Chemical Constituents from Croton Species and Their Biological Activities.

The genus Croton belongs to the Euphorbiaceae family, which comprises approximately 1300 species. Many Croton species have been used as folk medicines. This review focuses on the chemical constituents from Croton species and their relevant biological activities, covering the period from 2006 to 2018. A total of 399 new compounds, including 339 diterpenoids, were reported. Diterpenoids are characteristic components of the Croton species. These isolated compounds exhibited a broad spectrum of bioactivities, including cytotoxic, anti-inflammatory, antifungal, acetylcholinesterase inhibitory, and neurite outgrowth-promoting properties. The present review provides a significant clue for further research of the chemical constituents from the Croton species as potential medicines.

1. Introduction

The genus Croton belongs to the Euphorbiaceae family, and contains approximately 1300 species of trees, shrubs, and herbs, which are widely distributed throughout tropical and subtropical regions of the world. Many Croton species have been used as folk medicines in Africa, south Asia, and south America, for the treatment of many diseases such as stomachache, abscesses, inflammation, and malaria [1,2,3]. The seeds of C. tiglium, which are well-known as “badou”, had been utilized as a traditional Chinese medicine to treat gastrointestinal disorders, intestinal inflammation, and rheumatism. The roots of C. crassifolius, known as “jiguxiang” in China, are mainly used as a traditional medicine for the treatment of stomachache and sore throat [3]. The genus Croton is abundant in diverse diterpenoids, including clerodane, tigliane, kaurane, labdane, cembrane, and pimarane, with a wide range of biological activities, such as cytotoxic, anti-inflammatory, and anti-microbial [1,2,3,4,5]. Due to their great structural diversity and broad relevant bioactivities, Croton species have attracted increasing research attention. Several authors have provided reviews about the chemical constituents and biological activities of Croton species. A review came out in 2006 regarding clerodane diterpenes isolated from Croton species, their 13C-NMR spectroscopic data, and biological activities [2]. In 2007, a comprehensive review on the traditional uses, chemistry, and pharmacology of Croton species was published [1]. In 2013, anticancer and antioxidant activities of extracts and pure compounds from several Croton species were reviewed [4]. Five review articles were published in recent years which focused on ethnopharmacological uses, phytochemistry, and pharmacology of a single Croton species [6,7,8,9,10]. In the last decade, there has been a dramatic progress in the chemical constituents and relevant biological activities of Croton species. However, so far, no comprehensive review has been published since 2007. In the present review, we summarize systematically the research advances on the new chemical constituents and their biological activities of Croton species reported in the literature, as found on Web of Science, Google Scholar, PubMed, and SciFinder, from 2006 to March 2018, with the aim of providing a basis for further research of natural product drug discovery.

2. Chemical Constituents

To date, 399 new compounds have been isolated and identified from Croton species, including 339 diterpenoids (1–339), seven sesquiterpenoids (340–346), one sesterterpenoid (347), one triterpenoid (348), 21 glycosides (349–369), eight alkaloids (370–377), three benzoate derivatives (378–380), three pyran-2-one derivatives (381–383), two cyclopeptide (384, 385), two tropone derivatives (386, 387), two limonoids (388, 389), and ten miscellaneous compounds (390–399). Their structures, molecular formula, names, corresponding sources, and references are summarized in Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9, Figure 10, Figure 11, Figure 12 and Figure 13 and Table 1, Table 2, Table 3, Table 4, Table 5, Table 6, Table 7, Table 8, Table 9, Table 10, Table 11, Table 12, Table 13, Table 14, Table 15, Table 16, Table 17, Table 18, Table 19, Table 20, Table 21, Table 22, Table 23, Table 24, Table 25, Table 26 and Table 27.

Figure 1

Clerodane type diterpenoids from the genus Croton.

Figure 2

Tigliane type diterpenoids from the genus Croton.

Figure 3

Kaurane type diterpenoids from the genus Croton 1.

Figure 4

Crotofolane type diterpenoids from the genus Croton.

Figure 5

Labdane type diterpenoids from the genus Croton.

Figure 6

Cembrane type diterpenoids from the genus Croton.

Figure 7

Abietane type diterpenoids from the genus Croton.

Figure 8

Casbane, Halimane, Pimarane and Cleistanthane type diterpenoids from the genus Croton.

Figure 9

Grayanane, Atisane, Phytane, Laevinane type diterpenoids and Meroditerpenoids from the genus Croton.

Figure 10

Sesquiterpenoids, Sesterterpenoid and Triterpenoid from the genus Croton.

Figure 11

Glycosides from the genus Croton.

Figure 12

Alkaloids from the genus Croton.

Figure 13

Miscellaneous compounds from the genus Croton.

Table 1

Clerodane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
1	ent-3,13E-clerodadiene-15-formate	C21H34O2	C. sylvaticus	[12]
2	9-[2-(2(5H)-furanone-4-yl)ethyl]-4,8,9-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-4-carboxylic acid	C20H28O4	C. crassifolius	[14]
3	9-[2-(2(5H)-furanone-4-yl)ethyl]-4,8,9-trimethyl-1,2,3,4,5,6,7,8-octahydronaphthalene-4-carboxylic ester	C21H30O4	C. crassifolius	[14]
4	Centrafricine I	C21H24O6	C. mayumbensis	[19]
5	Marrubiagenin	C20H28O4	C. glabellus	[15]
6	Methyl 15,16-epoxy-3,13(16),14-ent-clerodatrien-18,19-olide-17-carboxylate	C21H26O5	C. oblongifolius	[29]
7	Dimethyl 15,16-epoxy-12-oxo-3,13(16),14-ent-clerodatriene-17,18-dicarboxylate	C22H28O6	C. oblongifolius	[29]
8	Isoteucvin	C19H20O5	C. jatrophoides	[30]
9	Jatrophoidin	C21H22O7	C. jatrophoides	[30]
10	8-Epicordatin	C21H26O6	C. palanostigma	[31]
11	laevigatbenzoate	C27H31O5	C. laevigatus	[13]
12	3,4,15,16-diepoxy-cleroda-13(16),14-diene-12,17-olide	C20H26O4	C. oblongifolius	[22]
13	Crassifolin A	C21H30O4	C. crassifolius	[16]
14	Crassifolin B	C20H29O4	C. crassifolius	[16]
15	Crassifolin C	C21H24O5	C. crassifolius	[16]
16	Crassifolin D	C21H24O6	C. crassifolius	[16]
17	Crassifolin E	C20H23O6	C. crassifolius	[16]
18	Crassifolin F	C23H29O7	C. crassifolius	[16]
19	Crassifolin G	C19H20O6	C. crassifolius	[16]
20	Methyl 3-oxo-12-epibarbascoate	C21H26O6	C. urucurana	[32]
21	Laevinoids A	C20H22O5	C. laevigatus	[20]
22	Laevinoids B	C20H23O5Cl	C. laevigatus	[20]
23	Crotonolide A	C20H18O6	C. laui	[21]
24	Crotonolide B	C21H24O6	C. laui	[21]
25	Isocrotonolide B	C21H24O6	C. laui	[21]
26	Crotonolide C	C23H26O8	C. laui	[21]
27	Isocrotonolide C	C23H26O8	C. laui	[21]
28	Crotonolide D	C21H26O6	C. laui	[21]
29	Isocrotonolide D	C21H26O6	C. laui	[21]
30	Crotonolide E	C20H26O4	C. laui	[21]
31	Crotonolide F	C20H26O4	C. laui	[21]
32	Crotonolide G	C20H32O	C. laui	[21]
33	Crotonolide H	C20H32O4	C. laui	[21]
34	12-Deoxycrotonolide H	C20H32O3	C. laui	[21]
35	Crotonoligaketone	C23H26O8	C. oligandrum	[33]
36	Crotonpene A	C20H26O3	C. yanhuii	[23]
37	Crotonpene B	C21H28O5	C. yanhuii	[23]
38	Crassifolin I	C20H22O6	C. crassifolius	[34]
39	Crassifolin H	C19H20O5	C. crassifolius	[34]
40	Crotoeurin A	C38H36O1	C. euryphyllus	[25]
41	Crotoeurin B	C20H24O6	C. euryphyllus	[25]
42	Crotoeurin C	C20H22O6	C. euryphyllus	[25]
43	3-Oxo-15,16-epoxy-4α,12-dihydroxy-ent-neo-clerodan-13(16),14-diene	C20H30O4	C. limae	[35]
44	15,16-Epoxy-3α,4α,12-trihydroxy-ent-neo-clerodan- 13(16),14-diene	C20H32O4	C. limae	[35]
45	3α,4α,15,16-Tetrahydroxy-ent-neo-cleroda-13E-ene	C20H36O4	C. limae	[35]
46	Cracroson A	C19H21O6	C. crassifolius	[26]
47	Cracroson B	C20H22O6	C. crassifolius	[26]
48	Cracroson C	C19H19O4N	C. crassifolius	[26]
49	Crassifolin J	C20H20O5	C. crassifolius	[36]
60	Crotocorylifuran-2-one	C22H24O8	C.megalocarpoides	[27]
61	Megalocarpoidolide D	C22H22O8	C.megalocarpoides	[27]
62	7,8-Dehydrocrotocorylifuran	C22H24O7	C.megalocarpoides	[27]
63	Megalocarpoidolide E	C22H24O8	C.megalocarpoides	[27]
64	Megalocarpoidolide F	C22H24O8	C.megalocarpoides	[27]
65	Megalocarpoidolide G	C22H24O9	C.megalocarpoides	[27]
66	Megalocarpoidolide H	C24H28O10	C.megalocarpoides	[27]
67	Launine K	C27H36O3	C. laui	[37]
68	Crassin A	C17H20O4	C. crassifolius	[17]
69	Crassin B	C17H20O4	C. crassifolius	[17]
70	Crassin C	C21H24O6	C. crassifolius	[17]
71	Crassin D	C20H20O5	C. crassifolius	[17]
72	Crassin E	C19H20O3	C. crassifolius	[17]
73	Crassin F	C19H18O7	C. crassifolius	[17]
74	Crassin G	C20H26O5	C. crassifolius	[17]
75	Crassin H	C21H30O5	C. crassifolius	[17]
76	Crassifolius A	C20H22O5	C. crassifolius	[38]
77	Crassifolius B	C21H24O6	C. crassifolius	[38]
78	Crassifolius C	C21H26O5	C. crassifolius	[38]
79	Crolaevinoid C	C27H28O6	C. laevigatus	[39]
80	Crolaevinoid D	C27H32O8	C. laevigatus	[39]
81	Crolaevinoid E	C20H28O6	C. laevigatus	[39]
82	Crolaevinoid F	C21H30O5	C. laevigatus	[39]
83	Norcrassifolin	C19H18O4	C. crassifolius	[28]
84	Hypolein A	C20H26O4	C. hypoleucus	[24]
85	Hypolein B	C20H28O3	C. hypoleucus	[24]
86	Hypolein C	C20H28O3	C. hypoleucus	[24]
87	Cracroson E	C19H20O6	C. crassifolius	[40]
88	Cracroson F	C19H20O6	C. crassifolius	[40]
89	Cracroson G	C21H26O7	C. crassifolius	[40]
90	12-Epi-megalocarpoidolide D	C22H22O8	C. oligandrus	[18]
91	Crotonolins A	C22H22O10	C. oligandrus	[18]
92	Crotonolins B	C22H22O10	C. oligandrus	[18]

