Natural products from the genus tephrosia.

The genus Tephrosia, belonging to the Leguminosae family, is a large pantropical genus of more than 350 species, many of which have important traditional uses in agriculture. This review not only outlines the source, chemistry and biological evaluations of natural products from the genus Tephrosia worldwide that have appeared in literature from 1910 to December 2013, but also covers work related to proposed biosynthetic pathways and synthesis of some natural products from the genus Tephrosia, with 105 citations and 168 new compounds.

1. Introduction

The genus Tephrosia, belonging to the Leguminosae family, is a large pantropical genus of more than 350 species, many of which have important traditional uses [1,2]. Phytochemical investigations have revealed the presence of glucosides, rotenoids, isoflavones, chalcones, flavanones, flavanols, and prenylated flavonoids [1,2,3,4,5,6,7,8,9] of chemotaxonomic importance in the genus [10]. Moreover, bioactivity has been studied extensively, indicating that chemical constituents and extracts of the genus Tephrosia exhibited diverse bioactivities, such as insecticidal [11], antiviral [12], antiprotozoal [13], antiplasmodial [14] and cytotoxic [15] activities.

So far, the reviews on natural products isolated from the genus Tephrosia are limited [16]. To gain a comprehensive and systematic understanding of this genus, this review outlines the chemistry, proposed biosynthetic pathways, synthesis, and biological evaluations of natural products from the genus Tephrosia worldwide that have appeared in literature from 1971 to December 2013, with 105 citations and 168 new compounds from them.

2. Chemical Constituents

The chemical constituents of the genus Tephrosia reported since 1910 (compounds 1–168) are shown in Table 1 and Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6, Figure 7, Figure 8, Figure 9, and Figure 10 below with their names, and their biological sources. As listed in the table and Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6 and Figure 7, flavonoids are the predominant constituents of this genus.

Table 1

Chemical constituents from the genus Tephrosia.

