Kopsia. A total of five isolates 327–331 were summarized in Table 1 and Fig. 4.[23,31-34,36,43,48,49] Aspidodasycarpine (327) was recorded by various authors and was detected in K. singapurensis root and stem bark, K. teoi stem, and stem bark.[23,32,34,36,43,48,49] Two new phyto constituents aspidophyllines A–B (328–329), were determined to exist in K. singapurensis stem bark, while the new analog vincophylline (331) was found in its leaves.[32,48] It can be concluded that lonicerine (330) was a major component in the group of aspidophyllines because it has occurred in various Kopsia plants such as K. fruticosa stem bark, K. singapurensis bark and stem bark, and K. teoi stem, stem bark and leaf.[23,31-34,36,43,48]

Strychnoses

Compounds 332–357 have been fallen into the group of alkaloidal strychnos derivatives (Table 1 and Fig. 5). Similar to aspidofractinines and eburnamines, Kopsia strychnoses were presented in both mono-or dimer forms, and they were mainly sourced from K. deverri, K. hainanensis, K. jasminiflora, K. officinalis, K. pauciflora, K. singapurensis, especially K. arborea.[8,10,12,22-24,29,35,36,64,94-102] Significantly, except for akuammicine (332), (E)-condylocarpine (335), (E)-condylocarpine N-oxide (336), leuconicine B (351), precondylocarpine (355), and tubotaiwine (356), the remaining compounds were new in nature.

Fig. 5

Strychnoses and stemmadenine from genus Kopsia.

By the analysis of NMR, MS, and CD data, two isolated dimeric compounds, arbolodinines B–C (333–334), were elucidated as bulk novel strychnoses, which were derived from K. arborea stem bark.[8] Compound 335 is a known compound,[22,95] but its 14α-hydroxy and 14(S)-hydroxy-19(R)-methoxy derivatives 337–338 were new in the literature and first were isolated from K. deverri stem bark and K. singapurensis root, respectively.[35,94] Mossambine (354) was another new strychnos found in K. singapurensis stem bark.[23]K. arborea aerial part has so far distributed thirteen new compounds, isocondylocarpine (340), isocondylocarpine N-oxide (341), kopsiyunnanines A, I, J1–J2, L, M, and F1–F3 (342–350), 19(R)-methoxytubotaiwine (352), and 19(S)-methoxytubotaiwine (353).[10,95-98,100,101] The well-known compound tubotaiwine (356) was characteristic of K. arborea aerial part, K. hainanensis stem and stem bark, but its 14(S)-hydroxy-19(R)-methoxy derivative 339 isolated from the MeOH extract of K. jasminiflora stem bark has been determined as a new metabolite.[24,29,64,95] Stemmadenine (357) from K. pauciflora leaves was the only stemmadenine detected in the genus Kopsia.[22]

Mersinines and pauciflorines

Mersinines with tetracyclic quinolinic skeleton are a new subclass of monoterpenoid indole alkaloids, which were only found in the plants genus Kopsia. Kopsia mersinines 358–378 were only detected in K. singapurensis leaves and occasionally in K. fruticosa leaves (Table 1 and Fig. 6).[23,103-108] Of particular interest, all these isolates were novel compounds in literature. Searching for cytotoxic agents from plants, sixteen novel mersinines, comprising of mersidasines A–G (358–364), mersifolines A–C (365–367), mersiloscine (369), mersiloscines A–B (370–371), and mersinines A–C (373–375) were isolated from the acidic EtOH extract of K. singapurensis leaf.[103] Their stereochemistry was confirmed by NMR, IR, UV, and X-ray analysis. K. singapurensis leaf has further been shown to contain five novel congeners, mersilongine (368), mersinaline (372), mersiphyllines A–B (376–377), and mersirachine (378).[23,106,108]

Fig. 6

Mersinines and pauciflorines from genus Kopsia.

It is similar to mersinines, Kopsia pauciflorines 379–390 have induced interest since all isolates were novel in the literature, except for 11,12-demethoxy-16-deoxypauciflorine (379). K. arborea, K. jasminiflora, K. officinalis, and K. pauciflora might be a reservoir of this chemical class.[22,40,56,109,110]

Besides aspidofractinines, the MeOH extract of K. jasminiflora leaf has associated with the presence of three novel pauciflorines 20-deoxykopsijasminilam (380), kopsijasminilam (382), and Δ14-kopsijasminilam (383).[40] In addition to known compound 379, three novel derivatives, kopsioffines A–C (384–386) were arisen from the 95% EtOH extract of K. officinalis dried stem and leaves.[109] Pauciflorines A–B (387–388) reached 0.22 and 0.03 g kg−1 in K. pauciflora leaf.[110] In the meantime, two other novel compounds, pauciflorine C (389) and paucifoline (390), were minor components in the acidic EtOH extract of K. pauciflora leaves.[22] It is possible to conclude that mersinines and pauciflorines could be used as chemical indicators to distinguish the genus Kopsia and other genera of the family Apocynaceae.

Skytanthines, rhazinilams, and lundurines

It is recognized that the unique chemical class of skytanthines can be arranged as a new group of alkaloids. These phytochemicals were isolated from Apocynaceae Skytanthus acutus for the first time in 1960.[123] From Table 1 and Fig. 7, ten new skytanthines 391–400 have been summarized. The extracts of K. dasyrachis and K. macrophylla, especially K. pauciflora, are accompanied by the presence of this type.[27,30,112,113] Two publications in 1996 and 1997 by Kam and partners successfully reported the structures of serial new skytanthines kinabalurines A–F (391–396) from K. pauciflora leaves.[111,112] while their following congener kinabalurine G (397) was derived from K. dasyrachis leaf.[30] Significantly, the novel alkaloidal kopsirachine (399) isolated from K. dasyrachis leaves was determined to be a hybrid compound by the combination of catechin and skytanthine.[113] After being run Sephadex LH-20 and silica gel CC, a new monoterpene alkaloids containing a lactone ring, kopsilactone (398), and other new monoterpene alkaloids possessing 2-azabicyclo[3.3.1] backbone, kopsone (400), were isolated from the MeOH extract of K. macrophylla bark.[27] Based on these findings, skytanthines can be seen as chemical evidence to determine the close relationship among Apocynaceae plants, especially between genera Skytanthus and Kopsia.

Fig. 7

Skytanthines, rhazinilams and lundurines from genus Kopsia.

Rhazinilam (409) is an alkaloid discovered in the Apocynaceae plant Melodinus australis in 1965.[124] It was then isolated from the shrub of the other Apocynaceae plant Rhazya stricta as well as other organisms.[125] This compound was established as a main component in the group of Kopsia rhazinilams since it was found in K. arborea aerial parts and stem bark, K. officinalis leaf and twig, K. pauciflora leaf and stem bark, K. singapurensis leaf, bark and stem bark, and K. teoi stem, stem bark and leaf.[13,16,22,23,25,32-34,36,45,47,48,114] Leuconolam (405) can be also seen as another main component because of its occurrence in K. griffithii leaves and stem bark, K. hainanensis twig, stem and leaf, K. officinalis leaf, K. pauciflora leaves, and K. singapurensis stem bark.[7,9,12,15,17,22,23,25,32] As shown in Table 1, known compound 5,21-dihydrorhazinilam (401) existed in K. arborea stem bark and K. singapurensis stem bark and leaves.[10,23,48] From Fig. 7, three new compounds, kopsiyunnanines C1–C3 (402–404), which were isolated from the aerial part of K. arborea and K. officinalis, established the same backbone with rhazinilam (409).[96,114]O-Methylleuconolam (406) and rhazinal (407) were two well-known compounds, but their congener rhazinicine (408) separated from K. arborea stem bark, K. dasyrachis stem, and K. singapurensis root was a new derivative.[10,12,18,32,49,60,87] To the best of our knowledge, rhazinilams were only observed in the family Apocynaceae, as well as the plants of three genus Melodinus, Rhazya, and Kopsia being the main resources.

Kopsia lundurines 410–426 have generally been formed by the combination of an indole ring and a lactam ring through an eight-ring member (Fig. 7). Notably, all of these seventeen compounds were novel in nature, and the three plants, K. lapidilecta, K. grandifolia, and K. tenuis, are the main reservoirs (Table 1).

Awang and partners also isolated and identified six novel pauciflorines, epilapidilectinol (410), isolapidilectine A (414), lapidilectam (415), lapidilectines A–B (416–417), and lapidilectinol (418) from aerial part of K. lapidilecta.[81,115] Three novel indole alkaloids, grandilodines A–C (411–413) were extracted from the EtOH extract of K. grandifolia stem bark or leaves with the yield ranging from 0.07 to 3.18%, and their chemical structures were proved by NMR, MS, and X-ray spectral data.[72] The eight remainders, including lundurines A–B (419–422), tenuisine A–C (423–425), and tenuiphylline (426), were novel lundurines presented in the K. tenuis leaf.[71,116,117] In which compounds 423–425 were unprecedented dimers, while compound 426 is unique due to the incorporation between aspidofractinine and lundurine units. As of a consequence, Kopsia lundurines, especially compounds 423–426, could be seen as significant chemotaxonomic agents.