Table 2

Tigliane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
93	12-O-isobutyrylphorbol-13-decanoate	C34H52O8	C. tiglium	[45]
94	12-O-(2-methyl)butyrylphorbol-13-octanoate	C33H50O8	C. tiglium	[45]
95	12-O-[(2R)-N,N-dimethyl-3-methylbutanoyl]-4-deoxyphorbol 13-acetate	C29H43NO7	C. ciliatoglandulifer	[41]
96	12-O-[(2S)-N,N-dimethyl-3-methylbutanoyl]-4-deoxyphorbol 13-acetate	C29H43NO7	C. ciliatoglandulifer	[41]
97	12-O-[(2R)-N,N-Dimethyl-3-methylbutanoyl]phorbol 13-acetate	C29H43NO8	C. ciliatoglandulifer	[41]
98	12-O-[3-Methyl-2-butenoyl]-4-deoxyphorbol 13-acetate	C27H36NO7	C. ciliatoglandulifer	[41]
99	12-O-(2-methyl)butyrylphorbol-13-tiglate	C30H42O8	C. tiglium	[46]
100	12-O-tiglylphorbol-13-propionate	C28H38O8	C. tiglium	[46]
101	13-O-acetylphorbol-20-oleate	C40H62O8	C. tiglium	[46]
106	12-O-tiglyl-4-deoxy-4α-phorbol-13-(2-methyl)butyrate	C30H42O7	C. tiglium	[46]
107	Alienusolin	C42H66O8	C. alienus	[42]
108	12-O-acetyl-5,6-didehydro-7-oxophorbol-13-yl 2-methylbutanoate	C27H36O9	C. tiglium	[47]
109	12-O-acetyl-5,6-didehydro-7-oxophorbol-13-yl2-methylpropanoate	C26H34O9	C. tiglium	[47]
110	12-Oacetyl-5,6-didehydro-6,7-dihydro-7-hydroxyphorbol-13-yl 2-methylbutanoate	C27H38O9	C. tiglium	[47]
111	12-O-decanoyl-7-hydroperoxy-phorbol-5-ene-13-acetate	C32H42O10	C. mauritianus	[43]
112	20-deoxy-20-oxophorbol12-tiglate 13-(2-methyl)butyrate	C30H40O8	C. tiglium	[48]
113	12-O-acetylphorbol-13-isobutyrate	C26H36O8	C. tiglium	[48]
114	12-O-benzoylphorbol-13-(2-methyl)butyrate	C32H40O8	C. tiglium	[48]
115	12-O-tiglyl-7-oxo-5-ene-phorbol-13-(2-methyl)butyrate	C30H40O9	C. tiglium	[48]
116	13-O-(2-metyl)butyryl-4-deoxy-4a-phorbol	C25H36O6	C. tiglium	[48]
117	Crotignoid A	C30H42O10	C. tiglium	[49]
118	Crotignoid B	C29H40O10	C. tiglium	[49]
119	Crotignoid C	C30H42O9	C. tiglium	[49]
120	Crotignoid D	C29H40O9	C. tiglium	[49]
121	Crotignoid E	C29H38O9	C. tiglium	[49]
122	Crotignoid F	C28H36O9	C. tiglium	[49]
123	Crotignoid G	C30H44O8	C. tiglium	[49]
124	Crotignoid H	C29H38O8	C. tiglium	[49]
125	Crotignoid I	C30H44O8	C. tiglium	[49]
126	Crotignoid J	C31H38O8	C. tiglium	[49]
127	Crotignoid K	C29H34O7	C. tiglium	[49]
128	Crotusin A	C36H54O10	C. caudatus	[44]
129	Crotusin B	C46H72O11	C. caudatus	[44]
130	Crotusin C	C36H52O11	C. caudatus	[44]
131	12-O-tiglylphorbol-4-deoxy- 4β-phorbol-13-acetate	C27H36O7	C. tiglium	[50]
132	12-O-tiglylphorbol-4-deoxy-4β-phorbol-13-hexadecanoate	C41H64O7	C. tiglium	[50]
133	13-O-acetylphorbol-4-deoxy-4β-phorbol-20-oleate	C40H62O7	C. tiglium	[50]
134	13-O-acetylphorbol-4-deoxy-4β-phorbol-20-linoleate	C40H60O7	C. tiglium	[50]
135	4-deoxy-20-oxophorbol 12-tiglyl 13-acetate	C27H34O7	C. tiglium	[51]
136	7-oxo-5-ene-phorbol-13-(2-methylbutyrate)	C25H34O8	C. tiglium	[51]
137	7-hydroxyl-phorbol-5-ene-13-(2-methyl)butyrate	C25H36O8	C. tiglium	[51]

Table 3

Kaurane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
149	Caracasine	C21H30O3	C. caracasana	[53]
150	Caracasine acid	C20H28O3	C. caracasana	[53]
151	Kongensin A	C22H30O5	C. kongensis	[56]
152	Kongensin B	C22H30O6	C. kongensis	[56]
153	Kongensin C	C20H28O5	C. kongensis	[56]
154	Kongensin D	C20H28O4	C. kongensis	[57]
155	Kongensin E	C26H36O7	C. kongensis	[57]
156	Kongensin F	C24H34O5	C. kongensis	[58]
157	Crotonkinin A	C20H30O2	C. tonkinensis	[62]
158	Crotonkinin B	C22H32O4	C. tonkinensis	[62]
159	14-epi-hyalic acid	C20H28O4	C. argyrophylloides	[63]
160	14-[(2-methylbutanoyl)oxy]-3,4-seco-ent-kaura-4(19),16-dien-3-oic acid	C25H39O4	C. megistocarpus	[54]
161	14-{[(2Z)-2-methylbut-2-enoyl]oxy}-3,4-seco-ent-kaura-4(19),16-dien-3-oic acid	C25H37O4	C. megistocarpus	[54]
162	ent-11β-acetoxykaur-16-en-18-ol	C22H34O3	C. tonkinensis	[64]
163	ent-11α-hydroxy-18-acetoxykaur-16-ene	C22H34O3	C. tonkinensis	[64]
164	ent-14β-hydroxy-18-acetoxykaur-16-ene	C22H34O3	C. tonkinensis	[64]
165	ent-7α-hydroxy-18-acetoxykaur-16-ene	C22H34O3	C. tonkinensis	[64]
166	ent-14S*-hydroxykaur-16-en-19-oic acid	C20H30O3	C. pseudopulchellus	[65]
167	ent-14S*,17-dihydroxykaur-15-en-19-oic acid	C20H30O4	C. pseudopulchellus	[65]
168	ent-3,4-seco-17-oxo-kaur-4(19),15(16)-dien-3-oic acid	C20H28O3	C. oblongifolius	[55]
169	Crotonkinin C	C22H30O5	C. tonkinensis	[66]
170	Crotonkinin D	C24H34O6	C. tonkinensis	[66]
171	Crotonkinin E	C24H34O5	C. tonkinensis	[66]
172	Crotonkinin F	C24H34O5	C. tonkinensis	[66]
173	Crotonkinin G	C23H36O5	C. tonkinensis	[66]
174	Crotonkinin H	C22H36O4	C. tonkinensis	[66]
175	Crotonkinin I	C24H36O5	C. tonkinensis	[66]
176	Crotonkinin J	C23H34O5	C. tonkinensis	[66]
177	14β-hydroxy-3-oxo-ent-kaur-16-ene	C20H30O2	C. kongensis	[67]
178	Kongeniod A	C21H30O3	C. kongensis	[59]
179	Kongeniod B	C21H30O4	C. kongensis	[59]
180	Kongeniod C	C23H32O5	C. kongensis	[59]
181	15-oxo-17(10′-α-pinenyl)-kauran-18-oic acid	C30H44O3	C. limae	[35]
182	Micansinoic acid	C40H58O7	C. micans	[60]
183	Isomicansinoic acid	C40H58O7	C. micans	[60]
184	Dimethylester of micansinoic	C42H62O7	C. micans	[60]
185	Methyl-micansinoic acid	C41H60O7	C. micans	[60]
186	Ethyl-micansinoic acid	C42H62O7	C. micans	[60]
187	Crotonkinensin C	C40H62O8	C. tonkinensis	[61]
188	Crotonkinensin D	C44H66O10	C. tonkinensis	[61]