No.	Compound class and name	Source	Ref.
Flavones
1	tephroglabrin	T. purpurea	[3]
2	tepurindiol	T. purpurea	[3]
3	glabratephrin	T. apollinea	[10]
4	tachrosin	Tephrosia polystachyoides	[17]
5	staohyoidin	T. polystachyoides	[18]
6	tephrodin	T. polystachyoides	[18]
7	semiglabrin	T. semiglabra, T. apollinea	[19,20]
8	semiglabrinol	T. semiglabra, T. apollinea	[10,19]
9	tephrostachin	T. polystachyoides	[21]
10	emoroidone	T. emoroides	[22]
11	tephroapollin C	T. apollinea	[23]
12	tephroapollin D	T. apollinea	[23]
13	tephroapollin E	T. apollinea	[23]
14	tephroapollin F	T. apollinea	[23]
15	tephroapollin G	T. apollinea	[23]
16	multijugin	T. multijuga	[24]
17	multijuninol	T. multijuga	[24]
18	pseudosemiglabrinol	T. apollinea	[25]
19	(−)-pseudosemiglabrin	T. semiglabra	[26]
20	polystachin	T. polystachya	[27]
21	5-methoxy-6,6-dimethylpyrano[2,3:7,6]flavone	T. praecans	[28]
22	candidin	T. candida	[29]
23	hookerianin	T. hookeriana	[30]
24	fulvinervin B	T. fulvinervis	[31]
25	fulvinervin C	T. fulvinervis	[32]
26	enantiomultijugin	T. viciodes	[33]
27	apollinine	T. purpurea	[34]
28	demethylapollinin 7-O-β-D-glucopyranoside	T. cinerea	[35]
29	tephropurpulin A	T. apollinea, T. purpurea	[36,37]
30	isoglabratephrin	T. purpurea	[37]
31	terpurinflavone	T. purpurea	[38]
Flavonols
32	6-hydroxykaempferol 6-methyl ether 3-O-α-rhamno-pyranosyl(7→6)-β-galactopyranoside-7-O-α-rhamno-pyranoside	T. vogelii	[1]
33	6-hydroxykaempferol 6-methyl ether 3-O-α-rhamno-pyranosyl(1→2)[α-rhamnopyranosyl(1→6)-β-galacto-pyranoside	T. vogelii	[1]
34	6-hydroxykaempferol 6-methyl ether 3-O-α-rhamno-pyranosyl(1→2)[α-rhamnopyranosyl(1→ 6)]-β-galacto-pyranoside-7-O-α-rhamnopyranoside	T. vogelii	[1]
35	6-hydroxykaempferol 6-methyl ether 3-O-α-rhamnopyranosyl (1→2)[(3-O-E-feruloyl)-α-rhamnopyranosyl(1→6)]-β-galacto-pyranosides	T. vogelii	[1]
36	6-hydroxykaempferol 4'-methyl ether	T. candida	[39]
37	candidol		[40]
38	candirone	T. candida	[41,42]
39	7-ethoxy-3,3',4'-trihydroxyflavone	T. procumbens	[43]
Flavanonols
40	(2R,3R)-3-hydroxy-5-methoxy-6'',6''-dimethylpyrano-[2'',3'':7,8]flavanone	T. vogelii	[1]
41	lupinifolinol	T. lupinifolia	[44]
42	lupinifolinol triacetate	T. lupinifolia	[44]
Flavans
43	(2S)-4'-hydroxy-5-methoxy-6'',6''-dimethylpyrano[2'',3'':7,8]-flavanone	T. vogelii	[1]
44	(2S)-7-hydroxy-5-methoxy-8-prenylflavanone	T. vogelii	[1]
45	(2S)-5-methoxy-6'',6''-dimethy1-4'',5''-dihydrocyclopropa-[4'',5'']furano[2'',3'':7,8]flavanone	T. vogelii	[1]
46	(2S)-5,7-dimethoxy-8-(3-methylbut-1,3-dienyl)flavanone	T. vogelii	[1]
47	tephrocandidin A	T. candida	[2]
48	tephrocandidin B	T. candida	[2]
49	(+)-tephrorin A	T. purpurea	[4]
50	(+)-tephrorin B	T. purpurea	[4]
51	(2S)-5-hydroxy-7,4'-di-O-(γ,γ-dimethylallyl)flavanone	T. calophylla	[6]
52	6-hydroxy-E-3-(2,5-dimethoxybenzylidine)-2',5'-dimethoxyflavanone	T. calophylla	[6]
53	pumilanol	T. pumila	[13]
54	emoroidenone	T. emoroides	[22]
55	tephroapollin A	T. apollinea	[23]
56	tephroapollin B	T. apollinea	[23]
57	fulvinervin A	T. fulvinervis	[30]
58	lupinifolin	T. lupinifolia	[44]
59	5,4'-O,O-dimethyl-lupinifolin	T. lupinifolia	[44]
60	lupinifolin diacelate	T. lupinifolia	[44]
61	obovatin	T. obovata	[45]
62	obovatin methyl-ether	T. obovata	[45]
63	methylhildardtol B	T. hildebrandtii	[46]
64	hildgardtol B	T. hildebrandtii	[46]
65	hildgardtene	T. hildebrandtii	[46]
66	methylhildgardtol A	T. hildebrandtii	[46]
67	hildgardtol A	T. hildebrandtii	[46]
68	purpurin	T. purpurea	[47]
69	tephrinone	T. villosa	[48]
70	5,7-dimethoxy-8-prenylflavan	T. madrensis	[49]
71	tephrowatsin A	T. watsoniana	[50]
72	tephrowatsin C	T. watsoniana	[50]
73	tephrowatsin B	T. watsoniana	[50]
74	tephrowatsin D	T. watsoniana	[50]
75	tephrowatsin E	T. watsoniana	[50]
76	nitenin	T. nitens	[51]
77	falciformin	T. falciformis	[52]
78	candidone	T. candida	[53]
79	quercetol A	T. quercetorum	[54]
80	quercetol B	T. quercetorum	[54]
81	quercetol C	T. quercetorum	[54]