Aspidospermas, catharinensines, leuconoxines, pericines, alstonines, and quebrachamines

Alkaloid type aspidospermas were named following the name of the genus Aspidospermas (family Apocynaceae). With regard to genus Kopsia, five known isolates 427–431 were summarized in Table 1 and Fig. 8. It turns out that buchtienine (427) was presented in either the leaf or stem of K. griffithii.[15,17] The MeOH extract of K. hainanensis twig and leaf consisted of two aspidospermas, corynantheol (428) and dihydrocorynantheol (430).[9] Only K. officinalis stem was found to contain 19,20-dihydroisositsirikine (429), while its congener 16(R)-19,20-E-isositsirikine (431) has been observed in the leaf of both K. griffithii and K. pauciflora.[15,17,22] Therefore, alkaloidal aspidospermas are usefully chemotaxonomic agents to confirm the close relationship between the genus Kopsia and other genera in the family Apocynaceae.

Fig. 8

Aspidospermas, catharinensines, leuconoxines, pericines, alstonines and quebrachamines from genus Kopsia.

Catharinensines, which belong to the group of oxindole alkaloids, can be found in several higher plants, such as Peschiera catharinensis.[126] In Kopsia plants, five catharinensines 432–436 were detected (Table 1 and Fig. 8). Phytochemical research conducted by Gan and partners revealed that the use of mobile phase CHCl3–MeOH is appropriate to isolate alkaloidal catharinensines.[22] By this approach, three new compounds, kopsirensines A–C (433–435), together with known analog catharinensine (432), have been successfully purified from the acidic EtOH extract of K. pauciflora leaves.[22] New catharinensine kopsiyunnanine B (436) was first collected as a light yellow solid from the alcoholic extract of K. officinalis aerial part, and then was detected in the K. arborea aerial part.[96,97]

Phytochemical studies on Kopsia plants have also led to the isolation of alkaloid leuconoxines 437–442, and their structures were compiled in Fig. 8. Leuconoxine (441) was described as a major component since it occurred in K. arborea stem bark, K. griffithii leaf and stem bark, K. pauciflora stem, stem bark and leaf, K. singapurensis stem bark, K. teoi stem bark.[15,17,19,22,23,43] Arboloscine (437) was one of the new compounds in K. arborea stem bark, while melodinine E (442) was a known metabolite extracted from its twigs.[10,21,118] New compound arboloscine A (438) isolated from K. pauciflora leaf has a similarity in structural feature with compound 437, but the methyl group of 437 was replaced by the ethyl group in 438.[22] In the genus Kopsia, leuconodine D (439) was only detected in K. officinalis stems, whereas leuconodine F (440) was characteristic of K. griffithii leaves and K. pauciflora leaves.[22,43,75]

To find bioactive molecules from medicinal plants, four alkaloids type pericines, including two new compounds pericidine (443) and pericine N-oxide (445) and two known analogs pericine (444) and valparicine (446) were isolated (Table 1 and Fig. 8). All of these isolates originated from K. arborea stem bark.[10,118,119]

To the best of our knowledge, only three compounds 447–449 were classified as alkaloid alstonines (Table 1 and Fig. 8). Oxayohimban-16-carboxy acid (447) derived from K. officinalis stem has never been isolated from the genus Kopsia before.[75] The major component (−)-tetrahydroalstonine (448) appeared in K. arborea stem bark, K. dasyrachis stem, K. griffithii leaf, K. officinalis root, twig and leaf, K. larutensis stem bark and leaf, K. pauciflora stem, stem bark and leaf, K. singapurensis stem bark; K. teoi stem bark.[10,15,17-19,22,23,25,32,42,43,66] Compound 449, a pseudoindoxyl derivative of compound 448, was identified to be a new constituent from the acidic EtOH extract of K. pauciflora leaves.[22]

In the same manner, there are only three quebrachamines from the genus Kopsia till now (Table 1 and Fig. 8). (−)-Quebrachamine (452) is now abundant in nature and can be found in K. arborea aerial parts, K. hainanensis twigs and leaves, K. officinalis roots, and K. pauciflora leaves.[9,22,69,114] However, kopsiyunnanines D and H (450–451) from K. arborea aerial part were confirmed to be two new analogs.[90,114]

Others indole alkaloids and non-alkaloids

Phytochemical studies on Kopsia plants also recorded the appearance of other alkaloidal types (Table 1 and Fig. 9). Chromatographic procedure on the acidic MeOH extract of K. arborea bark has resulted in the isolation of three new metabolites, arbophyllinines A–B (453–454) and arbophyllidine (463).[59] Arboflorine (455) from K. arborea stem bark was a known alkaloid type arboflorine, but its new analog kopsiyunnanine E (456) was detected in the aerial part of K. arborea and K. officinalis.[10,96,99,121] Besides the main constituents, the EtOH extract of K. pauciflora leaves has composed of a new component, andransinine A (458), along with a known one andransinine (457).[22] New corynantheines arboricine (459) and arboricine (460) were found in both the leaves and stem of K. arborea.[10,120] The new carboline harmane (461) was presented in both leaves and stem of K. griffithii, but the new congener harmicine (462) was only detected in its leaves.[15,17] To find bioactive compounds from plants, mersicarpine (464) was first isolated from K. arborea stem bark.[10] It was then further found in K. pauciflora leaves and K. singapurensis stem bark.[22,23] Two final alkaloids, a new alkaloid type, azepane-fused tetrahydro-β-carboline kopsiyunnanine K (465) and a known alkaloid type andranginine (466), were constituents of K. arborea aerial part.[102]

Fig. 9

Others type indole alkaloids from genus Kopsia.

To date, there have not been many results on the separation of non-alkaloidal constituents from the plants of the genus Kopsia. A phytochemical report from Shan and partner (2017) identified that the n-hexane extract of K. singapurensis dried leaf and bark has accompanied with the existence of five triterpenoids β-amyrin (467), β-amyrin acetate (468), β-amyrone (469), lupeol (470), lupeol acetate (471), and one sterol stigmasterol (472) (Table 1 and Fig. 10).[122] This is the first time to observe these compounds in the genus Kopsia.

Fig. 10

Triterpenoids and sterol from genus Kopsia.

Taken together, despite the fact that there have been preliminary chemotaxonomic and synthetic reviews.[127,128] This is the first time that we provide fully information on phytochemical separation, a detailed list of almost isolated compounds, chemical classification, botanical resource, and the great value of Kopisa monoterpene alkaloids in botanical and chemical relationship.

Pharmacological activities

Cytotoxic, antimicrobial, anti-inflammatory, anti-diabetic, cardiovascular, vasorelaxant, and other positive properties have been studied utilizing Kopsia secondary metabolites and extracts in pharmacological research. In Table 2, a summary of prior pharmacological appraisals on Kopsia plant materials is presented in detail.

Pharmacological activities of isolated compounds and plant extracts from the genus Kopsia