Table 4

Crotofolane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
189	Crotocascarin A	C25H32O7	C. cascarilloides	[68]
190	Crotocascarin B	C25H32O7	C. cascarilloides	[68]
191	Crotocascarin C	C25H32O8	C. cascarilloides	[68]
192	Crotocascarin D	C25H32O6	C. cascarilloides	[68]
193	Crotocascarin E	C26H34O8	C. cascarilloides	[68]
194	Crotocascarin F	C24H30O7	C. cascarilloides	[68]
195	Crotocascarin G	C24H30O7	C. cascarilloides	[68]
196	Crotocascarin H	C24H30O8	C. cascarilloides	[68]
197	Crotocascarin α	C24H32O8	C. cascarilloides	[68]
198	Crotocascarin β	C24H32O7	C. cascarilloides	[68]
199	(5β,6β)-5,6: 13,16-diepoxycrotofola-4(9),10(18),13,15-tetraen-1-one	C20H22O3	C. argyrophyllus	[72]
200	(5β,6β)-5,6: 13,16-diepoxy-2-epicrotofola-4(9),10(18),13,15-tetraen-1-one	C20H22O3	C. argyrophyllus	[72]
201	(5β,6β)-5,6: 13,16-diepoxy-16-hydroxycrotofola-4(9),10(18),13,15-tetraen-1-one	C20H22O4	C. argyrophyllus	[72]
202	(5β,6β)-5,6: 13,16-diepoxy-16-hydroxy-2-epi-crotofola-4(9),10(18),13,15-tetraen-1-one	C20H22O4	C. argyrophyllus	[72]
203	Crotocarasin A	C20H22O4	C. caracasanus	[73]
204	Crotocarasin B	C20H22O4	C. caracasanus	[73]
205	Crotocarasin C	C22H26O5	C. caracasanus	[73]
206	Crotocarasin D	C22H26O5	C. caracasanus	[73]
207	EBC-162	C20H24O2	C. insularis	[74]
208	EBC-233	C20H24O4	C. insularis	[74]
209	EBC-300	C20H24O4	C. insularis	[74]
210	EBC-240	C20H26O5	C. insularis	[74]
211	EBC-241	C20H26O5	C. insularis	[74]
212	Crotocascarin I	C20H24O5	C. cascarilloides	[69]
213	Crotocascarin J	C20H24O6	C. cascarilloides	[69]
214	Crotocascarin K	C20H24O5	C. cascarilloides	[69]
215	Crotocascarin γ	C19H24O6	C. cascarilloides	[69]
216	Crotocascarin L	C22H26O7	C. cascarilloides	[70]
217	Crotocascarin M	C21H26O6	C. cascarilloides	[70]
218	Crotocascarin N	C20H22O6	C. cascarilloides	[70]
219	Crotocascarin O	C25H34O9	C. cascarilloides	[70]
220	Crotocascarin P	C25H34O8	C. cascarilloides	[70]
221	Crotocascarin Q	C25H32O7	C. cascarilloides	[70]
222	Neocrotocascarin	C25H32O8	C. cascarilloides	[70]
223	Crotodichogamoin A	C20H22O4	C. dichogamus	[75]
224	Crotodichogamoin B	C20H22O2	C. dichogamus	[75]
225	Cascarinoid A	C28H31NO5	C. cascarilloides	[71]
226	Cascarinoid B	C28H31NO5	C. cascarilloides	[71]
227	Cascarinoid C	C28H31NO6	C. cascarilloides	[71]

Table 5

Labdane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
228	Labdinine N	C20H34O3	C. laui	[76]
229	ent-12,15-dioxo-3,4-seco-4,8,13-labdatrien-3-oic acid	C20H28O4	C. stipuliformis	[78]
230	ent-12,15-epoxy-3,4-seco-4,8,12,14-labdatetraen-3-oic acid	C20H28O3	C. stipuliformis	[78]
231	ent-15-nor-14-oxo-3,4-seco-4,8,12(E)-labdatrien-3-oic acid	C19H28O3	C. stipuliformis	[78]
232	ent-12,15-dioxo-8,13-labdadien-3a-ol	C20H28O3	C. stipuliformis	[78]
233	Crotonlaevin A	C18H30O4	C. laevigatus	[79]
234	Crotonlaevin B	C20H32O5	C. laevigatus	[79]
235	Crotonlaevin C	C21H34O5	C. laevigatus	[79]
236	Crotonlaevin D	C18H30O3	C. laevigatus	[79]
237	Crotonlaevin E	C20H32O5	C. laevigatus	[79]
238	Crotonlaevin F	C22H34O6	C. laevigatus	[79]
239	Crotonlaevin G	C22H36O5	C. laevigatus	[79]
240	Crotonlaevin H	C22H36O5	C. laevigatus	[79]
241	Crotonlaevin I	C20H34O4	C. laevigatus	[79]
242	Crotonlaevin J	C20H30O3	C. laevigatus	[79]
243	Crotonlaevin K	C20H28O3	C. laevigatus	[79]
244	Crotonlaevin L	C20H30O4	C. laevigatus	[79]
245	Crotonlaevin M	C20H30O4	C. laevigatus	[79]
246	Crotonlaevin N	C20H30O3	C. laevigatus	[79]
247	Crotonlaevin O	C20H30O3	C. laevigatus	[79]
248	Crotonlaevin P	C20H30O3	C. laevigatus	[79]
249	Crotonolide I	C20H34O3	C. laui	[21]
250	Crotonolide J	C19H30O3	C. laui	[21]
251	Launine A	C19H32O3	C. laui	[82]
252	Launine B	C19H32O4	C. laui	[82]
253	Launine C	C20H34O3	C. laui	[82]
254	Launine D	C20H34O3	C. laui	[82]
255	Launine E	C20H32O5	C. laui	[82]
256	Launine F	C20H32O5	C. laui	[82]
257	Launine G	C20H30O4	C. laui	[82]
258	Launine H	C20H30O4	C. laui	[82]
259	Launine I	C20H34O3	C. laui	[82]
260	15,16-epoxy-4-hydroxy-labda-13(16),14-dien-3,12-dione	C20H28O4	C. jacobinensis	[77]
261	Crotondecalvatin A	C29H42O4	C. decalvatus	[80]
262	Crotondecalvatin B	C30H42O6	C. decalvatus	[80]
263	Bicrotonol A	C40H68O4	C. crassifolius	[81]

Table 6

Cembrane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
264	Launine O	C20H34O2	C. laui	[76]
265	Launine P	C21H36O2	C. laui	[76]
266	Furanocembranoid 1	C20H30O2	C. oblongifolius	[83]
267	Furanocembranoid 2	C20H30O3	C. oblongifolius	[83]
268	Furanocembranoid 3	C20H32O4	C. oblongifolius	[83]
269	Furanocembranoid 4	C20H32O5	C. oblongifolius	[83]
270	Laevigatlactone A	C20H30O3	C. laeVigatus	[84]
271	Laevigatlactone C	C20H30O3	C. laeVigatus	[84]
272	Laevigatlactone B	C20H30O3	C. laeVigatus	[84]
273	Laevigatlactone D	C20H30O3	C. laeVigatus	[84]
274	Laevigatlactone E	C20H30O4	C. laeVigatus	[84]
275	Laevigatlactone F	C20H30O5	C. laeVigatus	[84]
276	(+)-[1R*,2S*,7S*,8S*,12R*]-7,8-Epoxy-2,12-cyclocembra-3E,10Zdien-20,10-olide	C20H28O3	C. gratissimus	[85]
277	(+)-[1R*,10R*]-Cembra-2E,4E,7E,11Z-tetraen-20,10-olide	C20H28O2	C. gratissimus	[85]
278	(+)-[1R*,4S*,10R*]-4-Hydroxycembra-2E,7E,11Z-trien-20,10-olide	C20H30O3	C. gratissimus	[85]
279	(−)-[1R*,4R*,10R*]-4-Hydroxycembra-2E,7E,11Z-trien-20,10-olide	C20H30O3	C. gratissimus	[85]
280	(−)-(1R*,4R*,10R*)-4-Methoxycembra-2E,7E,11Z-trien-20,10-olide	C21H32O3	C. gratissimus	[86]
281	(−)-(1S*,4R*,10R*)-1-Hydroxy-4-methoxycembra-2E,7E,11Ztrien-20,10-olide	C21H32O4	C. gratissimus	[86]
282	(−)-(1S*,4S*,10R*)-1,4-Dihydroxycembra-2E,7E,11Z-trien-20,10-olide	C20H30O4	C. gratissimus	[86]
283	(−)-(1S*,4S*,10R*)-1,4-Dihydroxycembra-2E,7E,11Z-trien-20,10-olide	C20H30O4	C. gratissimus	[86]
284	(+)-(10R*)-Cembra-1E,3E,7E,11Z,16-pentaen-20,10-olide	C20H26O	C. gratissimus	[86]
285	(+)-(10R*)-Cembra-1Z,3Z,7E,11Z,15-pentaen-20,10-olide	C20H26O	C. gratissimus	[86]
286	(+)-(5R*,10R*)-5-Methoxycembra-1E,3E,7E,11Z,15-pentaen-20,10-olide	C21H30O3	C. gratissimus	[86]
287	(+)-(1S*,4S*,7R*,10R*)-1,4,7-Trihydroxycembra-2E,8(19),11Z-trien-20,10-olide	C20H30O5	C. gratissimus	[86]
288	(−)-(1S*,4S*,7S*,10R*)-1,4,7-Trihydroxycembra-2E,8(19),11Z-trien-20,10-olide	C20H30O3	C. gratissimus	[86]
289	(+)-(1S*,4R*,8S*,10R*)-1,4,8-Trihydroxycembra-2E,6E,11Z-trien-20,10-olide	C20H30O5	C. gratissimus	[86]
290	Cembranoid 1	C20H30O4	C. longissimus	[87]
291	Cembranoid 2	C20H30O3	C. longissimus	[87]
281	(−)-(1S*,4R*,10R*)-1-Hydroxy-4-methoxycembra-2E,7E,11Ztrien-20,10-olide	C21H32O4	C. gratissimus	[86]
282	(−)-(1S*,4S*,10R*)-1,4-Dihydroxycembra-2E,7E,11Z-trien-20,10-olide	C20H30O4	C. gratissimus	[86]
283	(−)-(1S*,4S*,10R*)-1,4-Dihydroxycembra-2E,7E,11Z-trien-20,10-olide	C20H30O4	C. gratissimus	[86]
284	(+)-(10R*)-Cembra-1E,3E,7E,11Z,16-pentaen-20,10-olide	C20H26O	C. gratissimus	[86]
285	(+)-(10R*)-Cembra-1Z,3Z,7E,11Z,15-pentaen-20,10-olide	C20H26O	C. gratissimus	[86]
286	(+)-(5R*,10R*)-5-Methoxycembra-1E,3E,7E,11Z,15-pentaen-20,10-olide	C21H30O3	C. gratissimus	[86]
287	(+)-(1S*,4S*,7R*,10R*)-1,4,7-Trihydroxycembra-2E,8(19),11Z-trien-20,10-olide	C20H30O5	C. gratissimus	[86]
288	(−)-(1S*,4S*,7S*,10R*)-1,4,7-Trihydroxycembra-2E,8(19),11Z-trien-20,10-olide	C20H30O3	C. gratissimus	[86]
289	(+)-(1S*,4R*,8S*,10R*)-1,4,8-Trihydroxycembra-2E,6E,11Z-trien-20,10-olide	C20H30O5	C. gratissimus	[86]
290	Cembranoid 1	C20H30O4	C. longissimus	[87]
291	Cembranoid 2	C20H30O3	C. longissimus	[87]

