Recent studies on the chemical constituents of Trigonostemon plants

Jin-Biao Xu and Jian-Min Yue *
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhangjiang Hi-Tech Park, Shanghai, 201203, People's Republic of China. E-mail: jmyue@simm.ac.cn; Fax: (+86) 21-50806718

Received 30th May 2014 , Accepted 5th October 2014

First published on 6th October 2014


Abstract

The plants of the Trigonostemon genus (Euphorbiaceae family) comprising about 50 species are mainly distributed in tropical and subtropical Asia. Chemical studies on this plant genus have led to the discovery of about 200 structurally diverse compounds in the last two decades, some of which have shown promising biological activities. Diterpenoids and alkaloids are the major and most important components of Trigonostemon plants, and are also the hot topics in synthetic chemistry. This review was attempted to provide the timely and comprehensive coverage of the chemical and biological studies on Trigonostemon plants, and especially to focus on the recent research progress.


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Jin-Biao Xu

Jin-Biao Xu was born in Fujian, China, in 1985. He received his B.S. degree in Pharmaceutical Engineering from Jiangsu University in 2008. In 2009, he joined the research group of Professor Jian-Min Yue as a Ph.D. candidate at Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences (CAS), where he worked for his Ph.D. dissertation in natural products chemistry, and published 5 papers in peer-reviewed journals.

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Jian-Min Yue

Jian-Min Yue is a full-time Professor in Medicinal Chemistry at Shanghai Institute of Materia Medica (SIMM), CAS. He received his B.Sc. degree in Chemistry in 1984 from Lanzhou University, where he received his Ph.D. degree in Organic Chemistry in 1990. After his post-doctoral research at Kunming Institute of Botany (KIB), CAS (1991–1993), and University of Bristol (1993–1994), he worked at KIB as an Associate Professor (1994–1996). He joined the staff of the Joint Laboratory of Unilever Research and the Shanghai Institute of Organic Chemistry, CAS, as a Senior Research Scientist (1996–1999) in Natural Products Chemistry. He then moved to SIMM where he has been working up to now. During his research career, he has published over 250 scientific papers, book chapters, and patents. He currently serves as an associate editor of Natural Products and Bioprospecting, and is an editorial member for Journal of Asian Natural Products Research, and Journal of Chinese Pharmaceutical Sciences. His group is actively involved in the isolation, structure determination, and synthetic optimization of natural products, and is currently focusing on natural products with significant bioactivities against infectious diseases, cancer, and neurodegenerative disorders.


1. Introduction

The Trigonostemon genus belongs to the Euphorbiaceae family, and comprises about 50 species globally. The plants of this genus are trees or shrubs, and are mainly distributed in tropical and subtropical Asia.1 The plants of the Trigonostemon genus have long been used as folk medicine to treat asthma, diarrhea, and skin diseases in China and Thailand. These plants metabolize diverse compound classes including diterpenoids, triterpenoids, alkaloids, phenolics, and steroids. In particular, the structurally highly modified and biologically active daphnane diterpenoids and/or daphnane diterpenoid orthoesters (DDOs), and some alkaloids are the most important components, which have attracted great interest from the scientific communities in both natural products and organic synthesis fields. Since the first chemical investigation on the plant T. reidioides in 1990,2 over 10 plant species of the Trigonostemon genus have been extensively investigated chemically in the last two decades, which resulted in the isolation of about 200 structurally diversified compounds including terpenoids (triterpenoids, diterpenoids, and sesquiterpenoids), alkaloids, phenolics (flavonoids, lignans, coumarins, and phenyl propanoids), and steroids.3