Compounds	Models	Effect	Positive control	Effect	References
Anti-cancer activity
39	In vitro	CD50 > 60 μg mL−1/NIH/3T3 and HeLa cells	Vincristine	CD50 > 60 μg mL−1/NIH/3T3 cells	49
		CD50 = 6.9 μg mL−1/HL-60 cells		CD50 = 1.8 μg mL−1/HL-60 cells
				CD50 = 0.4 μg mL−1/HeLa cells
40	In vitro	CD50 > 60 μg mL−1/NIH/3T3, HL-60 and HeLa cells	Vincristine	CD50 > 60 μg mL−1/NIH/3T3 cells	49
				CD50 = 1.8 μg mL−1/HL-60 cells
				CD50 = 0.4 μg mL−1/HeLa cells
43	In vitro	IC50 = 33.7 μM/HS-1 cells	Adiamycin	IC50 = 17.8 μM/HS-1 cells	52
		IC50 = 28.4 μM/HS-4 cells		IC50 = 24.7 μM/HS-4 cells
		IC50 = 32.4 μM/SCL-1 cells		IC50 = 21.8 μM/SCL-1 cells
		IC50 = 29.7 μM/A-431 cells		IC50 = 33.7 μM/A-431 cells
		IC50 = 30.9 μM/BGC-823 cells		IC50 = 28.4 μM/BGC-823 cells
		IC50 = 27.1 μM/MCF-7 cells		IC50 = 37.6 μM/MCF-7 cells
		IC50 = 31.2 μM/W-480 cells		IC50 = 14.1 μM/W-480 cells
44	In vitro	IC50 = 34.9 μM/HS-1 cells	Adiamycin	IC50 = 17.8 μM/HS-1 cells	52
		IC50 = 29.9 μM/HS-4 cells		IC50 = 24.7 μM/HS-4 cells
		IC50 = 33.1 μM/SCL-1 cells		IC50 = 21.8 μM/SCL-1 cells
		IC50 = 30.1 μM/A-431 cells		IC50 = 33.7 μM/A-431 cells
		IC50 = 35.5 μM/BGC-823 cells		IC50 = 28.4 μM/BGC-823 cells
		IC50 = 31.2 μM/MCF-7 cells		IC50 = 37.6 μM/MCF-7 cells
		IC50 = 32.6 μM/W-480 cells		IC50 = 14.1 μM/W-480 cells
45	In vitro	IC50 = 12.4 μM/HS-1 cells	Adiamycin	IC50 = 17.8 μM/HS-1 cells	52
		IC50 = 12.3 μM/HS-4 and BGC-823 cells		IC50 = 24.7 μM/HS-4 cells
		IC50 = 12.9 μM/SCL-1 cells		IC50 = 21.8 μM/SCL-1 cells
		IC50 = 11.8 μM/A-431 cells		IC50 = 33.7 μM/A-431 cells
		IC50 = 12.6 μM/MCF-7 cells		IC50 = 28.4 μM/BGC-823 cells
		IC50 = 13.8 μM/W-480 cells		IC50 = 37.6 μM/MCF-7 cells
				IC50 = 14.1 μM/W-480 cells
46	In vitro	IC50 = 11.6 μM/HS-1 cells	Adiamycin	IC50 = 17.8 μM/HS-1 cells	52
		IC50 = 11.4 μM/HS-4 cells		IC50 = 24.7 μM/HS-4 cells
		IC50 = 12.1 μM/SCL-1 cells		IC50 = 21.8 μM/SCL-1 cells
		IC50 = 10.3 μM/A-431 cells		IC50 = 33.7 μM/A-431 cells
		IC50 = 11.7 μM/BGC-823 cells		IC50 = 28.4 μM/BGC-823 cells
		IC50 = 10.4 μM/MCF7 cells		IC50 = 37.6 μM/MCF-7 cells
		IC50 = 12.5 μM/W-480 cells		IC50 = 14.1 μM/W-480 cells
47	In vitro	IC50 = 7.3 μM/HS-1 cells	Adiamycin	IC50 = 17.8 μM/HS-1 cells	52
		IC50 = 8.6 μM/HS-4 and MCF-7 cells		IC50 = 24.7 μM/HS-4 cells
		IC50 = 8.2 μM/SCL-1 cells		IC50 = 21.8 μM/SCL-1 cells
		IC50 = 9.5 μM/A431 cells		IC50 = 33.7 μM/A-431 cells
		IC50 = 8.9 μM/BGC-823 cells		IC50 = 28.4 μM/BGC-823 cells
		IC50 = 9.2 μM/W-480 cells		IC50 = 37.6 μM/MCF-7 cells
				IC50 = 14.1 μM/W-480 cells
48	In vitro	IC50 = 11.3 μM/A-549 cells	Doxorubicin	IC50 = 0.02 μM/A-549, HepG-2 and W-480 cells	53
		IC50 = 9.4 μM/BGC-823 cells		IC50 = 0.01 μM/BGC-823 cells
		IC50 = 10.1 μM/HepG-2 cells		IC50 = 0.03 μM/HL-60 cells
		IC50 = 11.1 μM/HL-60 cells		IC50 = 0.04 μM/SMMC-7721 cells
		IC50 = 10.4 μM/MCF-7 cells
		IC50 = 9.7 μM/SMMC-7721 cells
		IC50 = 11.7 μM/W-480 cells
49	In vitro	IC50 = 12.7 μM/A-549 cells	Doxorubicin	IC50 = 0.02 μM/A-549, HepG-2 and W-480 cells	53
		IC50 = 12.2 μM/BGC-823 cells		IC50 = 0.01 μM/BGC-823 cells
		IC50 = 12.8 μM/HepG-2 cells		IC50 = 0.03 μM/HL-60 cells
		IC50 = 13.8 μM/HL-60 cells		IC50 = 0.04 μM/SMMC-7721 cells
		IC50 = 14.3 μM/MCF-7 and SMMC-7721 cells
		IC50 = 15.9 μM/W-480 cells
50	In vitro	IC50 = 31.9 μM/A-549 cells	Doxorubicin	IC50 = 0.02 μM/A-549, HepG-2 and W-480 cells	53
		IC50 = 31.2 μM/BGC-823 cells		IC50 = 0.01 μM/BGC-823 cells
		IC50 = 30.7 μM/HepG-2 cells		IC50 = 0.03 μM/HL-60 cells
		IC50 = 32.2 μM/HL-60 cells		IC50 = 0.04 μM/SMMC-7721 cells
		IC50 = 28.1 μM/MCF-7 cells
		IC50 = 29.9 μM/SMMC-7721 cells
		IC50 = 27.6 μM/W-480 cells
51	In vitro	IC50 = 29.7 μM/A-549 cells	Doxorubicin	IC50 = 0.02 μM/A-549, HepG-2 and W-480 cells	53
		IC50 = 29.6 μM/BGC-823 cells		IC50 = 0.01 μM/BGC-823 cells
		IC50 = 29.4 μM/HepG-2 and HL-60 cells		IC50 = 0.03 μM/HL-60 cells
		IC50 = 27.1 μM/MCF-7 cells		IC50 = 0.04 μM/SMMC-7721 cells
		IC50 = 30.1 μM/SMMC-7721 cells
		IC50 = 24.9 μM/W-480 cells
52	In vitro	IC50 = 76.3 μM/A-549 cells	Doxorubicin	IC50 = 0.02 μM/A-549, HepG-2 and W-480 cells	53
		IC50 = 68.7 μM/BGC-823 cells		IC50 = 0.01 μM/BGC-823 cells
		IC50 = 66.8 μM/HepG-2 cells		IC50 = 0.03 μM/HL-60 cells
		IC50 = 72.3 μM/HL-60 cells		IC50 = 0.04 μM/SMMC-7721 cells
		IC50 = 76.2 μM/MCF-7 cells
		IC50 = 70.8 μM/SMMC-7721 cells
		IC50 = 69.4 μM/W-480 cells
53	In vitro	IC50 = 80.2 μM/A-549 cells	Doxorubicin	IC50 = 0.02 μM/A-549, HepG-2 and W-480 cells	53
		IC50 = 78.8 μM/BGC-823 cells		IC50 = 0.01 μM/BGC-823 cells
		IC50 = 79.4 μM/HepG-2 cells		IC50 = 0.03 μM/HL-60 cells
		IC50 = 80.3 μM/HL-60 cells		IC50 = 0.04 μM/SMMC-7721 cells
		IC50 = 80.5 μM/MCF-7 cells
		IC50 = 81.6 μM/SMMC-7721 cells
		IC50 = 81.8 μM/W-480 cells
54	In vitro	IC50 = 15.8 μM/BGC-823 cells	Doxorubicin	IC50 = 0.02 μM/BGC-823 cells	54
		IC50 = 16.8 μM/HepG-2 cells		IC50 = 0.01 μM/HepG-2 and SK-OV-3 cells
		IC50 = 16.5 μM/MCF-7 cells		IC50 = 0.06 μM/MCF-7 cells
		IC50 = 18.7 μM/SGC-7901 cells		IC50 = 0.05 μM/SGC-7901 cells
		IC50 = 19.7 μM/SK-MEL-2 cells		IC50 = 0.03 μM/SK-MEL-2 cells
		IC50 = 17.6 μM/SK-OV-3 cells
55	In vitro	IC50 = 13.8 μM/BGC-823 cells	Doxorubicin	IC50 = 0.02 μM/BGC-823 cells	54
		IC50 = 12.4 μM/HepG-2 cells		IC50 = 0.01 μM/HepG-2 and SK-OV-3 cells
		IC50 = 14.8 μM/MCF-7 cells		IC50 = 0.06 μM/MCF-7 cells
		IC50 = 13.9 μM/SGC-7901 and SK-OV-3 cells		IC50 = 0.05 μM/SGC-7901 cells
		IC50 = 12.6 μM/SK-MEL-2 cells		IC50 = 0.03 μM/SK-MEL-2 cells
56	In vitro	IC50 = 7.3 μM/BGC-823 cells	Doxorubicin	IC50 = 0.02 μM/BGC-823 cells	54
		IC50 = 8.6 μM/HepG-2 cells		IC50 = 0.01 μM/HepG-2 and SK-OV-3 cells
		IC50 = 8.2 μM/MCF-7 cells		IC50 = 0.06 μM/MCF-7 cells
		IC50 = 9.5 μM/SGC-7901 cells		IC50 = 0.05 μM/SGC-7901 cells
		IC50 = 8.9 μM/SK-MEL-2 cells		IC50 = 0.03 μM/SK-MEL-2 cells
		IC50 = 8.6 μM/SK-OV-3 cells
57	In vitro	IC50 = 9.5 μM/BGC-823 cells	Doxorubicin	IC50 = 0.02 μM/BGC-823 cells	54
		IC50 = 10.6 μM/HepG-2 cells		IC50 = 0.01 μM/HepG-2 and SK-OV-3 cells
		IC50 = 9.3 μM/MCF-7 cells		IC50 = 0.06 μM/MCF-7 cells
		IC50 = 10.4 μM/SGC-7901 cells		IC50 = 0.05 μM/SGC-7901 cells
		IC50 = 9.2 μM/SK-MEL-2 cells		IC50 = 0.03 μM/SK-MEL-2 cells
		IC50 = 10.3 μM/SK-OV-3 cells
58	In vitro	IC50 = 33.1 μM/BGC-823 cells	Doxorubicin	IC50 = 0.02 μM/BGC-823 cells	54
		IC50 = 32.4 μM/HepG-2 cells		IC50 = 0.01 μM/HepG-2 and SK-OV-3 cells
		IC50 = 29.7 μM/MCF-7 cells		IC50 = 0.06 μM/MCF-7 cells
		IC50 = 30.9 μM/SGC-7901 cells		IC50 = 0.05 μM/SGC-7901 cells
		IC50 = 27.1 μM/SK-MEL-2 cells		IC50 = 0.03 μM/SK-MEL-2 cells
		IC50 = 30.1 μM/SK-OV-3 cells
59	In vitro	IC50 = 12.9 μM/95-D cells	Doxorubicin	IC50 = 24.7 μM/95-D cells	55
		IC50 = 12.4 μM/A-549 cells		IC50 = 21.8 μM/A-549 cells
		IC50 = 13.8 μM/ATCC cells		IC50 = 33.7 μM/ATCC cells
		IC50 = 14.8 μM/H-446 cells		IC50 = 22.3 μM/H-446 cells
		IC50 = 13.3 μM/H-460 cells		IC50 = 14.1 μM/H-460 cells
		IC50 = 12.6 μM/H-292 cells		IC50 = 13.7 μM/H-292 cells
		IC50 = 13.9 μM/SPCA-1 cells		IC50 = 14.1 μM/SPCA-1 cells
60	In vitro	IC50 = 46.8 μM/95-D cells	Doxorubicin	IC50 = 24.7 μM/95-D cells	55