Table 7

Abietane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
292	Isolophanthin E	C20H30O3	C. megalocarpoides	[27]
293	rel-(1R,4aR,5R,8R)-methyl-7-(1-(methoxycarbonyl)vinyl)-5,8-diacetoxy-1,2,3,4a,5,6,7,8,9,10,10a-dodecahydro-1,4a-dimethyl-2-oxophenanthrene-1-carboxylate	C26H34O9	C. argyrophylloides	[63]
294	Crotontomentosin A	C20H26O2	C. caudatus	[88]
295	Crotontomentosin B	C20H30O3	C. caudatus	[88]
296	Crotontomentosin D	C20H24O2	C. caudatus	[88]
297	Crotontomentosin C	C20H28O2	C. caudatus	[88]
298	Crotontomentosin E	C22H32O3	C. caudatus	[88]
299	Crotolaevigatone A	C20H24O3	C. laevigatus	[89]
300	Crotolaevigatone B	C20H26O2	C. laevigatus	[89]
301	Crotolaevigatone C	C20H26O3	C. laevigatus	[89]
302	Crotolaevigatone D	C20H28O4	C. laevigatus	[89]
303	Crotolaevigatone E	C19H24O2	C. laevigatus	[89]
304	Crotolaevigatone F	C20H30O4	C. laevigatus	[89]
305	Crotolaevigatone G	C20H30O4	C. laevigatus	[89]

Table 8

Casbane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
306	1,4-dihydroxy-2E,6E,12E-trien-5-one-casbane	C20H30O3	C. nepetaefolius	[90]
307	4-hydroxy-2E,6E,12E-5-one-casbane	C20H29O3	C. nepetaefolius	[90]
308	1-hydroxy-(2E,6Z,12E)-casba-2,6,12-triene-4,5-dione	C20H28O3	C. argyrophyllus	[91]
309	6E,12E-casba-1,3,6,12-tetraen-1,4-epoxy-5-one	C20H26O2	C. argyrophyllus	[91]
310	(2E,5β,6E,12E)-5-hydroxycasba-2,6,12-trien-4-one	C20H30O2	C. argyrophyllus	[72]
311	EBC-324	C20H28O5	C. insularis	[92]
312	EBC-329	C20H26O4	C. insularis	[92]

Table 9

Halimane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
313	Crassifoliusin A	C21H24O5	C. crassifolius	[95]
314	Crotontomentosin F	C21H30O3	C. caudatus	[88]
315	Crolaevinoid A	C27H30O7	C. laevigatus	[39]
316	Crolaevinoid B	C20H26O4	C. laevigatus	[39]
317	Crothalimene A	C20H26O4	C. dichogamus	[75]
318	Crothalimene B	C20H30O2	C. dichogamus	[75]

Table 10

Pimarane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
319	ent-3β-hydroxypimara-8(14),9,15-trien-12-one	C20H28O2	C. insularis	[98]
320	EBC-316	C20H26O2	C. insularis	[99]
321	EBC-325	C20H26O4	C. insularis	[99]
322	EBC-326	C20H26O4	C. insularis	[99]
323	EBC-327	C20H24O3	C. insularis	[99]
324	EBC-345	C20H30O4	C. insularis	[99]

Table 11

Cleistanthane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
325	3-hydroxycleistantha-13(17),15-diene	C20H32O	C. oblongifolius	[93]
326	3,4-seco-cleistantha-4(18),13(17),15-trien-3-oic acid	C20H30O2	C. oblongifolius	[93]
327	rel-(5β,8α,10α)-8-hydroxy-13-methylpodocarpa-9(11),13-diene-3,12-dione	C18H25O3	C. regelianus	[94]

Table 12

Grayanane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
328	Crotonkinensin A	C20H24O4	C. tonkinensis	[100]
329	Crotonkinensin B	C20H26O3	C. tonkinensis	[100]

Table 13

Atisane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
330	Crotobarin	C22H28O5	C. barorum	[101]
331	Crotogoudin	C20H26O3	C. goudotii	[101]

Table 14

Phytane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
332	Launine L	C20H32O3	C. laui	[37]
333	Launine M	C20H32O2	C. laui	[37]

Table 15

Laevinane type diterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
334	Crolaevinoid G	C20H24O6	C. laevigatus	[39]
335	Crolaevinoid H	C21H26O6	C. laevigatus	[39]

Table 16

Meroditerpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
336	Steenkrotin A	C20H24O6	C. steenkampianus	[102]
337	Steenkrotin B	C20H28O7	C. steenkampianus	[102]
338	Norcrassin A	C17H22O7	C. crassifolius	[81]
339	Cracroson D	C21H26O6	C. crassifolius	[40]

Table 17

Sesquiterpenoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
340	6α -methoxy-cyperene	C16H26O	C. muscicarpa	[103]
341	rel-(1R,4S,6R,7S,8αR)-decahydro-1-(hydroxymethyl)-4,9,9-trimethyl-4,7-(epoxymethano)azulen-6-ol	C15H26O3	C. regelianus	[94]
342	Blumenol A	C13H20O3	C. pedicellatus	[104]
343	Crocrassins A	C15H24O3	C. crassifolius	[105]
344	Crocrassins B	C16H26O3	C. crassifolius	[105]
345	1,3,5-cadinatriene-(7R,10S)-diol	C15H25O2	C. dichogamus	[75]
346	Cracroson H	C15H22O3	C. crassifolius	[40]

Table 18

Sesterterpenoid from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
347	Pseudopulchellol	C25H40O	C.pseudopulchellus	[106]

Table 19

Triterpenoid from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
348	3α-hydroxy-urs-12,15-dien	C30H48O	C. bonplandianum	[107]

Table 20

Glycosides from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
349	Cyperenoic acid-9-O-β-d-glucopyranoside	C21H32O8	C. crassifolius	[108]
350	3-O-β-d-xylopyranosylspathodic acid	C35H56O9	C. lachnocarpus	[109]
351	Helichrysoside-3′-methylether	C31H28O14	C. zambesicus	[110]
352	Crotonionoside A	C29H42O11	C. cascarilloides	[111]
353	Crotonionoside B	C30H44O12	C. cascarilloides	[111]
354	Crotonionoside C	C24H42O12	C. cascarilloides	[111]
355	Crotonionoside D	C31H46O14	C. cascarilloides	[111]
356	Crotonionoside E	C35H52O16	C. cascarilloides	[111]
357	Crotonionoside F	C24H42O11	C. cascarilloides	[111]
358	Crotonionoside G	C29H40O11	C. cascarilloides	[111]
359	Oblongionoside A	C24H42O12	C. oblongifolius	[112]
360	Oblongionoside B	C24H42O12	C. oblongifolius	[112]
361	Oblongionoside C	C24H44O11	C. oblongifolius	[112]
362	Oblongionoside D	C24H44O11	C. oblongifolius	[112]
363	Oblongionoside E	C19H36O8	C. oblongifolius	[112]
364	Oblongionoside F	C19H36O8	C. oblongifolius	[112]
365	Blumenol A glucoside	C19H30O8	C. pedicellatus	[10]
366	Sparsioside	C53H102O10	C. sparsiorus	[113]
367	3,12-dioxo-15,16-epoxy-4α-hydroxy-6-(β-glucopyranosyl)-ent-neo-clerodan-13(16),14-diene	C26H38O10	C. limae	[35]
368	Isocrotofolane glucoside	C26H38O9	C. cascarilloides	[69]
369	2-methoxyphenol-β-d-(6-O-β-d-apiofuranosyl) glucopyranoside	C18H26O11	C. cascarilloides	[69]

Table 21

Alkaloids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
370	Crotamide A	C36H65NO	C. sparsiflorus	[114]
371	Crotamide B	C38H69NO	C. sparsiflorus	[114]
372	Crotonine	C12H14N2O4	C. tiglium	[97]
373	Crotonimide A	C16H20N2O3	C. pullei	[115]
374	Crotsparsidine	C17H17O3N	C. sparsiflorus	[96]
375	Crotonimide C.	C20H20N2O3	C. alienus	[42]
376	6-Hydroxy-1-methyl-2-dimethyl-3,4-tetrahydro-b-carbo-line	C14H19N2O	C. heliotropiifolius	[116]
377	N-trans-feruloyl-3,5-dihydroxyindolin-2-one	C20H20N2O6	C. echioides	[117]

Table 22

Benzoate derivatives from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
378	2′-(3′’,4′’-dihydroxyphenyl)-ethyl-4-hydroxybenzoate	C15H14O5	C. sylvaticus	[118]
379	3-(4-hydroxy-3,5-dimethoxyphenyl)-propyl benzoate	C18H20O5	C. hutchinsonianus	[119]
380	3-(4-hydroxyphenyl)-propyl benzoate	C16H16O3	C. hutchinsonianus	[119]

Table 23

Pyran-2-one derivatives from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
381	Crotonpyrone A	C17H28O3	C. crassifolius	[120]
382	Crotonpyrone B	C17H26O3	C. crassifolius	[120]
383	Crotonpyrone C	C19H28O3	C. crassifolius	[121]

Table 24

Cyclicpeptides from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
384	Crotogossamide	C37H56N10O11	C. gossypifolius	[122]
385	[1−9-NαC]-crourorb A1	C37H56N10O11	C. urucurana	[123]

Table 25

Tropone derivatives from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
386	Crototropone	C10H12O4	C. zehntneri	[124]
387	Pernambucone	C15H18O2	C. argyroglossum	[125]

Table 26

Limonoids from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
388	Musidunin	C31H38O11	C. jatrophoides	[126]
389	Musiduol	C30H38O10	C. jatrophoides	[126]

Table 27

Miscellaneous compounds from the genus Croton.