82	5,7-dimethoxy-8-(2,3-epoxy-3-methylbutyl)-flavanone	T. hamiltonii	[55]
83	tephroleocarpin A	T. leiocarpa	[56]
84	tephroleocarpin B	T. leiocarpa	[56]
85	spinoflavanone A	T. spinosa	[57]
86	spinoflavanone B	T. spinosa	[57]
87	maxima flavanone A	T. maxima	[58]
88	tepicanol A	T. tepicana	[59]
89	crassifolin	T. crassifolia	[60]
90	astraciceran	T. strigosa	[61]
91	(+)-apollineanin	T. apollinea	[62]
92	(2S)-5,4'-dihydroxy-7-O-[E-3,7-dimethyl-2,6-octadienyl]flavanone	T. villosa	[63]
Isoflavones
93	(2S)-5,4'-dihydroxy-7-O-[E-3,7-dimethyl-2,6-octa-dienyl]-8-C-[E-3,7-dimethyl-2,6-octadienyl]flavanone	T. villosa	[63]
94	7,4'-dihydroxy-3',5'-dimethoxyisoflavone	T. purpurea	[5]
95	emoroidocarpan	T. emoroides	[22]
96	elongatin	T. elongate	[64]
97	pumilaisoflavone D	T. pumila	[65]
98	pumilaisoflavone C	T. pumila	[65]
99	barbigerone	T. barbigera	[66]
100	4'-demethyltoxicarol isoflavone	T. polyphylla	[67]
101	maxima isoflavone D	T. maxima	[68]
102	maxima isoflavone E	T. maxima	[68]
103	maxima isoflavone F	T. maxima	[68]
104	maxima isoflavone G	T. maxima	[68]
105	viridiflorin	T. viridiflora	[69]
106	maxima isoflavone J	T. maxima	[70]
107	pumilaisoflavone A	T. pumila	[71]
108	pumilaisoflavone B	T. pumila	[71]
109	7-O-geranylbiochanin A	T. tinctoria	[72]
110	5,7-di-O-prenylbiochanin A	T. tinctoria	[73]
111	toxicarol	T. toxicaria	[74]
112	villosinol	T. villosa	[75]
113	villosol	T. villosa	[75]
114	villosin	T. villoss	[76]
115	villol	T. villoss	[76]
116	villosone	T. villoss	[76]
117	villinol	T. villoss	[76]
118	dehydrodihydrorotenone	T. candida	[77]
119	dihydrostemonal	T. pentaphylla	[78]
120	9-demethyldihydrostemonal	T. pentaphylla	[78]
121	6-acetoxydihydrostemonal	T. pentaphylla	[78]
122	6a,12a-dehydro-2,3,6-trimethoxy-8-(3',3'-dimethylallyl)-9,11-dihydroxyrotenone	T. villosa	[79]
123	12a-dehydro-6-hydroxysumatrol	T. villosa	[80]
124	12a-hydroxyrotenone	T. uniflora	[81]
125	12a-hydroxy-β-toxicarol	T. candida	[82]
126	tephrosol	T. villosa	[83]
127	tephrocarpin	T. bidwilli	[84]
128	hildecarpin	T. hildebrandtii	[85,86]
129	hildecarpidin	T. hildebrandtii	[87]
130	2-methoxy-3,9-dihydroxy coumestone	T. hamiltonii	[88]
131	3,4:8,9-dimethylenedioxypterocarpan	T. aequilata	[89]
132	tephcalostan	T. calophylla	[90]
133	tephcalostan B	T. calophylla	[91]
Chalcones
134	tephcalostan C	T. calophylla	[91]
135	tephcalostan D	T. calophylla	[91]
136	candidachalcone	T. candida	[2]
137	O-methylpongamol	T. purpurea	[3]
138	(+)-tephrosone	T. purpurea	[4]
139	(+)-tephropurpurin	T. purpurea	[5]
140	2',6'-dimethoxy-4',5'-(2''2''dimethyl)-pyranochalcone	T. pulcherrima	[7]
141	(S)-elatadihydrochalcone	T. elata	[14]
142	purpuritenin	T. purpurea	[15]
143	praecansone A	T. praecans	[28]
144	praecansone B	T. praecans	[28]
145	obovatachalcone	T. obovata	[45]
146	spinochalcone C	T. spinosa	[57]
147	crassichalone	T. crassifolia	[60]
148	oaxacacin	T. woodii	[92]
149	6'-demethoxypraecansone B	T. purpurea	[93]
150	tephrone	T. candida	[94]
151	spinochalcone A	T. spinosa	[95]
152	spinochalcone B	T. spinosa	[95]
153	3',5'-diisopentenyl-2',4'-dihydroxychalcone	T. spinosa	[96]
154	tunicatachalcone	T. tunicate	[97]
155	epoxyobovatachalcone	T. carrollii	[98]
156	2',6'-dihydroxy-3'-prenyl-4'-methoxy-β-hydroxychalcone	T. major	[99]
Other Flavonoids
157	purpureamethied	T. purpurea	[15]
158	calophione A	T. calophylla	[91]
159	tephrospirolactone	T. candida	[100]
160	tephrospiroketone I	T. candida	[100]
161	tephrospiroketone II	T. candida	[100]
Triterpenoid
162	oleanolic acid	T. strigosa	[61]
Sesquiterpenes
163	1β-hydroxy-6,7α-dihydroxyeudesm-4(15)-ene	T. candida	[2]
164	linkitriol	T. purpurea	[34]
165	1β,6α,10α-guai-4(15)-ene-6,7,10-triol	T. vogelii	[101]
Others
166	2-propenoic acid, 3-(4-(acetyloxy) -3-methoxypheny)-3(4-actyloxy)-3-methoxyphenyl)-2-propenyl ester	T. purpurea	[34]
167	cineroside A	T. cinerea	[35]
168	(+)-lariciresinol-9'-stearate	T. vogelii	[101]