		IC50 = 47.1 μM/ATCC cells		IC50 = 33.7 μM/ATCC cells
		IC50 = 46.6 μM/H-446 cells		IC50 = 22.3 μM/H-446 cells
		IC50 = 45.9 μM/H-292 cells		IC50 = 13.7 μM/H-292 cells
61	In vitro	IC50 = 9.5 μM/95-D cells	Doxorubicin	IC50 = 24.7 μM/95-D cells	55
		IC50 = 8.6 μM/A-549 cells		IC50 = 21.8 μM/A-549 cells
		IC50 = 9.3 μM/ATCC and H-292 cells		IC50 = 33.7 μM/ATCC cells
		IC50 = 9.4 μM/H-446 cells		IC50 = 22.3 μM/H-446 cells
		IC50 = 9.2 μM/H-460 cells		IC50 = 14.1 μM/H-460 cells
		IC50 = 9.7 μM/SPCA-1 cells		IC50 = 13.7 μM/H-292 cells
				IC50 = 14.1 μM/SPCA-1 cells
73	In vitro	CD50 = 20.7 μg mL−1/NIH/3T3 cells	Vincristine	CD50 > 60 μg mL−1/NIH/3T3 cells	49
		CD50 = 0.9 μg mL−1/HL-60 cells		CD50 = 1.8 μg mL−1/HL-60 cells
		CD50 = 36.5 μg mL−1/HeLa cells		CD50 = 0.4 μg mL−1/HeLa cells
74	In vitro	To suppress the bound of [3H]azidopine to P-glycoprotein			61
76	In vitro	IC50 = 67.3 μM/HS-4 cells	Adiamycin	IC50 = 24.7 μM/HS-4 cells	52
		IC50 = 74.2 μM/A-431 cells		IC50 = 33.7 μM/A-431 cells
		IC50 = 66.2 μM/W-480 cells		IC50 = 14.1 μM/W-480 cells
88	In vitro	IC50 = 38.7 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	43
93	In vitro	IC50 = 19.5 μg mL−1/KB cells	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	32
		IC50 = 18.0 μg mL−1/KB (VJ300) cells
		IC50 = 3.80 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
102	In vitro	IC50 = 15.0 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	23
103	In vitro	IC50 = 3.9 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	23
104	In vitro	IC50 = 13.0 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	23
105	In vitro	IC50 = 18.2 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	23
106	In vitro	IC50 = 9.2 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	23
107	In vitro	IC50 = 18.0 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	23
214	In vitro	IC50 = 29.7 μM/BGC-823 cells	Doxorubicin	IC50 = 29.7 μM/BGC-823 cells	85
		IC50 = 37.6 μM/HepG-2 cells		IC50 = 37.6 μM/HepG-2 cells
		IC50 = 35.8 μM/MCF-7 cells		IC50 = 35.8 μM/MCF-7 cells
		IC50 = 36.8 μM/SGC-7901 cells		IC50 = 36.8 μM/SGC-7901 cells
		IC50 = 36.5 μM/SK-MEL-2 cells		IC50 = 36.5 μM/SK-MEL-2 cells
215	In vitro	IC50 = 32.1 μM/BGC-823 cells	Doxorubicin	IC50 = 29.7 μM/BGC-823 cells	85
		IC50 = 29.8 μM/HepG-2 cells		IC50 = 37.6 μM/HepG-2 cells
		IC50 = 31.9 μM/MCF-7 cells		IC50 = 35.8 μM/MCF-7 cells
		IC50 = 27.9 μM/SGC-7901 cells		IC50 = 36.8 μM/SGC-7901 cells
		IC50 = 33.3 μM/SK-MEL-2 cells		IC50 = 36.5 μM/SK-MEL-2 cells
237	In vitro	IC50 = 8.6 μM/BGC-823 cells	Doxorubicin	IC50 = 29.7 μM/BGC-823 cells	85
		IC50 = 7.2 μM/HepG-2 cells		IC50 = 37.6 μM/HepG-2 cells
		IC50 = 8.3 μM/MCF-7 cells		IC50 = 35.8 μM/MCF-7 cells
		IC50 = 8.2 μM/SGC-7901 cells		IC50 = 36.8 μM/SGC-7901 cells
		IC50 = 8.9 μM/SK-MEL-2 cells		IC50 = 36.5 μM/SK-MEL-2 cells
282	In vitro	IC50 = 9.7 μg mL−1/PC-3 cells	Cisplatin	IC50 = 1.5 μg mL−1/PC-3 cells	19
		IC50 = 15.9 μg mL−1/HCT-116 cells		IC50 = 3.2 μg mL−1/HCT-116 cells
		IC50 = 14.1 μg mL−1/MCF-7 cells		IC50 = 4.2 μg mL−1/MCF-7 cells
		IC50 > 25 μg mL−1/A-549 and KB (VJ300) cells		IC50 = 4.3 μg mL−1/A-549 cells
		IC50 = 8.6 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Verapamil	IC50 = 4.7 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
289	In vitro	IC50 = 7.1 μg mL−1/PC-3 cells	Cisplatin	IC50 = 1.5 μg mL−1/PC-3 cells	19
		IC50 = 7.6 μg mL−1/HCT-116 cells		IC50 = 3.2 μg mL−1/HCT-116 cells
		IC50 = 9.7 μg mL−1/MCF-7 cells		IC50 = 4.2 μg mL−1/MCF-7 cells
		IC50 = 20.4 μg mL−1/A-549 cells		IC50 = 4.3 μg mL−1/A-549 cells
		IC50 = 23 μg mL−1/KB (VJ300) cells
		IC50 = 4.80 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Verapamil	IC50 = 4.7 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
302	In vitro	CD50 > 60 μg mL−1/NIH/3T3 cells	Vincristine	CD50 > 60 μg mL−1/NIH/3T3 cells	49
		CD50 = 30.2 μg mL−1/HL-60 cells		CD50 = 1.8 μg mL−1/HL-60 cells
		CD50 = 2.8 μg mL−1/HeLa cells		CD50 = 0.4 μg mL−1/HeLa cells
327	In vitro	CD50 = 6.4 μg mL−1/NIH/3T3 cells	Vincristine	CD50 > 60 μg mL−1/NIH/3T3 cells	49
		CD50 > 60 μg mL−1/HL-60 cells		CD50 = 1.8 μg mL−1/HL-60 cells
		CD50 = 7.5 μg mL−1/HeLa cells		CD50 = 0.4 μg mL−1/HeLa cells
333	In vitro	IC50 = 1.3 μg mL−1/HT-29 cells	Cisplatin	IC50 = 8.8 μg mL−1/HT-29 cells	8
		IC50 = 4.9 μg mL−1/MCF-7 cells		IC50 = 6.6 μg mL−1/MCF-7 cells
		IC50 = 4.7 μg mL−1/PC-3 cells		IC50 = 4.2 μg mL−1/PC-3 cells
		IC50 = 7.0 μg mL−1/MDA-MB -231 cells		IC50 = 2.1 μg mL−1/MDA-MB -231 cells
		IC50 = 7.3 μg mL−1/HCT-116 cells		IC50 = 4.6 μg mL−1/HCT-116 cells
		IC50 = 9.6 μg mL−1/A-549 cells		IC50 = 5.4 μg mL−1/A-549 cells
		IC50 = 3.0 μg mL−1/KB (VJ300) cells	Vincristine	IC50 = 0.8 μg mL−1/KB (VJ300) cells
366	In vitro	IC50 = 3.70 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	103
367	In vitro	IC50 = 7.0 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	103
373	In vitro	IC50 = 4.1 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	103
374	In vitro	IC50 = 3.2 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	103
375	In vitro	IC50 = 11.2 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	103
402	In vitro	IC50 = 5.38 μM/A-549 cells	Docetaxel	IC50 = 4.95 × 10−4 μM/A-549 cells	114
		IC50 = 4.67 μM/HT-29 cells		IC50 = 3.34 × 10−4 μM/HT-29 cells
403	In vitro	IC50 = 7.44 μM/A-549 cells	Docetaxel	IC50 = 4.95 × 10−4 μM/A-549 cells	114
		IC50 = 6.39 μM/HT-29 cells		IC50 = 3.34 × 10−4 μM/HT-29 cells
404	In vitro	IC50 = 8.21 μM/A-549 cells	Docetaxel	IC50 = 4.95 × 10−4 μM/A-549 cells	114
		IC50 = 8.89 μM/HT-29 cells		IC50 = 3.34 × 10−4 μM/HT-29 cells
407	In vitro	IC50 = 0.24 μg mL−1/KB cells	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	32
		IC50 = 0.25 μg mL−1/KB (VJ300) cells
		IC50 = 0.30 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
408	In vitro	CD50 = 20.8 μg mL−1/NIH/3T3 cells	Vincristine	CD50 > 60 μg mL−1/NIH/3T3 cells	49
		CD50 > 60 μg mL−1/HL-60 cells		CD50 = 1.8 μg mL−1/HL-60 cells
		CD50 = 2.9 μg mL−1/HeLa cells		CD50 = 0.4 μg mL−1/HeLa cells
		IC50 = 0.19 μg mL−1/KB cells	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	32
		IC50 = 0.25 μg mL−1/KB (VJ300) cells
		IC50 = 0.34 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
409	In vitro	IC50 = 0.35 μM/A-549 and HT-29 cells	Docetaxel	IC50 = 4.95 × 10−4 μM/A-549 cells	114
		IC50 = 1.25 μg mL−1/KB cells		IC50 = 3.34 × 10−4 μM/HT-29 cells
		IC50 = 2.50 μg mL−1/KB (VJ300) cells	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	32
		IC50 = 1.85 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
411	In vitro	IC50 = 4.35 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	72
413	In vitro	IC50 = 4.11 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	72
417	In vitro	IC50 = 0.39 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	72
434	In vitro	IC50 = 21.8 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	22
437	In vitro	IC50 = 15.0 μg mL−1/KB cells	Vincadifformine	IC50 = 10.2 μg mL−1/KB cells	10
		IC50 = 11.0 μg mL−1/KB (VJ300) cells		IC50 = 6.3 μg mL−1/KB (VJ300) cells