No.	Compound Name	Molecular Formula	Sources	Ref
390	Crotoncaudatin	C22H22O9	C. caudatus	[127]
391	8S-(−)-8-(4-hydroxy-3-methoxybenzoyl)-dihydrofuran-8(8′H)-one	C20H30O2	C. kongensis	[67]
392	Lobaceride	C35H58O6	C. lobatus	[129]
393	Laevifolin A	C29H38O4	C. laevifolius	[128]
394	Laevifolin B	C29H38O4	C. laevifolius	[128]
395	2,6-Dimethyl-1-oxo-4-indanecarboxylic acid	C12H12O3	C. steenkampianus	[102]
396	3(3′-Methoxy-5′-phenylfuran-2′-yl)propan-1-ol	C14H16O3	C. oblongifolius	[22]
397	Sparsifol	C7H15O6	C. sparsiflorus	[96]
398	Sparsioamide	C43H81NO5	C. sparsiflorus	[113]
399	hexyl Z-ferulate	C16H22O4	C. laevigatus	[89]

2.1. Diterpenoids

Phytochemical investigations on Croton species revealed the predominant secondary metabolites as diterpenoids, including clerodane, tigliane, kaurane, crotofolane, labdane, cembrane, abietane, casbane, halimane, pimarane, cleistanthane, grayanane, atisane, phytane, and laevinane diterpenoids. Three hundred & thirty-nine new diterpenoids (1–339) were reported from Croton species.

2.1.1. Clerodanes

Ninety-two new clerodane diterpenoids (1–92) were isolated from Croton species, including two clerodane diterpenoid with acyclic at C-9s, eight clerodane diterpenoids with butenolide at C-9, and 82 furan-clerodane diterpenoids [11]. Their structures, molecular formula, names, corresponding sources, and references are listed in Figure 1 and Table 1. Two new clerodane diterpenoids with acyclic side chain at C-9, ent-3,13E-clerodadiene-15-formate (1) and 3α,4α,15,16-tetrahydroxy-ent-neo-cleroda-13E-ene (45), were isolated from the roots of C. sylvaticus [12] and the roots of C. limae [13], respectively. Eight new clerodane diterpenoids with butenolide at C-9 (2, 3, 5, 13, 14, 75, 91, 92) were obtained from three Croton species (C. crassifolius, C. glabellus, and C. oligandrus) [14,15,16,17,18]. Furan-clerodane diterpenoids are abundant in Croton species, and 82 new ones were isolated from different Croton species. For example, Centrafricine I (4) from C. mayumbensis was a new furan-clerodane diterpenoid with a 6, 18-γ-lactone ring [19]. Two novel rearranged ent-clerodane diterpenoids Laevinoids A, B (21, 22) containing an unusual 3/5 bicyclic ring were obtained from the branches and leaves of C. laevigatus; 22 represents the first chlorinated example of the clerodane family [20]. Compounds (23–27) bearing a C-19/C-20 six-membered ring were identified from C. laui [21]. Phytochemical investigations on three Croton species (C. oblongifolius, C. yanhuii, and C. hypoleucus) afforded six new furan-clerodanoids (12, 36, 37, 84–86) with a 3,4-epoxy moiety [22,23,24]. Crotoeurins A–C (40–42) were found from the twigs and leaves of C. euryphyllus. Among them, crotoeurin A (40) was a nor-clerodane diterpenoid dimer with a unique cyclobutane ring via a [2 + 2] cycloaddition [25]. Three new furan-clerodane diterpenoids, cracroson A–C (46–48) were obtained from C. crassifolius, while cracroson C (48) represents the first example of a clerodane diterpenoid alkaloid [26]. Twelve new ent-clerodanoids (55, 66) were isolated from the roots of C. megalocarpoides. Among them, compounds (58–66) possessed 9, 12-γ-lactone ring [27]. Investigation on the roots of C. crassifolius afforded eight new clerodanoids, crassins A−H (68–75). Among them, crassins A–B (68, 69) represents ring B rearranged clerodanoids, whereas crassins C (70) was ring A rearranged one [17]. One new nor-clerodane diterpenoid, norcrassifolin (83), with a 1,12-lactone six-membered ring, was isolated from C. crassifolius [28].

2.1.2. Tiglianes

Fifty-six new tigliane diterpenoids (93–148) were reported from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 2 and Table 2. Investigations on the aerial parts of C. ciliatoglandulifer produced four new tiglianoids (95–98). Among them, tiglianoids (95–97) possess a N,N-dimethyl moiety at 2′position [41]. Alienusolin (107) and compound (111) were obtained from the roots and the leaves of C. alienus and the leaves of C. mauritianus, respectively [42,43]. The twigs and leaves of C. caudatus produced three new tiglianoids, crotusins A–C (128–130) [44]. Tigliane diterpenoids were abundant in C. tiglium, other 47 new ones (93, 94, 99–106, 108–110, 112–127, 131–148) were isolated from C. tiglium [45,46,47,48,49,50,51,52]. Among them, compound (112) was the first tiglianoid with the C20-aldehyde group [48].

2.1.3. Kauranes

Fourty new kaurane diterpenoids (149–188) were found from Croton species. Their structures, molecular formula, names, corresponding sources, and references are listed in Figure 3 and Table 3. Five new 3,4-seco ent-kauranes (149–150, 160–161, 168) were isolated from C. caracasana [53], C. megistocarpus [54], and C. oblongifolius [55], respectively. Investigations on C. kongensis afforded eight new 8,9-seco-ent-kaurane diterpenes (151–154, 156, 178–180) [56,57,58,59]. Compound 181, one new kaurane bearing a monoterpene unit at C-16, was found from C. limae [35]. From the stems of C. micans, five new 3,4-seco-ent-kaurene dimers (182–186) were isolated [60], while other two dimeric ent-kaurane diterpenoids (187–188) were elucidated from C. tonkinensis [61].

2.1.4. Crotofolanes

Thirty-nine new crotofolane diterpenoids (189–227) were obtained from Croton species. Their structures, molecular formula, names, corresponding sources, and references are summarized in Figure 4 and Table 4. Twenty-four new crotofolane diterpenoids (189–198, 212–222, 225–227) were isolated from C. caracasanus [68,69,70,71]. Among them, three new crotofolane diterpenoid alkaloids, cascarinoids A–C (225–227), were firstly found. Investigations on C. argyrophyllus gave four new crotofolanes (199–202) [72]. Crotocarasin A–D (203–206) were isolated from the stems of C. caracasanus [73]. Five new 1, 14-seco-crotofolanes from C. insularis were obtained [74], while C. dichogamus yielded crotodichogamoin A–B (223–224) [75].

2.1.5. Labdanes

Thirty-six new labdane diterpenoids (228–263) were isolated from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 5 and Table 5 12 new labdanes (228, 249–259) were isolated from C. laui [21,76,77]. From the leaves of C. stipuliformis, three 3,4-seco-ent-labdanes (229–231) and one ent-labdane (232) were obtained [78]. Investigation of C. laevigatus led to the isolation of 16 new labdanes (233–248). Among them, crotonlaevins A–B (233, 234), represents rare labdanes with a dodecahydronaphtho [1,2-c] furan moiety [79]. Three new labdane diterpenoids (260–262) were found from C. jacobinensis [77] and C. decalvatus [80], respectively. Bicrotonol A (263), one dimeric labdane-type diterpenoid, was obtained from the roots of C. crassifolius [81].

2.1.6. Cembranes

A total of 28 new cembrane diterpenoids (264–291) were obtained from Croton species. Their structures, molecular formula, names, corresponding sources, and references are listed in Figure 6 and Table 6. launine O-P (264, 265), two new cembranes, were reported from the aerial parts of C. laui [76]. Investigations on the stem bark of C. oblongifolius afforded four new furanocembranoids (266–269) [83]. laevigatlactones A–F (270–275), six new cembranoids possessing a rare six-membered lactone moiety attached to C-1 and C-20, were firstly isolated from C. laevigatus [84]. 14 new cembranoids (276–289) were found from C. gratissimus [85,86]. Among them, compound 276 was first example of a 2,12-cyclocembranolide. The leaves of C. longissimus produced two new cembranes (290, 291) [87].

2.1.7. Abietanes

Fourteen new abietane diterpenoids (292–305) were isolated from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 7 and Table 7. Two new abietanes (292, 293) were obtained from C. megalocarpoides [27], and C. argyrophylloides [63], respectively. Investigation of C. caudatus led to the isolation of 5 new abietanes (294–298). Among them, crotontomentosin A (294) was a 9,10-seco abietane [88]. Crotolaevigatones A–G (299–305), 7 new abietanes were found from the twigs and leaves of C. laevigatus, and compounds (304, 305) possessed a 9,13-epidioxy moiety [89].