Figure 1

Flavones from genus Tephrosia.

Figure 2

Flavonols from genus Tephrosia.

Figure 3

Flavanonols from genus Tephrosia.

Figure 4

Flavans from genus Tephrosia.

Figure 5

Isoflavones from genus Tephrosia.

Figure 6

Chalcones from genus Tephrosia.

Figure 7

Other flavonoids from genus Tephrosia.

Figure 8

Triterpenoid from genus Tephrosia.

Figure 9

Sesquiterpenes from genus Tephrosia.

Figure 10

Other compounds from genus Tephrosia.

2.1. Flavonoids

Flavonoids were the most main constituents of the genus Tephrosia, even of the Leguminosae family. From the year of 1971, 161 flavonoids isolated from the genus Tephrosia are divided into several categories depending on their skeletons (Figure 1, Figure 2, Figure 3, Figure 4, Figure 5, Figure 6 and Figure 7).

2.1.1. Flavones

Thirty-one flavones (1–31), were isolated from T. polystachyoides, T. semiglabra, T. multijuga, T. polystachya, T. praecans, T. apollinea, T. candida, T. purpurea, T. fulvinervis, T. viciodes, T. emoroids and T. hookeriana [3,10,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38].

2.1.2. Flavonols

Eight flavonols (32–39), were isolated, four, i.e., 32–34 were obtained from T. vogelii [1], one, i.e., 35–38, from T. candida [39,40,41,42] and 39 from T. procumbens [43].

2.1.3. Flavanonols

Only three flavanonols, 40, 41 and 42 were isolated from T. vogelii and T. lupinifolia, respectively [1,44].

2.1.4. Flavans

Fifty-one flavans, 43–93, were isolated from twenty-three species of the genus Tephrosia, i.e., T. obovata, T. villosa, T. madrensis, T. nitens, T. watsoniana, T. hildebrandtii, T. falciformis, T. hamiltonii, T. quercetorum, T. leiocarpa, T. spinosa, T. maxima, T. emoroides, T. tepicana, T. crassifolia, T. strigosa, T. pumila, T. calophylla, T. vogelii, T. apollinea, T. candida, T. purpurea and T. fulvinervis [1,2,4,6,13,22,23,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63].

2.1.5. Isoflavones

Forty-two isoflavones, 94–135, have been isolated and identified from this genus [5,22,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91]. Among them, 111–125 were identified as rotenoids [74,75,76,77,78,79,80,81,82], 94 and 126–135 were identified as coumestan derivatives [22,83,84,85,86,87,88,89,90,91].