		IC50 = 3.8 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine		IC50 = 4.5 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
438	In vitro	IC50 = 6.4 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine	Vincristine	IC50 = 1.0 μg mL−1/KB (VJ300)	22
446	In vitro	IC50 = 0.25 μg mL−1/Jurkat cells	Vincadifformine	IC50 = 21.8 μg mL−1/Jurkat cells	10
		IC50 = 3.6 μg mL−1/KB cells		IC50 = 10.2 μg mL−1/KB cells
		IC50 = 0.75 μg mL−1/KB (VJ300) cells		IC50 = 6.3 μg mL−1/KB (VJ300) cells
		IC50 = 0.46 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine		IC50 = 4.5 μg mL−1/KB (VJ300) + 0.1 μg mL−1 vincristine
450 and 452	In vitro	IC50 > 30 μM/A-549 cells	Docetaxel	IC50 = 4.95 × 10−4 μM/A-549 cells	114
		IC50 = 30 μM/HT-29 cells		IC50 = 3.34 × 10−4 μM/HT-29 cells
463	In vitro	IC50 = 6.2 μM/HT-29 cells			59
467	In vitro	IC50 = 15.5 μg mL−1/MCF-7 cells			122
468	In vitro	IC50 = 22.5 μg mL−1/MCF-7 cells			122
469	In vitro	IC50 = 21.5 μg mL−1/MCF-7 cells			122
470	In vitro	IC50 = 17 μg mL−1/MCF-7 cells			122
471	In vitro	IC50 = 26 μg mL−1/MCF-7 cells			122
472	In vitro	IC50 = 14.5 μg mL−1/MCF-7 cells			122
Anti-microbial activity
14	In vitro	MIC = 31.3 μg mL−1/E. coli, E. carotovra, B. subtilis, B. cereus, and S. aureus	Ampicillin	MIC = 100 μg mL−1/E. coli and E. carotovra	7
		MIC = 15.5 μg mL−1/E. carotovra		MIC = 12.5 μg mL−1/B. subtilis
				MIC = 25.0 μg mL−1/B. cereus and S. aureus
		EC50 = 33.3 μg mL−1/R. solani	Mildothane	EC50 = 17.0 μg mL−1/R. solani
		EC50 = 29.2 μg mL−1/P. italicum		EC50 = 7.8 μg mL−1/P. italicum
		EC50 = 16.3 μg mL−1/F. oxysporum f. sp. Cubense		EC50 = 57.0 μg mL−1/F. oxysporum f. sp. Cubense
		EC50 = 31.8 μg mL−1/F. oxysporum f. sp. Niveum		EC50 = 101.0 μg mL−1/F. oxysporum f. sp. Niveum
43	In vitro	IZ = 11 mm/K. pneumoniae	Sanguinarine	IZ = 25 mm/S. mutans and S. viridans	52
		IZ = 10 mm/E. coli, S. aureus and S. viridans	Netilmicin	IZ = 21 mm/S. aureus
		IZ = 9 mm/C. glabrata, E. cloacae and S. mutans		IZ = 8 mm/S. epidermidis and K. pneumoniae
		IZ = 8 mm/S. epidermidis and S. dysenteriae		IZ = 24 mm/E. coli
		IZ = 7 mm/C. albicans, C. tropicalis and P. aeruginosa		IZ = 22 mm/E. cloacae
				IZ = 23 mm/P. aeruginosa and S. dysenteriae
44	In vitro	IZ = 12 mm/P. aeruginosa and S. mutans	Sanguinarine	IZ = 25 mm/S. mutans and S. viridans	52
		IZ = 11 mm/E. coli	Netilmicin	IZ = 21 mm/S. aureus
		IZ = 10 mm/C. glabrata		IZ = 8 mm/S. epidermidis and K. pneumoniae
		IZ = 9 mm/E. cloacae, S. aureus and S. dysenteriae		IZ = 24 mm/E. coli
		IZ = 8 mm/C. albicans, K. pneumoniae and S. epidermidis		IZ = 22 mm/E. cloacae
		IZ = 7 mm/C. tropicalis and S. viridans		IZ = 23 mm/P. aeruginosa and S. dysenteriae
45	In vitro	IZ = 18 mm and MIC = 0.77 mM/K. pneumoniae	Sanguinarine	IZ = 25 mm/S. mutans and S. viridans	52
		IZ = 18 mm and MIC = 0.87 mM/S. viridans	Netilmicin	IZ = 21 mm/S. aureus
		IZ = 17 mm and MIC = 0.89 mM/E. coli		IZ = 8 mm/S. epidermidis and K. pneumoniae
		IZ = 18 mm and MIC = 0.97 mM/S. aureus and S. epidermidis		IZ = 24 mm/E. coli
		IZ = 18 mm and MIC = 0.97 mM/E. cloacae		IZ = 22 mm/E. cloacae
		IZ = 19 mm and MIC = 1.01 mM/P. aeruginosa		IZ = 23 mm/P. aeruginosa and S. dysenteriae
		IZ = 18 mm and MIC = 1.13 mM/S. mutans
		IZ = 19 mm and MIC = 1.18 mM/C. tropicalis
		IZ = 18 mm and MIC = 2.68 mM/S. dysenteriae
		IZ = 17 mm and MIC = 2.87 mM/C. albicans
		IZ = 17 mm and MIC = 3.09 mM/C. glabrata
46	In vitro	IZ = 20 mm and MIC = 0.72 mM/E. coli	Sanguinarine	IZ = 25 mm/S. mutans and S. viridans	52
		IZ = 20 mm and MIC = 0.82 mM/S. mutans
		IZ = 20 mm and MIC = 0.91 mM/S. epidermidis
		IZ = 20 mm and MIC = 1.03 mM/S. dysenteriae
		IZ = 20 mm and MIC = 1.11 mM/S. viridans
		IZ = 20 mm and MIC = 1.18 mM/P. aeruginosa	Netilmicin	IZ = 21 mm/S. aureus
		IZ = 19 mm and MIC = 1.20 mM/E. cloacae		IZ = 8 mm/S. epidermidis and K. pneumoniae
		IZ = 20 mm and MIC = 1.23 mM/C. tropicalis and S. aureus		IZ = 24 mm/E. coli
		IZ = 17 mm and MIC = 1.32 mM/C. glabrata		IZ = 22 mm/E. cloacae
		IZ = 21 mm and MIC = 1.37 mM/K. pneumoniae		IZ = 23 mm/P. aeruginosa and S. dysenteriae
		IZ = 17 mm and MIC = 2.87 mM/C. albicans
47	In vitro	IZ = 24 mm and MIC = 0.15 mM/E. coli	Sanguinarine	IZ = 25 mm/S. mutans and S. viridans	52
		IZ = 24 mm and MIC = 0.20 mM/S. epidermidis
		IZ = 23 mm and MIC = 0.22 mM/C. glabrata
		IZ = 23 mm and MIC = 0.30 mM/C. tropicalis
		IZ = 24 mm and MIC = 0.30 mM/S. dysenteriae and C. albicans
		IZ = 24 mm and MIC = 0.25 mM/S. aureus	Netilmicin	IZ = 21 mm/S. aureus
		IZ = 24 mm and MIC = 0.27 mM/E. cloacae		IZ = 8 mm/S. epidermidis and K. pneumoniae
		IZ = 24 mm and MIC = 0.32 mM/P. aeruginosa		IZ = 24 mm/E. coli
		IZ = 23 mm and MIC = 0.37 mM/K. pneumoniae		IZ = 22 mm/E. cloacae
		IZ = 23 mm and MIC = 0.87 mM/S. viridans		IZ = 23 mm/P. aeruginosa and S. dysenteriae
		IZ = 24 mm and MIC = 1.14 mM/S. mutans
48	In vitro	IZ = 23 mm and MIC = 0.12 mM/K. pneumoniae	Netilmicin	IZ = 25 mm and MIC = 0.009 mM/K. pneumoniae	53
		IZ = 24 mm and MIC = 0.12 mM/S. dysenteriae		IZ = 23 mm and MIC = 0.011 mM/S. dysenteriae
		IZ = 24 mm and MIC = 0.13 mM/P. aeruginosa		IZ = 23 mm and MIC = 0.015 mM/P. aeruginosa
		IZ = 23 mm and MIC = 0.15 mM/E. cloacae		IZ = 22 mm and MIC = 0.01 mM/E. cloacae
		IZ = 23 mm and MIC = 0.16 mM/S. epidermidis		IZ = 25 mm and MIC = 0.004 mM/S. epidermidis
		IZ = 24 mm and MIC = 0.18 mM/S. aureus		IZ = 21 mm and MIC = 0.005 mM/S. aureus
		IZ = 24 mm and MIC = 0.23 mM/E. coli		IZ = 24 mm and MIC = 0.015 mM/E. coli
49	In vitro	IZ = 24 mm and MIC = 0.14 mM/K. pneumoniae	Netilmicin	IZ = 25 mm and MIC = 0.009 mM/K. pneumoniae	53
		IZ = 23 mm and MIC = 0.16 mM/P. aeruginosa		IZ = 23 mm and MIC = 0.015 mM/P. aeruginosa
		IZ = 24 mm and MIC = 0.17 mM/S. aureus		IZ = 21 mm and MIC = 0.005 mM/S. aureus
		IZ = 22 mm and MIC = 0.18 mM/S. dysenteriae		IZ = 22 mm and MIC = 0.01 mM/E. cloacae
		IZ = 24 mm and MIC = 0.19 mM/E. cloacae		IZ = 25 mm and MIC = 0.004 mM/S. epidermidis
		IZ = 23 mm and MIC = 0.19 mM/S. epidermidis		IZ = 24 mm and MIC = 0.015 mM/E. coli
		IZ = 24 mm and MIC = 0.26 mM/E. coli
50	In vitro	IZ = 18 mm and MIC = 0.94 mM/P. aeruginosa	Netilmicin	IZ = 23 mm and MIC = 0.015 mM/P. aeruginosa	53
		IZ = 17 mm and MIC = 1.10 mM/E. cloacae		IZ = 22 mm and MIC = 0.01 mM/E. cloacae
		IZ = 17 mm and MIC = 1.12 mM/K. pneumoniae and S. dysenteriae		IZ = 25 mm and MIC = 0.009 mM/K. pneumoniae
		IZ = 18 mm and MIC = 1.20 mM/S. aureus		IZ = 23 mm and MIC = 0.011 mM/S. dysenteriae
		IZ = 19 mm and MIC = 1.23 mM/S. epidermidis		IZ = 21 mm and MIC = 0.005 mM/S. aureus
		IZ = 18 mm and MIC = 1.32 mM/E. coli		IZ = 25 mm and MIC = 0.004 mM/S. epidermidis
				IZ = 24 mm and MIC = 0.015 mM/E. coli
51	In vitro	IZ = 17 mm and MIC = 0.92 mM/P. aeruginosa	Netilmicin	IZ = 23 mm and MIC = 0.015 mM/P. aeruginosa	53
		IZ = 18 mm and MIC = 1.01 mM/E. cloacae		IZ = 22 mm and MIC = 0.01 mM/E. cloacae
		IZ = 19 mm and MIC = 1.02 mM/S. dysenteriae		IZ = 23 mm and MIC = 0.011 mM/S. dysenteriae