2.1.8. Casbanes

Seven new casbane diterpenoids (306–312) were found from Croton species. Their structures, molecular formula, names, corresponding sources, and references are summarized in Figure 8 and Table 8. Five new casbane s (306–310) were reported from C. nepetaefolius [90], and C. argyrophyllus [72,91], respectively. Investigations on the stem bark of C. insularis afforded two new casbanes, EBC-324 (311) and EBC-329 (312). Among them, EBC-329 (312) represented the first natural seco-casbane diterpene, while EBC-324 (311) was the first endoperoxide casbane [92].

2.1.9. Halimanes

Six new halimane diterpenoids (313–318) were reported from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 8 and Table 9. Investigations on the stem bark of C. oblongifolius afforded two new cleistanthanes (325, 326). Among them, compound 326 was a 3,4-seco cleistanthane [93]. One new bis-nor-cleistanthane diterpenoid (327), was found from the twigs and leaves of C. caudatus [94].

2.1.10. Pimaranes

Six new pimarane diterpenoids (319–324) were obtained from Croton species. Their structures, molecular formula, names, corresponding sources, and references are listed in Figure 8 and Table 10. All six new pimaranes (319–324) were isolated from C. insularis [96,97]. Among them, compound 319 was an important biosynthetic intermediate.

2.1.11. Cleistanthanes

Three new cleistanthane diterpenoids (325–327) were ioslated from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 8 and Table 11. Investigations on the stem bark of C. oblongifolius afforded two new cleistanthanes (325, 326). Among them, compound 326 was a 3,4-seco cleistanthane [93]. One new bis-nor-cleistanthane diterpenoid (327), was found from the twigs and leaves of C. caudatus [94].

2.1.12. Grayananes, Atisanes, Phytanes, Laevinanes and Meroditerpenoids

From the leaves of C. tonkinensis, two new rare grayanane diterpenoids, crotonkinensins A (328) and B (329), were isolated [100]. Two new 3,4-seco atisane diterpenoids, crotobarin (330) from C. barorum and crotogoudin (331) from C. goudotii, were found [101]. Investigations on the aerial parts of C. laui gave two new phytane diterpenoids (332, 333) [37]. Two new laevinane diterpenoids, crolaevinoid G (334) and H (335), were obtained [39]. Two new meroditerpenoids, steenkrotin A (336) and B (337), containing new carbon skeletons, were isolated from the leaves of C. steenkampianus [102]. From the the roots of C. crassifolius, two new meroditerpenoids, norcrassin A (338) and cracroson D (339), were reported [35,69]. Among them, norcrassin A (338) possessing a new carbon skeleton with a 5/5/5/6 tetracyclic system, was a C16 tetranorditerpenoid, while cracroson D (339) featured a new skeleton with a rare cyclobutane ring. Their structures, molecular formula, names, corresponding sources, and references are listed in Figure 9 and Table 12, Table 13, Table 14, Table 15 and Table 16.

2.2. Sesquiterpenoids, Sesterterpenoids and Triterpenoids

Seven new sesquiterpenoids (340–346), one sesterterpenoid (347) and one triterpenoid (348) were ioslated from Croton species. Their structures, molecular formula, names, corresponding sources, and references are summarized in Figure 10 and Table 17, Table 18 and Table 19. From C. muscicarpa, one new patchoulane sesquiterpenoid (340) was obtained [103]. A guaiane sesquiterpenoid (341) was isolated from C. regelianus [94]. Investigations on the leaves of C. pedicellatus afforded a bis-nor-sesquiterpenoid (342) [104]. Two rare sesquiterpenoid, Crocrassins A (343) and B (344) having cyclopropylcyclopentane moiety, were reported [105]. Other two sesquiterpenoids, 1,3,5-cadinatriene-(7R,10S)-diol (345) and cracroson H (346) were found from C. dichogamus [75], and C. crassifolius [40], respectively. One rare sesterterpenoid, pseudopulchellol (347), was isolated from the leaves of C. pseudopulchellus [106]. From the root of C. bonplandianum, a new ursane triterpenoid (348) was obtained [107].

2.3. Glycosides

Twenty-one new glycosides (349–369) were ioslated from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 11 and Table 20. From C. crassifolius, a patchoulane sesquiterpenoid glycoside (349), an isocrotofolane glucoside (368), and a phenolic glycoside (369) were reported [69,108]. Compound 350, isolated from C. lachnocarpus, was the first triterpenoid glucoside reported from the genus Croton [109]. A new flavone glucoside (351) was found from the leaves of C. zambesicus [110]. Investigations on the leaves of C. cascarilloides and C. oblongifolius afforded 13 new megastigmane glycosides, crotonionosides A–G (352–358) and Oblongionosides A–F (359–364) [111,112]. One new bis-nor-sesquiterpenoid glycoside (365) was isolated from C. pedicellatus [104]. One new diglyceride galactoside (366) and one new clerodane glucoside (367) were obtained from C. sparsiorus [113], and C. limae [35], respectively.

2.4. Alkaloids

Eight new alkaloids (370–377) were reported from Croton species. Their structures, molecular formula, names, corresponding sources, and references are listed in Figure 12 and Table 21. From C. sparsiflorus, two new amide alkaloids crotamides A (370) and B (371), and one new proaporphine alkaloid, crotsparsidine (374) were isolated [96,114]. One new pyrazine derivative, crotonine (372) was obtained from the leaves of C. tiglium [97]. Investigations on C. cascarilloides afforded a new glutarimide alkaloid, crotonimide C (375) [42]. Other three new alkaloids (373, 376–377) were found from C. pullei, C. heliotropiifolius, and C. echioides, respectively [115,116,117].

2.5. Benzoate Derivatives, Pyran-2-One Derivatives, Cyclicpeptides, Tropone Derivatives and Limonoids

Three benzoate derivatives (378–380) were isolated from C. sylvaticus and C. hutchinsonianus [118,119]. Investigations on C. crassifolius afforded three new pyran-2-one derivatives, crotonpyrone A (381), B (382) and C (383) [120,121]. Two cyclicpeptides (384, 385) were obtained from C. gossypifolius and C. urucurana [122,123], while two tropone derivatives (386, 387) were isolated from C. zehntneri and C. argyroglossum [124,125]. From the root bark of C. jatrophoides, two new limonoids, musidunin (388) and musiduol (389), were found [126]. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 13 and Table 22, Table 23, Table 24, Table 25 and Table 26.

2.6. Miscellaneous Compounds

Flavonoids, lignans, and other types of 10 compounds were also isolated from Croton species. Their structures, molecular formula, names, corresponding sources, and references are collected in Figure 13 and Table 27. From the stems of C. caudatus, one new flavone, crotoncaudatin (390), was isolated [127]. A new nor-lignan (391) was obtained from the twigs and leaves of C. kongensis [67]. Investigations on C. laevifolius gave two new prenylated dihydrostilbenes, laevifolin A (393), B (394) and one new aromatic compound (399) [89,128]. A long chain linear ester, lobaceride (392) was isolated from the twigs and leaves of C. lobatus [129]. One indanone derivative (395) was found from the leaves of C. steenkampianus [102], while a trisubstituted furan derivative (396) was isolated from the bark of C. oblongifolius [22]. From C. sparsiflorus, an inositol, sparsifol (397), and a sphingolipid, sparsioamide (398), were obtained [96,113].

3. Biological Activities

Compounds isolated from Croton species exert a wide range of biological activities, including cytotoxic, anti-inflammatory, antifungal, acetylcholinesterase inhibitory, and neurite outgrowth-promoting activities.

3.1. Cytotoxic Activity

The anti-tumor activity of many plants from the Croton species have been reported. Therefore, the cytotoxicity of the isolated compounds is the most commonly studied bioactivity. The cytotoxic activities of the isolated compounds from the Croton species are listed in Table 28. Four new tigliane diterpene esters (135–137, 139) from the leaves of C. tiglium, exhibited most potent cytotoxic activity against K562 cell line with IC50 values of 0.03, 0.03, 0.07 and 0.05 μM, respectively [51].

Table 28

Cytotoxic activity of compounds from the genus Croton.