2.1.6. Chalcones

Twenty-one chalcones, 136–156, isolated from twelve species of genus Tephrosia, i.e., T. obovata, T. praecans, T. purpurea, T. candida, T. woodii, T. spinosa, T. crassifolia, T. tunicate, T. carrollii, T. major, T. pulcherrima and T. elata [2,3,4,5,7,14,15,28,45,57,60,92,93,94,95,96,97,98,99].

2.1.7. Other Flavonoids

157 was isolated from T. purpurea seeds [15]. 158 was isolated from T. calophylla [91]. 159–161 were isolated from T. candida [100].

2.2. Triterpenoid

Only one triterpenoid has been isolated from this genus, that is 162 from T. strigosa [61].

2.3. Sesquiterpenes

Three sesquiterpenes, 163, 164 and 165 were isolated from T. candida [2], T. purpurea [33] and T. vogelii [101], respectively.

2.4. Others

166–168 have been isolated from T. purpurea [34], T. cinerea [35] and T. vogelii [101], respectively.

3. Proposed Biosynthetic Pathways and Synthesis

8-Substituted isoflavonoids such as toxicarol isoflavone and rotenoids are well known [3]. Compounds 4–6 from T. polystachyoides could be explained to be evolved biogenetically from naturally occurring chrysins (A) as illustrated in the Scheme 1 [102]. It would appear that the complex substituents at C-8 arise from the ability of Tephrosia species to oxidise a 7-OMe group to a ‒O+=CH2 group (Scheme 2), in the same way that closely related species of Leguminosae oxidise the 2'-OMe group of isoflavonoids to yield rotenoids [103]. A pattern that explains the various C-8 substituents in T. purpurea and T. apollinea is shown in Scheme 3. In T. polystachoides this process is taken even further and the carbon of yet another 7-OMe group is incorporated into the additional rings attached to C-7 and C-8 (Scheme 4) [3]. We could confirm the structures of compounds 7 and 8 by their conversion into semiglabrinone, isoemiglabrinone and tephroglabrin (3) as shown in Scheme 5 [3]. Purpuritenin (142) was isolated from T. purpurea has been synthesed as showed in Scheme 6 [104].

Scheme 1

Possible biogenetic pathway of compounds 4–6 of T. polystachyoides.

Scheme 2

Possible biogenetic pathway of compounds 8 and 11.

Scheme 3

Possible biogenetic pathway of compounds 3, 8, 11, 27 and 137.

Scheme 4

Possible biogenetic pathway of compounds 4, 5 and 137.

Scheme 5

Transform of compounds 3 and 8.

Scheme 6

The synthesis of 144.

4. Biological Activities

The chemical constituents from the genus Tephrosia have been shown to exhibit various bioactivities, such as estrogenic, antitumor, antimicrobial, antiprotozoal, and antifeedant activities [2,105].

4.1. Estrogenic Activity

Candidachalcone (136) isolated from T. candida exhibited estrogenic activity with IC50 value of 80 µM, compared with 18 µM for the natural steroid 17 β-estradiol [2].

4.2. Antitumor Activities

Calophione A (158) and tephcalostans B–D (133–135) from T. calphylla were evaluated for cytotoxicity against RAW (mouse macrophage cells) and HT-29 (colon cancer cells) cancer cell lines. 158 exhibited significant cytotoxicity with IC50 of 5.00 (RAW) and 2.90 µM (HT-29), respectively, while 133–135 showed moderated cytotoxicity against both RAW and HT-29 cell lines [91]. (+)-Tephrorins A (49) and B (50), and (+)-tephrosone (138) isolated from T. purpurea were evaluated for their potential cancer chemopreventive properties using a cell-based quinone reductase induction assay [4]. 7,4'-dihydroxy-3',5'-dimethoxyisoflavone (94), and (+)-tephropurpurin (139), were obtained as active compounds from T. purpurea, using a bioassay based on the induction of quinone reductase (QR) activity with cultured Hepa 1c1c7 mouse hepatoma cells [5].