		IZ = 18 mm and MIC = 1.09 mM/K. pneumoniae		IZ = 25 mm and MIC = 0.009 mM/K. pneumoniae
		IZ = 19 mm and MIC = 1.15 mM/S. epidermidis		IZ = 25 mm and MIC = 0.004 mM/S. epidermidis
		IZ = 20 mm and MIC = 1.18 mM/S. aureus		IZ = 21 mm and MIC = 0.005 mM/S. aureus
		IZ = 17 mm and MIC = 1.24 mM/E. coli		IZ = 24 mm and MIC = 0.015 mM/E. coli
52	In vitro	IZ = 17 mm and MIC = 1.19 mM/K. pneumoniae	Netilmicin	IZ = 25 mm and MIC = 0.009 mM/K. pneumoniae	53
		IZ = 18 mm and MIC = 1.21 mM/E. coli		IZ = 24 mm and MIC = 0.015 mM/E. coli
		IZ = 17 mm and MIC = 1.21 mM/P. aeruginosa		IZ = 23 mm and MIC = 0.015 mM/P. aeruginosa
		IZ = 17 mm and MIC = 1.31 mM/E. cloacae		IZ = 22 mm and MIC = 0.01 mM/E. cloacae
		IZ = 15 mm and MIC = 1.31 mM/S. dysenteriae		IZ = 23 mm and MIC = 0.011 mM/S. dysenteriae
53	In vitro	IZ = 16 mm and MIC = 0.99 mM/K. pneumoniae	Netilmicin	IZ = 25 mm and MIC = 0.009 mM/K. pneumoniae	53
		IZ = 18 mm and MIC = 1.01 mM/S. dysenteriae		IZ = 23 mm and MIC = 0.011 mM/S. dysenteriae
		IZ = 17 mm and MIC = 1.24 mM/P. aeruginosa		IZ = 23 mm and MIC = 0.015 mM/P. aeruginosa
		IZ = 15 mm and MIC = 1.31 mM/E. coli		IZ = 24 mm and MIC = 0.015 mM/E. coli
		IZ = 17 mm and MIC = 1.32 mM/E. cloacae		IZ = 22 mm and MIC = 0.01 mM/E. cloacae
74	In vitro	IZ = 9.7 mm/S. aureus	Kanamycin sulfate	IZ = 24.7 mm/S. aureus	12
76	In vitro	IZ = 13 mm/S. aureus	Kanamycin sulfate	IZ = 24.7 mm/S. aureus	12
		IZ = 12 mm/S. epidermidis
		IZ = 9 mm/ C. albicans and C. glabrata
		IZ = 8 mm/C. tropicalis, S. mutans and S. dysenteriae
		IZ = 7 mm/E. coli and K. pneumoniae
85	In vitro	IZ = 11.2 mm/S. aureus	Kanamycin sulfate	IZ = 24.7 mm/S. aureus	12
86	In vitro	IZ = 9.1 mm/S. aureus	Kanamycin sulfate	IZ = 24.7 mm/S. aureus	12
87	In vitro	IZ = 10.3 mm/S. aureus	Kanamycin sulfate	IZ = 24.7 mm/S. aureus	12
206	In vitro	MIC = 15.5 μg mL−1/E. coli, Erwinia carotovra, Bacillus subtilis, B. cereus, and S. aureus	Ampicillin	MIC = 100 μg mL−1/E. coli and E. carotovra	7
		MIC = 7.8 μg mL−1/E. carotovra
		EC50 = 21.9 μg mL−1/R. solani	Mildothane	MIC = 12.5 μg mL−1/B. subtilis
		EC50 = 19.4 μg mL−1/P. italicum		MIC = 25.0 μg mL−1/B. cereus and S. aureus
		EC50 = 15.2 μg mL−1/F. oxysporum f. sp. Cubense		EC50 = 17.0 μg mL−1/R. solani
		EC50 = 43.8 μg mL−1/F. oxysporum f. sp. Niveum		EC50 = 7.8 μg mL−1/P. italicum
				EC50 = 57.0 μg mL−1/F. oxysporum f. sp. Cubense
				EC50 = 101.0 μg mL−1/F. oxysporum f. sp. Niveum
267 and 297	In vitro	MIC = 32 μg mL−1/E. coli			21
Anti-inflammatory activity
11	In vitro	IC50 = 25.4 μM/T cell inhibition			16
170	In vitro	IC50 = 21.6 μM/T cell inhibition			16
222	In vitro	IC50 = 27.8 μM/T cell inhibition			16
409	In vitro	IC50 = 1.0 μM/T cell inhibition			16
		To arrest the G2/M phase of the T cell cycle
		To decrease IL-6 and IL-17 levels in T cells
219, 225, 228, 279–280, 291, and 439	In vitro	The inhibitory effects on IL-1β and TNF-α, and PGE2 were comparable with positive control dexamethasone			75
Anti-allergic activity
90	In vitro	IC10 = 3.73 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	Ketotifen fumarate	IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	66
126	In vitro	IC10 = 7.06 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	Ketotifen fumarate	IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	66
257	In vitro	IC10 = 5.51 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	Ketotifen fumarate	IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	66
448	In vitro	IC10 = 11.78 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	Ketotifen fumarate	IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	66
The MeOH extract of K. larutensis bark	In vitro	IC10 = 2.17 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	Ketotifen fumarate	IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	66
The MeOH extract of K. arborea bark	In vitro	IC10 = 3.82 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	Ketotifen fumarate	IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	129
The MeOH extract of K. larutensis leaf	In vitro	IC10 = 3.01 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	Ketotifen fumarate	IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	66
The MeOH extract of K. arborea leaf	In vitro	IC10 = 2.58 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	Ketotifen fumarate	IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	129
The MeOH extract of K. larutensis root	In vitro	IC10 = 1.61 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	Ketotifen fumarate	IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	66
The MeOH extract of K. arborea root	In vitro	IC10 = 4.32 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	Ketotifen fumarate	IC10 = 1.37 μg mL−1/histamine and β-hexosaminidase inhibition in RBL-2H3 cell	129
Anti-diabetic activity
29	In vitro	EC50 = 24.5 μM/glucose-evoked podocyte injury inhibition	Astragaloside IV	EC50 = 15.4 μM/glucose-evoked podocyte injury inhibition	25
126	In vitro	EC50 = 3.0 μM/glucose-evoked podocyte injury inhibition	Astragaloside IV	EC50 = 15.4 μM/glucose-evoked podocyte injury inhibition	25
224	In vitro	EC50 = 10.2 μM/glucose-evoked podocyte injury inhibition	Astragaloside IV	EC50 = 15.4 μM/glucose-evoked podocyte injury inhibition	25
264	In vitro	EC50 = 12.0 μM/glucose-evoked podocyte injury inhibition	Astragaloside IV	EC50 = 15.4 μM/glucose-evoked podocyte injury inhibition	25
405	In vitro	EC50 = 3.80 μM/glucose-evoked podocyte injury inhibition	Astragaloside IV	EC50 = 15.4 μM/glucose-evoked podocyte injury inhibition	25
379 and 384–386	In vitro	IC50 > 50 μM/α-glucosidase inhibition			109
AChE inhibitory activity
39	In vitro	MIR = 12.5 μg/AChE inhibition	Galanthamine	MIR = 0.004 μg/AChE inhibition	21
220	In vitro	IC50 = 12.5 μg/AChE inhibition			6
221	In vitro	IC50 = 12.5 μg/AChE inhibition			6
Anti-manic activity
165	In vitro	IC50 = 12.5 mg mL−1/anti-manic activity in Drosophila			13
Anti-tussive activity
126	In vivo	88% Cough inhibition/citric acid activated Guinea pig cough model			65
		Interaction to δ-opioid receptor
250	In vivo	76% Cough inhibition/citric acid activated Guinea pig cough model			65
Anti-nociceptive activity
The alkaloidal extract of K. macrophylla	In vivo	To decrease in the number of contortion and stretching via peripheral mechanism			130
Cardiovascular and vasorelaxant activities
112	In vivo	To decrease arterial blood pressure and heart rate			131
208	In vivo	13% Relaxation occurred rat aorta ring			84
210	In vivo	24% Relaxation occurred rat aorta ring			84
211	In vivo	26% Relaxation occurred rat aorta ring			84
216	In vivo	28% Relaxation occurred rat aorta ring			84
219	In vivo	40% Relaxation occurred rat aorta ring			84
225	In vivo	41% Relaxation occurred rat aorta ring			84
227	In vivo	15% Relaxation occurred rat aorta ring			84
228	In vivo	37% Relaxation occurred rat aorta ring			84
229	In vivo	19% Relaxation occurred rat aorta ring			84
230	In vivo	19% Relaxation occurred rat aorta ring			84
239	In vivo	23% Relaxation occurred rat aorta ring			84