Compounds	Tumor Cell Line	Activity (IC50)	Ref
Methyl 15,16-epoxy-3,13(16),14-ent-clerodatrien-18,19-olide-17-carboxylate (6)	HuCCA-1	36.0 μg/mL	[29]
	KB	26.0 μg/mL	[29]
	HeLa	30.0 μg/mL	[29]
	MDA-MB231	29.0 μg/mL	[29]
	T47D	10.0 μg/mL	[29]
Dimethyl-15,16-epoxy-12-oxo-3,13 (16)14-ent-clerodatriene-17,18-dicarboxylate (7)	HuCCA-1	39.0 μg/mL	[29]
	KB	27.0 μg/mL	[29]
	HeLa	29.0 μg/mL	[29]
	MDA-MB231	27.0 μg/mL	[29]
	T47D	25.0 μg/mL	[29]
Laevigatbenzoate (8)	HeLa	45.4 μM	[13]
Crotonolide A (23)	HL-60	9.42 μM	[21]
	P-388	7.45 μM	[21]
15-oxo-17(10′-α-pinenyl)-kauran-18-oic acid (181)	HCT-116	7.14 μg/mL	[35]
	OVCAR-8	8.19 μg/mL	[35]
	SF-295	>10.0 μg/mL	[35]
Launine K (67)	HeLa	14.5 μM	[37]
	MCF-7	62.5 μM	[37]
Crassin H (75)	HL-60	11.8 ± 2.1 μM	[17]
	A549	5.2 ± 0.4 μM	[17]
Crassifolius A (76)	Hep3B	17.91 μM	[38]
	HepG2	42.04 μM	[38]
Cracroson D (339)	T24	14.48 ± 0.65 μM	[40]
	A549	25.64 ± 2.14 μM	[40]
Cracroson E (87)	T24	22.99 ± 1.76 μM	[40]
	A549	51.88 ± 14.07μM	[40]
	Hela	3.9 μM	[48]
	DU145	7.2 μM	[48]
	A549	5.8 μM	[48]
	SGC-7091	13 μM	[48]
	H1975	10 μM	[48]
	HL60	12 μM	[48]
	293T	291.6 μM	[48]
	LX-2	>500.0 μM	[48]
12-O-benzoylphorbol-13-(2-methyl)butyrate (114)	K562	15 μM	[48]
	MOLT-4	12 μM	[48]
	U937	17 μM	[48]
	MCF-7	20 μM	[48]
	Hela	4.6 μM	[48]
	DU145	4.3 μM	[48]
	A549	6.9 μM	[48]
	SGC-7091	10 μM	[48]
	H1975	3.3 μM	[48]
	HL60	6.8 μM	[48]
	293T	420.4 μM	[48]
	LX-2	>500.0 μM	[48]
12-O-tiglyl-7-oxo-5-ene-phorbol-13-(2-methyl)butyrate (115)	K562	17 μM	[48]
	MOLT-4	4.8 μM	[48]
	U937	21 μM	[48]
	MCF-7	20 μM	[48]
	Hela	5.0 μM	[48]
	DU145	10 μM	[48]
	A549	19 μM	[48]
	SGC-7091	23 μM	[48]
	H1975	10 μM	[48]
	HL60	10 μM	[48]
	293T	455.3 μM	[48]
	LX-2	>500.0 μM	[48]
13-O-(2-metyl)butyryl-4-deoxy-4a-phorbol (116)	K562	8.0 μM	[48]
	MOLT-4	9.9 μM	[48]
	U937	18 μM	[48]
	MCF-7	24 μM	[48]
	H1975	10 μM	[48]
	HL60	10 μM	[48]
	293T	455.3 μM	[48]
	LX-2	>500.0 μM	[48]
	Hela	10 μM	[48]
	DU145	10 μM	[48]
	A549	4.5 μM	[48]
	SGC-7091	5.4 μM	[48]
	H1975	3.3 μM	[48]
	HL60	9.8 μM	[48]
	293T	191.0 μM	[48]
	LX-2	>500.0 μM	[48]
Crotignoid A (117)	HL-60	1.61 μM	[49]
	A549	2.85 μM	[49]
Crotignoid B (118)	HL-60	22.1 μM	[49]
	A549	31.0 μM	[49]
Crotignoid C (119)	HL-60	32.3 μM	[49]
	A549	5.03 μM	[49]
Crotignoid D (120)	HL-60	19.8 μM	[49]
	A549	10.2 μM	[49]
Crotignoid F (122)	HL-60	44.6 μM	[49]
	A549	6.96 μM	[49]
Crotignoid G (123)	HL-60	22.1 μM	[49]
	A549	3.89 μM	[49]
Crotignoid H (124)	HL-60	9.97 μM	[49]
	A549	8.08 μM	[49]
Crotignoid I (125)	HL-60	14.8 μM	[49]
	A549	24.4 μM	[49]
Crotignoid J (126)	HL-60	14.2 μM	[49]
	A549	29.5 μM	[49]
Crotusin A (128)	HL-60	12.53 ± 0.37 μM	[44]
	SMMC-7721	7.06 ± 0.72 μM	[44]
	A549	9.69 ± 0.41 μM	[44]
	MCF-7	9.56 ± 0.76 μM	[44]
	SW480	14.88 ± 0.43 μM	[44]
Crotusin B (129)	HL-60	19.39 ± 0.46 μM	[44]
	SMMC-7721	21.13 ± 0.29 μM	[44]
	A549	14.66 ± 1.66 μM	[44]
	MCF-7	1.49 ± 0.23 μM	[44]
	SW480	31.21 ± 3.20 μM	[44]
Crotusin C (130)	HL-60	4.19 ± 0.15 μM	[44]
	SMMC-7721	3.87 ± 0.12 μM	[44]
	A549	2.44 ± 0.35 μM	[44]
	MCF-7	0.49 ± 0.04 μM	[44]
	SW480	2.89 ± 0.01 μM	[44]
12-O-tiglylphorbol-4-deoxy-4β-phorbol-13-acetate (131)	SNU387	59.5 ± 2.1 μM	[50]
	SNU398	43.7 ± 1.5 μM	[50]
12-O-tiglylphorbol-4-deoxy-4β-phorbol-13-hexadecanoate (132)	SNU387	30.2 ± 1.4 μM	[50]
	SNU398	91.2 ± 3.7 μM	[50]
13-O-acetylphorbol-4-deoxy-4β-phorbol-20-oleate (133)	SNU387	1.9 ± 0.2 μM	[50]
	SNU398	13.5 ± 1.1 μM	[50]
13-O-acetylphorbol-4-deoxy-4β-phorbol-20-linoleate (134)	SNU387	0.71 ± 0.08 μM	[50]
	SNU398	18.2 ± 1.7 μM	[50]
4-deoxy-20-oxophorbol 12-tiglyl 13-acetate (135)	K562	0.03 μM	[51]
	A549	6.88 μM	[51]
	Huh-7	3.85 μM	[51]
7-oxo-5-ene-phorbol-13-(2-methylbutyrate) (136)	K562	0.03 μM	[51]
	A549	6.33 μM	[51]
	Huh-7	20.9 μM	[51]
7-hydroxyl-phorbol-5-ene-13-(2-methyl)butyrate (137)	K562	0.07 μM	[51]
	A549	8.86 μM	[51]
	Huh-7	11.6 μM	[51]
13-O-(2-metyl)butyryl-phorbol (139)	K562	0.05 μM	[51]
	A549	43.5 μM	[51]
	Huh-7	34.2 μM	[51]
7-keto-12-O-tiglylphorbol-13-acetate (140)	HL-60	6.22 ± 3.24 μg/mL	[52]
	A549	18.0 ± 9.48 μg/mL	[52]
Phorbol-13-isobutyrate (148)	HL-60	0.22 ± 0.15 μg/mL	[52]
14-epi-hyalic acid (159)	HL-60	8.2 μM	[63]
Kongeniod A (178)	HL-60	1.27 ± 0.24 μM	[59]]
	A549	5.74 ± 0.25 μM	[59]
Kongeniod B (179)	HL-60	0.47 ± 0.04 μM	[59]
	A549	3.25 ± 0.91 μM	[59]
Kongeniod C (180)	HL-60	0.58 ± 0.17 μM	[59]
Crotonkinensin D (188)	MCF-7	9.4 ± 1.7 μM	[61]
	MCF-7/TAMR	2.6 ± 0.9 μM	[61]
	MCF-7/ADR	18.9 ± 0.6 μM	[61]
	MDA-MB-231	22.0 ± 0.9 μM	[61]
EBC-162 (207)	HL-60	15 μg/mL	[74]
	HT29	15 μg/mL	[74]
	MCF-7	30 μg/mL	[74]
	MM96	10 μg/mL	[74]
	NNF	20 μg/mL	[74]
	K562	50 μg/mL	[74]
EBC-233 (208)	HL-60	10 μg/mL	[74]
	HT29	80 μg/mL	[74]
	MCF-7	20 μg/mL	[74]
	MM96	6 μg/mL	[74]
	NNF	50 μg/mL	[74]
	K562	50 μg/mL	[74]
EBC-300 (209)	HL-60	35 μg/mL	[74]
	HT29	100 μg/mL	[74]
	MCF-7	100 μg/mL	[74]
	MM96	80 μg/mL	[74]
	NNF	80 μg/mL	[74]
	K562	100 μg/mL	[74]
EBC-240 (210)	HL-60	45 μg/mL	[74]
	HT29	80 μg/mL	[74]
	MCF-7	50 μg/mL	[74]
	MM96	12 μg/mL	[74]
	NNF	80 μg/mL	[74]
	K562	60 μg/mL	[74]
EBC-241 (211)	HL-60	40 μg/mL	[74]
	HT29	80 μg/mL	[74]
	MCF-7	40 μg/mL	[74]
	MM96	12 μg/mL	[74]
	NNF	75 μg/mL	[74]
	K562	60 μg/mL	[74]
Furanocembranoid 1 (266)	BT474	7.8 μg/mL	[83]
	CHAGO	7.0 μg/mL	[83]
	Hep-G2	5.6 μg/mL	[83]
	KATO-3	5.9 μg/mL	[83]
	SW-620	6.3 μg/mL	[83]
Furanocembranoid 2 (267)	BT474	9.5 μg/mL	[83]
	CHAGO	>10 μg/mL	[83]
	Hep-G2	>10 μg/mL	[83]
	KATO-3	6.8 μg/mL	[83]
	SW-620	9.9 μg/mL	[83]
Furanocembranoid 3 (268)	BT474	9.6 μg/mL	[83]
	CHAGO	7.1 μg/mL	[83]
	Hep-G2	5.7 μg/mL	[83]
	KATO-3	8.2 μg/mL	[83]
	SW-620	5.6 μg/mL	[83]]
Furanocembranoid 4 (269)	BT474	9.6 μg/mL	[83]
	CHAGO	9.3 μg/mL	[83]
	Hep-G2	6.1 μg/mL	[83]
	KATO-3	8.1 μg/mL	[83]
	SW-620	6.0 μg/mL	[83]
Laevigatlactone B (272)	Hela	38.4 μM	[84]
(+)-[1R*,2S*,7S*,8S*,12R*]-7,8-Epoxy-2,12-cyclocembra-3E,10Zdien-20,10-olide (276)	PEO1	132 nM	[85]
	PEO1TaxR	200 nM	[85]
(+)-[1R*,4S*,10R*]-4-Hydroxycembra-2E,7E,11Z-trien-20,10-olide (278)	PEO1	125 nM	[85]
	PEO1TaxR	135 nM	[85]
Crotontomentosin A (294)	Hela	24.0 ± 2.6 μM	[88]
	Hep G2	87.9 ± 4.5 μM	[88]
	MDA-MB-231	54.1 ± 2.1 μM	[88]
	A549	40.6 ± 3.9 μM	[88]
Crotontomentosin B (295)	Hela	>100 μM	[88]
	Hep G2	28.1 ± 2.1 μM	[88]
	MDA-MB-231	28.7 ± 3.4 μM	[88]
	A549	29.1 ± 5.2 μM	[88]
Crotontomentosin C (297)	Hela	47.9 ± 3.3 μM	[88]
	Hep G2	83.3 ± 5.3 μM	[88]
	MDA-MB-231	>100 μM	[88]
	A549	>100 μM	[88]]
Crotontomentosin D (296)	Hela	59.7 ± 4.5 μM	[88]
	Hep G2	>100 μM	[88]
	MDA-MB-231	49.3 ± 2.8 μM	[88]
	A549	>100 μM	[88]
Crotolaevigatone B (300)	A549	21.2 μM	[89]
	MDA-MB-231	33.4 μM	[89]
Crotolaevigatone G (305)	A549	25.6 μM	[89]
	MDA-MB-231	32.7 μM	[89]
EBC-324 (311)	MCF-7	40 μM	[92]
	NFF	50 μM	[92]
	K562	6 μM	[92]
EBC-329 (312)	MCF-7	13 μM	[92]
	NFF	40 μM	[92]
	K562	0.6 μM	[92]
ent-3β-hydroxypimara-8(14),9,15-trien-12-one (319)	NFF	23 μg/mL	[98]
	Hela	13 μg/mL	[98]
	HT 29	13 μg/mL	[98]
	MCF-7	16 μg/mL	[98]
	MM96L	2.8 μg/mL	[98]
	K562	17 μg/mL	[98]
EBC-325 (321)	MCF-7	20 μM	[99]
	NFF	6 μM	[99]
	K562	3 μM	[99]
EBC-326 (322)	MCF-7	14 μM	[99]
	NFF	6 μM	[99]
	K562	6 μM	[99]
EBC-327 (323)	MCF-7	10 μM	[99]
	NFF	10 μM	[99]
	K562	10 μM	[99]
3-hydroxycleistantha-13(17),15-diene (325)	KATO-3	6.0 μg/mL	[93]
	SW-620	>10 μg/mL	[93]
	BT474	6.1 μg/mL	[93]
	Hep-G2	0.5 μg/mL	[93]
	CHAGO	5.5 μg/mL	[93]
3,4-seco-cleistantha-4(18),13(17),15-trien-3-oic acid (326)	KATO-3	9.6 μg/mL	[93]
	SW-620	>10 μg/mL	[93]
	BT474	10 μg/mL	[93]
	Hep-G2	8.6 μg/mL	[93]
	CHAGO	>10 μg/mL	[93]
Crotobarin (330)	KB	2.5 ± 0.10 μM	[101]
	HT29	2.1 ± 0.60 μM	[101]
	A549	0.79 ± 0.15 μM	[101]
	HL60	0.56 ± 0.02 μM	[101]
Crotogoudin (331)	KB	1.5 ± 0.03 μM	[101]
	HT29	1.9 ± 0.25 μM	[101]
	A549	0.54 ± 0.02 μM	[101]
	HL60	0.49 ± 0.01 μM	[101]
Crotonpyrone A (381)	Hela	10.21 μg/mL	[120]
	NCI-446	6.59 μg/mL	[120]
Crotonpyrone B (382)	Hela	9.54 μg/mL	[120]
[1−9-NαC]-crourorb A1 (385)	NCI-ADR/RES	4.8 μM	[123]