Recently, a minireview was provided by Chen's group,3 which included a total of 66 compounds isolated from Trigonostemon plants before early 2010. From that time on, a rapid research progress has been witnessed, e.g. over 117 new compounds with diverse structures along with a large array of known analogues were isolated and characterized from eight species of Trigonostemon plants. Biological evaluation of these isolates revealed that some of the compounds, e.g. daphnane diterpenoids and alkaloids, show a wide spectrum of significant biological activities. A number of diterpenoids and alkaloids isolated from this plant genus with interesting frameworks and/or important bioactivities have also been successfully synthesized. The present report is aimed to provide a timely update and a comprehensive summary of the chemical and biological studies of this plant genus, and to serve as a pointer to their diverse applications. The main aspects covered in this review are the chemical components of Trigonostemon plants, the biosynthetic considerations of the major metabolites, their biological activities, and the synthetic work on some important diterpenoids and alkaloids isolated. For the compounds described in the previous review, this report only tabulated their chemical names, structures, occurrences, and distributions in the plants, as well as their bioactivities, but no detailed discussions are further made.

2. Chemical constituents

2.1. Diterpenoids

Diterpenoids are the major and most important ingredients of Trigonostemon plants, which included the compound types of daphnane, norditerpenoid dimer, phenanthrenone, abietane, 3,4-seco cleistanthane, and tigliane.
2.1.1. Daphnane diterpenoids. A large number of daphnane diterpenoids were isolated from the genus Trigonostemon in the last two decades. This review included 90 daphnane diterpenoids (Table 1) obtained from the eight species of Trigonostemon plants, T. reidioides, T. thyrsoideum, T. chinensis, T. cherrieri, T. xyphophylloides, T. howii, T. lii, and T. heterophyllus. According to the modification and esterification patterns, they were categorized into five groups in this review, i.e. highly modified macrocyclic daphnane diterpenoid 9,12,14-orthoesters (Fig. 1), daphnane diterpenoid 9,12,14-orthoesters (Fig. 2), daphnane diterpenoid 9,13,14-orthoesters (Fig. 3), daphnane diterpenoid 12,13,14-orthoesters (Fig. 4), and simple daphnane (Fig. 5).
image file: c4qo00161c-f1.tif
Fig. 1 The structures of highly modified macrocyclic daphnane diterpenoid 9,12,14-orthoesters.

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Fig. 2 The structures of daphnane diterpenoid 9,12,14-orthoesters.

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Fig. 3 The structures of daphnane diterpenoid 9,13,14-orthoesters.

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Fig. 4 The structures of daphnane diterpenoid 12,13,14-orthoesters.

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Fig. 5 The structures of simple daphnane diterpenoids.
Table 1 Daphnane diterpenoids in the genus Trigonostemon
No. Compound Source Part Ref.
Highly modified macrocyclic daphnane diterpenoid 9,12,14-orthoesters
1 Rediocide A T. reidioides Stems, leaves and wood 4
2 Rediocide C T. reidioides Roots 5
3 Rediocide E T. reidioides Roots 5
4 Rediocide F T. reidioides Roots 6
5 Trigothysoid O T. thyrsoideum Twigs and leaves 10
6 Trigothysoid P T. thyrsoideum Twigs and leaves 10
7 Trigonosin E T. thyrsoideum Roots 9
8 Trigonosin F T. thyrsoideum Roots 9
9 Trigothysoid N T. thyrsoideum Twigs and leaves 10
10 Rediocide G T. reidioides Roots 7
11 Rediocide B T. reidioides Roots 5
12 Rediocide D T. reidioides Roots 5
13 Trigochilide A T. chinensis Leaves and twigs 8
14 Trigochilide B T. chinensis Leaves and twigs 8
15 Trigocherriolide A T. cherrieri Bark and wood 11
16 Trigocherriolide C T. cherrieri Bark and wood 11
17 Trigocherriolide B T. cherrieri Bark and wood 11
18 Trigocherriolide D T. cherrieri Bark and wood 11
19 Trigocherriolide E T. cherrieri Leaves 12
 