Cytotoxic activity

It is obvious to the view that monoterpene alkaloids are the major phytochemicals in Kopsia plants so that cytotoxic experiments using Kopsia constituents may be thought of as a big content in pharmacological development. Six alkaloidal constituents 39–40, 73, 302, 327, and 408 from K. singapurensis root were submitted to cytotoxic assay against NIH/3T3, HL-60, and HeLa cells.[49] Among them, kopsifine (73) induced the lowest CD50 value of 0.9 μg mL−1 against HL-60 cells in referencing with the positive control vincristine (CD50 1.8 μg mL−1).[49]

Kopsiafrutine E (47) possessing hydroxyl groups at carbons C-14 and C-15 demonstrated as the most bioactive compound against HS-1, HS-4, SCL-1, A-431, BGC-823, MCF-7, and W-480 with the IC50 values of 7.3–9.5 μM.[52] Meanwhile, its congeners kopsiafrutines C–D (45–46) containing a hydroxyl group at carbon C-15 have shown to associate with the respective IC50 values of 10.3–12.5 and 11.8–13.8 μM, but kopsiafrutines A–B (43–44) and kopsifoline A (76) did not inhibit cancer cell growth (IC50 > 20 μM).[52] In the same way, the following new aspidofractinines kopsiahainanins A–B (48–49) with a lactone bridge have induced the respective IC50 values of 9.4–11.7 and 12.2–15.9 μM against A-549, BGC-823, HepG-2, HL-60, MCF-7, SMMC-7721, and W-480 cells.[53] However, four new analogous kopsiahainanins C–F (50–53) accompanied by the IC50 values of >20 μM.[53]

From Table 2, new aspidofractines kopsiahainins A–E (54–58) were also further examined by cytotoxic test towards BGC-823, HepG-2, MCF-7, SGC-7901, SK-MEL-2, and SK-OV-3 cancer cells. It evidenced that compounds 56–57 demonstrated strong activity with IC50 values of ≤10 μM.[54] Similarly, in the N(4)-oxide group, new alkaloid 237 possessed the IC50 values from 7.2 to 8.9 μM to inhibit BGC-823, HepG-2, MCF-7, SGC-7901, and SK-MEL-2 cells, but new metabolites 214–215 was inactive (IC50 > 20 μM).[85]

The new metabolite kopsiaofficines C (61) showed the IC50 values of <10 μM towards cancer cell lines 95-D, A-549, ATCC, H-446, H-460, H-292, and SPCA-1, and was better than its analogs 59 (10 < IC50 ≤ 20 μM) and 60 (IC50 > 20 μM).[55] The bulk dimeric molecule arbolodinine B (333) successfully controlled the growth of HT-29, MCF-7, PC-3, KB (VJ300), MDA-MB-231, HCT-116, and A-549 with the IC50 values ranging from 1.3 to 9.6 μg mL−1, while arbolodinines A and C (1 and 334) failed to do so.[8]

Rhazinilam (409) itself displayed the potential application in cancer treatments because its strong inhibitory capacity to A-549 and HT-29 cells (IC50 0.35 μM), kopsiyunnanines A–C (402–404) indicated moderate activities (IC50 4.67–8.89 μM), but both kopsiyunnanine D (450) and (−)-quebrachamine (452) were inactive (>30 μM).[114] Novel alkaloidal arbophyllidine (463) suppressed HT-29 cell growth with the IC50 value of 6.2 μM, but the novel metabolite arbophyllinine A (453) failed to inhibit.[59] Six non-alkaloidal constituents 467–472 were also subjected to cytotoxic assay, in which their IC50 values ranged from 14.5 to 22.5 μg mL−1.[122]

Vincristine, a renowned chemotherapy medication, is usually used in combining with other drugs to treat many types of cancers.[132] In this scenario, experiments using a combination of Kopsia alkaloids and vincristine for anticancer treatments also bring out significant results. In VJ300 cells, kopsiflorine 74 (10 μg mL−1) showed reversal of multiple drug resistance (MRD) by suppressing the bound of [3H]azidopine to P-glycoprotein.[61] Alkaloidal compounds 88, 102–107, 411, 413, 417, 434, and 438 exhibited no appreciable cytotoxic activity against KB (VJ300) cells.[22,23,43,72] However, they possessed IC50 values of 0.39–38.7 μg mL−1 against KB (VJ300) cells in the presence of 0.1 μg mL−1 vincristine. Subramaniam et al. (2007) reported that kopsiloscine A (93), rhazinilam (409), especially two alkaloids rhazinal (407) and rhazinicine (408), showed inhibition to both KB, KB (VJ300), and KB (VJ300) + 0.1 μg mL−1 vincristine.[32]

Dimeric alkaloid norpleiomutine (282) exhibited cytotoxicity to PC-3, HCT-116, MCF-7, A-549, KB (VJ300), especially in terms of KB (VJ300) + 0.1 μg mL−1 vincristine, better than its analogous dimer kopsoffinol (289).[19] This can be explained by the functionality of OH group at carbon C-19. Most Kopsia mersinines seem not to be anticancer agents. However, novel compounds 366–367 and 373–375 also established the significant cytotoxicity to reserve MDR in drug-resistant KB (VJ300) with the IC50 values of 3.2–11.2 μg mL−1.[103] Valparicine (446) would be superior to the positive control vincadifformine in a cytotoxic assay against Jurkat cell growth.[10] In addition, this compound and arboloscine (437) showed positive signals to resist the growth of KB (VJ300) and KB (VJ300) + 0.1 μg mL−1 vincristine (Table 2).[10]

Anti-microbial activity

Nowadays, microbial resistance to well-known antibiotics has caused major concern about the treatment of infectious diseases. A vast amount of studies has recently been conducted to determine possible answers. Phytochemicals have been shown to exhibit antibacterial activity against sensitive and resistant infections through various approaches. To have a look at the IZ (inhibitory zone) and MIC values of Kopsia constituents (Table 2), compounds 43–47, 48–53, and 76 are not only potential anticancer molecules but also useful antimicrobial agents.[52,53] Especially, kopsiafrutine E (47) with the MIC values of 0.15–1.14 mM established a remarkable antimicrobial effect against twelve pathogenic microorganisms, including two Gram positive bacteria Staphylococcus aureus and S. epidermidis, five Gram negative bacteria Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Shigella dysenteriae, three fungi Candida albicans, C. tropicalis, and C. glabrata, and two oral pathogens Streptococcus mutans and S. viridans.[52] Likewise, compounds 48–49 showed strong antimicrobial activity with MIC values of less than 0.3 mM against seven bacteria E. cloacae, E. coli, K. pneumoniae, P. aeruginosa, S. aureus, S. dysenteriae, and S. epidermidis.[53]