3.2. Anti-Inflammatory Activity

Bioassay-guided fractionation of the aerial parts of C. ciliatoglandulifer led to the isolation of tigliane diterpenoids 95, 97, which inhibited the enzymes cyclooxygenases-1 (IC50, 0.001, and 1.0 μM, respectively) and cyclooxygenases-2 (IC50, 2.2 μM, for compound 95) [41]. A tigliane diterpenoid (114) was isolated from the branches and leaves of C. tiglium, which displayed moderate inhibition of the enzymes COX-1 and COX-2, with IC50 values of 0.14 and 8.5 μM, respectively [48]. crotonkinin A (157), isolated from C. tonkinensis, showed anti-inflammatory effect on LPS-induced iNOS-dependent NO production and NOX-dependent ROS production in microglial cells (IC50, 46.2 ± 3.1 μM in NOS; maximum inhibition of NOX activity at 50 μM, 11.2%) [62]. Eight ent-kauranes (169–176) from C. tonkinensis exhibited the anti-inflammatory potential for inhibition of superoxide Anion generation and elastase release. Among them, crotonkinins F (172) displayed significant inhibition of superoxide anion generation (IC50, 2.88 ± 0.52 μM) and elastase release (IC50, 4.44 ± 1.45 μM) [66]. Labdane diterpenoids 251, 254 and 257, 258, isolated from the aerial parts of C. laui, were found to show anti-inflammatory activities in LPS-stimulated RAW 264.7 cells with IC50 values in the range 42.73–93.04 μM [82]. Two grayanane diterpenoids, crotonkinensins A (328) and B (329) from the leaves of C. tonkinensis, were reported to decrease the LPS-induced COX-2 promoter activity in Raw 264.7 cells with IC50 values of 7.14 ± 0.2 and 5.49 ± 0.2 μM, respectively [100]. Two benzoate derivatives (379, 380) were obtained from C. hutchinsonianus. Compound 379 showed significant activity against COX-1 (IC50, 4.95 ± 0.58 μg/mL) and COX-2 (IC50, 2.11 ± 1.3 μg/mL), while compound 380 (IC50, 1.88 ± 0.17 μg/mL) preferentially inhibited COX-2 [119].

3.3. Antifungal Activity

Two benzoate derivatives (379–380) were isolated from C. hutchinsonianus, and exhibited antifungal activity against Candida albicans (IC50, 11.41 ± 1.44, and 5.36 ± 0.01 μg/mL, respectively) [119]. Ursane triterpenoid (348) from the root of C. bonplandianum, displayed the antifungal activity against Calletotricheme camellie (IC50, 10 μg/mL), Fussarium equisitae (IC50, <15 μg/mL), Alterneria alternata (IC50, 10 μg/mL), Curvularia eragrostidies (IC50, <10 μg/mL) and Colletorichum gloeosporiodes (IC50, 15 μg/mL) [107].

3.4. Acetylcholinesterase Inhibitory Activity

An indole alkaloid derivative 376, isolated from the leaves of C. heliotropiifolius, exhibited the acetylcholinesterase inhibitory activity with IC50 values of 17.8 ± 0.6 μM [116]. Compund 378 from C. sylvaticus, also displayed the same activity [118].

3.5. Neurite Outgrowth-Promoting Activity

Two clerodane diterpenoids, crotonpenes A (36) and B (37) were isolated from C. yanhuii, which markedly increased the NGF (20 ng/mL)-induced proportion of neurite bearing cells by 59%, and 47% at 15 μM, respectively [23]. Crotoeurins A–C (40–42) obtained from C. euryphyllus, were found to display neurite outgrowth-promoting activity on NGF mediated PC12 cells at concentration of 10 μM. The percentages of neurite-bearing cells were 9.72%, 14.90%, and 7.14%, respectively [25].

3.6. Other Activities

Besides the above activities, other biological activities have also been reported. Crotonolide G (32), from the aerial parts of C. laui, was found to exhibit potent antibacterial activity (MIC, 43.4 μM) against four strains of Gram-positive bacteria, namely, Staphylococcus aureus, Staphylococcus epidermidis, Micrococcus luteus, and Bacillus subtilis [21]. Crassifolin H (39) was obtained from roots of C. crassifolius as an angiogenic inhibitor by reducing vessel formation to 59.3% at 15 μg/mL [34]. Tigliane diterpene (111) was isolated from the leaves of C. mauritianus, which inhibited chikungunya virus-induced cell death in cell culture with EC50s of 4.0 ± 0.8 μM [43]. The leaves of C. tiglium yielded two tigliane diterpenoids (135, 136), which displayed significant antitubercular activities with MIC values of 19.5, and 20.9 μM, respectively [51]. Compounds (162–165) were four ent-kaurane diterpenes from C. tonkinensis, which significantly stimulated differentiation in osteoblasts [64]. From the twigs and leaves of C. cascarilloides, two crotofolane diterpenoid alkaloids cascarinoids B–C (226, 227) were obtained, both of which displayed moderate activities against the ConA-induced proliferation of T lymphocyte cells and/or LPS-induced proliferation of B lymphocyte cells with IC50 values ranging from 6.14 to 16.27 μM [71]. Meroditerpenoid (336), from C. steenkampianus, showed antiplasmodial activities of 15.8 (D10), 9.1 (W2), and 9.4 (Dd2) μM [102]. Indole alkaloid (377) was found in C. mauritianus with antioxidant activity (IC50, 30.0.0 ± 0.7 μM) by the DPPH radical scavenging assay [117]. Bioactivity-guided fractionation of the root bark of C. jatrophoides resulted in the isolation of musidunin (388) and musiduol (389), both of which showed insect antifeedant activities (PC50, 3 μg/mL, PC95, 10 μg/mL; PC50, 4 μg/mL, PC95, 20 μg/mL, respectively) against the second-instar larvae of Pectinophora gossypiella in a leaf disk assay [126].

4. Conclusions

In the present review, we systematically summarized the chemical constituents and biological activity studies of Croton species covering from 2006 to 2018. To date, a total of 399 new compounds were reported from Croton species, which included 339 diterpenoids, seven sesquiterpenoids, 21 glycosides, eight alkaloids, and 24 miscellaneous compounds (Figure 14). Obviously, diterpenoids are characteristic components for Croton species. The diterpenoids with clerodane, tigliane, kaurane, crotofolane, labdane, and cembrane skeletons are among the most studied diterpenoids isolated from Croton species (Figure 14). Although the current studies have shown that these isolated compounds from Croton species possessed diversified biological activities, many compounds have never been biologically tested. Moreover, most studies conducted so far have focused mainly on in vitro cytotoxic assays. Further studies on the mechanism of actions and the structure activity relationship are needed in order to provide a better understanding of the chemical constituents from Croton species as potential medicines. Increasing interest in the chemistry and pharmaceutics of Croton species may promote new progress in finding and developing novel compounds.

Figure 14

The percentage of each type of compounds (left), the percentage of each type of diterpenoids (right) from Croton Species.