Daphnane diterpenoid 9,12,14-orthoesters
20 Trigocherrin A T. cherrieri Bark 13
21 Trigocherrin B T. cherrieri Bark and wood 11
22 Trigocherrin C T. cherrieri Bark and wood 11
23 Trigocherrin D T. cherrieri Bark and wood 11
24 Trigocherrin F T. cherrieri Bark and wood 11
25 Trigocherrin E T. cherrieri Bark and wood 11
26 Trigochinin C T. chinensis Twigs and leaves 14
27 Trigothysoid K T. thyrsoideum Twigs and leaves 10
28 Trigoxyphin D T. xyphophylloides Twigs 15
29 Trigoxyphin E T. xyphophylloides Twigs 15
30 Trigohownin A T. howii Twigs 16
31 Trigohownin B T. howii Twigs 16
32 Trigohownin C T. howii Twigs 16
 
Daphnane diterpenoid 9,13,14-orthoesters
33 Trigonosin A T. thyrsoideum Roots 9
34 Trigonosin B T. thyrsoideum Roots 9
35 Trigonosin D T. thyrsoideum Roots 9
36 Trigothysoid D T. thyrsoideum Twigs and leaves 10
37 Trigothysoid E T. thyrsoideum Twigs and leaves 10
38 Trigothysoid F T. thyrsoideum Twigs and leaves 10
39 Trigothysoid G T. thyrsoideum Twigs and leaves 10
40 Trigoheterin D T. heterophyllus Twigs 18
41 Trigohownin E T. howii Twigs 16
42 Trigothysoid A T. thyrsoideum Twigs and leaves 10
43 Trigothysoid B T. thyrsoideum Twigs and leaves 10
44 Trigothysoid C T. thyrsoideum Twigs and leaves 10
45 Trigonothyrin G T. thyrsoideum Stems 17
46 Trigothysoid M T. thyrsoideum Twigs and leaves 10
47 Trigocherrierin A T. cherrieri Leaves 12
48 Trigonothyrin F T. thyrsoideum Stems 17
49 Trigoheterin C T. heterophyllus Twigs 18
50 Trigohownin D T. howii Twigs 16
51 Trigoheterin E T. heterophyllus Twigs 18
52 Trigoxyphin F T. xyphophylloides Twigs 15
53 Trigoxyphin I T. xyphophylloides Twigs 19
54 Trigoxyphin B T. xyphophylloides Twigs 15
55 Trigoxyphin C T. xyphophylloides Twigs 15
56 Trigochinin G T. chinensis Twigs and leaves 22
57 Trigochinin H T. chinensis Twigs and leaves 22
58 Trigochinin I T. chinensis Twigs and leaves 22
59 Trigoxyphin J T. xyphophylloides Stems 20
60 Trigoxyphin A T. xyphophylloides Twigs 15
61 Trigoxyphin K T. xyphophylloides Stems 20
62 Trigoxyphin H T. xyphophylloides Twigs 19
Daphnane diterpenoid 12,13,14-orthoesters
63 Trigonothyrin A T. thyrsoideum Stems 21
64 Trigonothyrin B T. thyrsoideum Stems 21
65 Trigonothyrin C T. thyrsoideum Stems 21
66 Trigothysoid L T. thyrsoideum Twigs and leaves 10
 