In another assessment, kopsiflorine (74) and kopsihainins D–F (85–87) showed suppression towards the Gram positive bacterium Staphylococcus aureus with IZ values ranging from 9.7 to 11.2 mm, but compounds 3, 17, 73, 109, 124, 405, and 406 were inactive.[12] In an antimicrobial assay against E. coli, Erwinia carotovra, Bacillus subtilis, B. cereus, and S. aureus, two best agents N-decarbomethoxykopsamine (14) and N1-decarbomethoxy chanofruticosinic acid (206) were associated with the MIC values of 7.8–15.5 and 15.5–31.3 μg mL−1, respectively.[7] These two molecules further showed antifungal activity against Rhizoctonia solani, Penicillium italicum, Fusarium oxysporum f. sp. Cubense, and F. oxysporum f. sp. Niveum (Table 2).[7] Lastly, two eburnamines 19-hydroxy-(−)-eburnamonine (267) and phutdonginin (297) showed moderate activity against the growth of E. coli with the same MIC value of 32 μg mL−1.[21]

Anti-inflammatory activity

Inflammation is a part of the complicated biological reaction of living bodies to harmful stimuli such as irradiation, physical injury, metabolic stress, and infection.[133-135]K. officinalis constituents are such useful agents to treat autoimmune diseases due to their inhibition of human T cell proliferation and proinflammatory cytokines.[16] Indeed, K. officinalis constituents decarbomethoxykopsine (11), N(4)-methylkopsininate (170), 12-methoxychanofruticosinic acid (222), and rhazinilam (409) inhibited T cell growth with the IC50 values of 25.4, 21.6, 27.8, and 1.0 μM, respectively.[16] The best molecule 409 also responded to the arrest in the G2/M phase of the T cell cycle and caused a decrease in IL-6 and IL-17 levels in activated T cells.[16]

The secretion of cytokines IL-1β and TNF-α or PGE2 levels has mainly caused inflammatory reactions. When LPS-stimulated RAW 264.7 cells, at the concentration of 5 μg mL−1, kopsia C (219), methyl N1-decarbomethoxychanofruticosinate (225), methyl 12-methoxychanofruticosinate (228), kopsiofficines I–J (279–280), (+)-O-methyleburnamine (290), (−)-O-methylisoeburnamine (291), and leuconodine D (439) have remarkable anti-inflammatory effects on IL-1β and TNF-α, and PGE2, and comparable with positive control dexamethasone at the concentration of 10 μg mL−1.[75]

Anti-allergic and antidiabetic activities

Naturally occurring compounds have been recognized as potential antiallergic agents. In an experiment against histamine and β-hexosaminidase in RBL-2H3 cells, the IC10 values of 3.73–11.78 μg mL−1 were assigned to four alkaloids kopsilarutensinine (90), kopsinine (126), (−)-eburnamine (257), and (−)-tetrahydroalstonine (448).[66] In the same model against histamine and β-hexosaminidase in RBL-2H3 cells, in contrast to the MeOH extract of K. arborea leaves, the MeOH extracts of K. larutensis bark and root were found better than those of K. arborea bark and root (Table 2).[66,129]

For antidiabetic activity, among tested compounds for the high glucose-evoked podocyte injury inhibition, the EC50 values were orderly run as kopsinine 126 (3.0 μM) > leuconolam 405 (3.8 μM) > methyl 11,12-dimethoxychanofruticosinate 224 (10.2 μM) > 16α-hydroxy-19-oxoeburnamine 264 (12.0 μM) > reference compound astragaloside IV (15.4 μM) > 11-hydroxykopsilongine 29 (24.5 μM).[25] However, four pauciflorine derivatives 11,12-demethoxy-16-deoxypauciflorine (379) and kopsioffines A–C (384–386) failed to suppress enzyme α-glucosidase (IC50 > 50 μM).[109]

AChE inhibitory, anti-manic, anti-tussive, and anti-nociceptive activities

In Alzheimer's disease treatment based AChE inhibitory examination, kopsamine (39) has the minimum inhibitory requirement (MIR) value of 12.5 μg, as compared with that of the reference compound galanthamine (MIR 0.004 μg).[21] Meanwhile, two novel chanofruticosinates, kopsihainanines A–B (220–221), displayed weak AChE inhibitory activity with the respective IC50 values of 38.5 and 50.6 μM.[6] (−)-12-Methoxykopsinaline (165) with the IC50 value of 12.5 mg mL−1, showed anti-manic activity in Drosophila.[13]

Kopsinine 126 (70 mg kg−1, i.p.) and methyl N1-decarbomethoxychanofruticosinate 225 (250 mg kg−1, i.p.) exhibited 88 and 76% cough inhibition in the antitussive assays when citric acid activated guinea pig cough model.[65] In addition, anti-tussive effect of compound 126 was due to its interaction with δ-opioid receptors.[65]

The alkaloidal extract of K. macrophylla (400 mg kg−1, p.o.) was responsible for a decrease in the number of contortions and stretching via the peripheral mechanism in anti-nociceptive assays when acetic acid stimulated pain in mice, but it has no effect in anti-pyretic assay.[130]

Cardiovascular and vasorelaxant activities

Cardiovascular disease (CVD) refers to a group of illnesses affecting the heart and blood arteries. CVD is the largest cause of death worldwide with 17.9 million deaths (32.1%) in 2015.[136] Drug discovery for CVD started from the 18th century at least.[137] To consider Kopsia constituents for cardiovascular treatment, at doses of 0.2–10.0 mg kg−1 intravenous injection, kopsingine (112) caused decreases in arterial blood pressure and heart rate when hypertensive mice were anesthetized.[123] However, kopsaporine (42) was reasonable for blood pressure increase, and kopsidine A (67) with the deletion of the methoxy group did not alter the responsible hypotension.[123]

Vasodilators can be used for cerebral vasospasm and hypertension treatments, as well as to enhance peripheral circulation.[138,139] Flavisiamines A, C, and D (208 and 210–211), kopreasin A (216), methyl 11,12-methylenedioxychanofruticosinate (219), methyl N1-decarbomethoxychanofruticosinate (225), methyl 12-methoxy-N1-decarbomethoxychanofruticosinate (227), methyl 12-methoxychanofruticosinate (228), methyl 11,12-methylenedioxy-N1-decarbomethoxychanofruticosinate (229), methyl 11,12-methylenedioxy-N1-decarbomethoxy-Δ14,15-chanofruticosinate (230), and prunifoline B (239) at the concentration of 3 × 10−5 M showed a moderate vasorelaxant effect of 14–41% when phenylephrine (3 × 10−7 M) precontracted rat aortic rings.[84]

Conclusion and future perspectives

To a certain extent, our comprehensive review establishes a panel of useful information on phytochemistry and pharmacology of the genus Kopsia. Since the 1950s, about nineteen Kopsia plants were used in phytochemical investigations, and more than four hundred seventy secondary metabolites have been isolated. Among 472 isolated compounds, monoterpene alkaloids (466 compounds) accounted for 98.73%. Kopsia monoterpene alkaloids have been fallen into about 30 structural skeletons, but aspidofractinines (204 compounds), eburnamines (48 compounds), and chanofruticosinates (37 compounds) predominated over. Various compounds were isolated from Kopsia plants for the first time. Many chemical classes of isolated compounds, such as mersinines and pauciflorines, can be seen as newly alkaloidal classes and were useful for chemotaxonomy. Some metabolites, such as kopsamine (39), kopsinine (126), (−)-eburnamine (257), (+)-isoeburnamine (274), rhazinilam (409), and (−)-tetrahydroalstonine (448), are characteristic metabolites of genus Kopsia. It also evidenced that Kopsia plant extracts and isolated compounds have induced a variety of pharmacological results, e.g., antimicrobial, anti-inflammatory, anti-diabetic, cardiovascular, vasorelaxant activities, especially cytotoxicity. With the great cytotoxic values, monoterpene alkaloids derived from Kopsia plants are promising anticancer agents in drug development programmes. However, studies on in vivo apoptotic mechanism, bioavailability, and metabolic approaches seem not available. To this end, no research was carried out to determine toxic effects of Kopsia plant extracts and their constituents. Therefore, it is necessary to deal with the extensive clinical studies to confirm the effects of Kopsia constituents on humans.

This review will be especially useful in offering fundamental insights into the medicinal usefulness of Kopsia plants. Furthermore, this evaluation can be used as a reference for clinical medication, long-term development, and plant consumption.

High performance liquid chromatography

Mass spectrum

Column chromatography

Half-maximal inhibitory concentration

Inhibitory zone

Multidrug resistance

Minimum inhibitory requirement

Minimum inhibitory concentration

lipopolysaccharide

Acetylcholinesterase

Normal mouse fibroblast cells

Human promyelocytic cells

Human cervical cancer cells

Dermatoma cells

Human gastric carcinoma cells

Human breast cancer cells

Colon cancer cells

Human hepatocellular carcinoma cells; SMMC-7721 cells

Human gastric adenocarcinoma cells

Human skin cancer cells

Ovarian cancer cells

Lung cancer cells

Colorectal cancer cells

Human prostate cancer cells

Human T lymphocyte cells

Epidermoid carcinoma cells

Conflicts of interest

The authors declare no conflict of interest, financial or otherwise.