4.3. Antimicrobial Activities

2',6'-Dimethoxy-4',5'-(2'',2''-dimethyl)-pyranochalcone (140) from T. pulcherrima showed significant antimicrobial activity when tested against a series of micro-organisms [7]. 3,4:8,9-Dimethylenedioxypterocarpan (131) from T. aequilata exhibited low activity against gram-positive bacteria, Bacillus subtilis and Micrococcus lutea [89]. Hildecarpin (128) from T. hildebrandtii had exhibited antifungal activity against Cladosporium cucumerinum [85,86].

4.4. Antiprotozoal Activities

Terpurinflavone (31) isolated from T. purpurea showed the highest antiplasmodial activity against the chloroquine-sensitive (D6) and chloroquine-resistant (W2) strains of Plasmodium falciparum with IC50 values of 3.12 ± 0.28 µM (D6) and 6.26 ± 2.66 µM (W2) [38]. The crude extract of the seedpods of T. elata showed antiplasmodial activities against D6 and W2 strains of P. falciparum with IC50 values of 8.4 ± 0.3 and 8.6 ± 1.0 µg/mL, respectively [14]. Obovatin (61) and obovatin methyl ether (62) from T. obovata [45] showed antiplasmodial activities against D6 and W2 strains of P. falciparum with IC50 values of 4.9 ± 1.7 and 6.4 ± 1.1 µg/mL, and 3.8 ± 0.3 and 4.4 ± 0.6 µg/mL, respectively [14]. (S)-Elatadihydrochalcone (141) from T. elata exhibited good antiplasmodial activity against the D6 and W2 strains of P. falciparum with IC50 values of 2.8 ± 0.3 (D6) and 5.5 ± 0.3 µg/mL (W2), respectively [14]. Tephcalostans C (134) and D (135) from T. calphylla were found to be weakly antiprotozoal activity in vitro [91]. Pumilanol (53) from T. pumila exhibited significant antiprotozoal activity against T. b. rhodensiense, T. cruzi and L. donovani with IC50 of 3.7, 3.35 and 17.2 µg/mL, respectively, but displayed high toxicity towards L-6 (IC50 of 17.12 µg/mL) rat skeletal myoblasts [13]. Tephrinone (69) from T. villosa [48] also exhibited high degree of activity and selectivity against both T. b. rhodensiense, T. cruzi and L. donovani with IC50 of 3.3 and 16.6 µg/mL [13].

4.5. Antifeedant Activities

Emoroidenone (54) from T. emoroides showed strong feeding deterrent activity against Chilo partellus larvae with a mean percentage deterrence of 66.1% at a dose of 100 µg/disc [22]. Hildecarpin (128) from T. hildebrandtii had exhibited insect antifeedant activity against the legume pod-borer Maruca testulalis, and important pest of cowpea (Vigna) [85,86].

4.6. Other Activities

(−)-Pseudosemiglabrin (19) from T. semiglabra displayed in vitro inhibitory effects on human platelet aggregation [26]. Obovatin (61), obovatin methyl-ether (62) and obovatachalcone (145) from T. obovata displayed moderate piscicidal activity against loach fish Misgurnus angullicaudatus. The TLm (median tolerance limit) values of 61, 62 and 145 were 1.25, 1.55 and 1.35 ppm, respectively [45]. Toxicarol (111) was a constituent of the South American fish poison T. toxicaria [74].

5. Conclusions

The genus Tephrosia, including ca. 400 species, with ca. 52 species being investigated worldwide, was reported to possess various chemical constituents and to display diverse bioactivities, especially antiplasmodial, estrogenic, antitumor, antimicrobial, antiprotozoal, antifeedant activities. Although the number of natural compounds was isolated from this genus, there are still many Tephrosia species that received no little attention further, phytochemical and biological studies on this genus are needed in the future. In addition, the biosynthetic pathways and synthesis of these bioactive molecules in the genus remained largely unexplored. Thus, much more chemical, biosynthetic, synthetic and biological studies should be carried out on natural compounds in Tephrosia species in order to disclose their potency, selectivity, toxicity, and availability.