Simple daphnane diterpenoids
67 Trigochinin A T. chinensis Twigs and leaves 14
68 Trigochinin B T. chinensis Twigs and leaves 14
69 Trigochinin D T. chinensis Twigs and leaves 22
70 Trigochinin E T. chinensis Twigs and leaves 22
71 Trigochinin F T. chinensis Twigs and leaves 22
72 Trigonosin E T. thyrsoideum Roots 9
73 Trigolin A T. lii Stems 23
74 Trigolin B T. lii Stems 23
75 Trigolin C T. lii Stems 23
76 Trigolin D T. lii Stems 23
77 Trigolin E T. lii Stems 23
78 Trigolin F T. lii Stems 23
79 Trigolin G T. lii Stems 23
80 Trigothysoid H T. thyrsoideum Twigs and leaves 10
81 Trigothysoid I T. thyrsoideum Twigs and leaves 10
82 Trigothysoid J T. thyrsoideum Twigs and leaves 10
83 Trigonothyrin D T. thyrsoideum Stems 17
84 Trigonothyrin E T. thyrsoideum Stems 17
85 Trigoheterin A T. heterophyllus Twigs 18
86 Trigoheterin B T. heterophyllus Twigs 18
87 Trigohownin F T. howii Twigs 16
88 Trigohownin G T. howii Twigs 16
89 Trigohownin H T. howii Twigs 16
90 Trigohownin I T. howii Twigs 16



2.1.1.1. Highly modified macrocyclic daphnane diterpenoid 9,12,14-orthoesters. Rediocide A (1), the first highly modified daphnane diterpenoid, was obtained from the leaves and stems of T. reidioides collected from Thailand by Singh's group in 2000 via a bioassay guided identification that was designed to kill mosquito larvae (Aedes aegypti). Rediocide A possessed a 9,12,14-orthoester group and an unusual 12-carbon polyketide appendage at C-16 furnishing a macro-lactone ring with C-3 (Fig. 1).4 Four additional minor analogues, rediocides B–E (11, 2, 12, and 3, resp.), were reported by the same research group from its roots four years later.5 Soon afterwards, Wongsinkongman's and Ruchirawat's groups identified two more congeners, rediocides F (4)6 and G (10),7 from the roots of the same Thai plant, respectively. In 2009, from the leaves of a Chinese species T. chinensis native to Yunnan Province of China, our research group reported the isolation of two unique macrocyclic daphnane diterpenoid 9,12,14-orthoesters, trigochilides A (13) and B (14), for the first time.8 Trigochilide A featured a unique 12-carbon polyketide appendage with a cyclopropane ring. Several years later, Hao's group reported five analogues, trigonosins E (7) and F (8) in 2011,9 and trigothysoids N–P (9, 5, and 6, resp.) in 2013[thin space (1/6-em)]10 from a Yunnan species T. thyrsoideum. Litaudon's group also identified five additional analogues trigocherriolides A–E (15–19) from T. cherrieri in 2012 and 2014, sequentially.11,12 The diagnostic features of this class of compounds are daphnane diterpenoids with diverse 12-carbon-containing polyketide appendages and a common 9,12,14-orthoester motif.
2.1.1.2. Daphnane diterpenoid 9,12,14-orthoesters. Trigocherrin A (20) (Fig. 2) was the first example of natural chlorinated daphnane diterpenoid 9,12,14-orthoester isolated by Litaudon et al. from the bark of T. cherrieri collected from the Poya region in the west of New Caledonia.13 The absolute configuration of 20 was determined by a combined strategy of comparing the experimental electronic circular dichroism (ECD) data with that of calculated ECD. Four more chlorinated congeners, trigocherrins B–F (21–25), were also reported from the bark and wood of T. cherrieri in the same period by the same research group.11 Two novel daphnane diterpenoid 9,12,14-orthoesters trigochinin C (26)14 and trigothysoid K (27)10 with a unique 4β,6β-oxetanyl group were isolated from twigs and leaves of T. chinensis and T. thyrsoideum, respectively. The absolute structure of trigochinin C was confirmed by X-ray crystallography analysis. Five highly oxygenated daphnane diterpenoid 9,12,14-orthoesters, trigoxyphins D (28) and E (29)15 from the twigs of T. xyphophylloides, and trigohownins A–C (30–32)16 from the twigs of T. howii, were further reported by Yue's research group, and both of the plant samples were collected from the Sanya area in Hainan Island of China.
2.1.1.3. Daphnane diterpenoid 9,13,14-orthoesters. To date, 30 daphnane diterpenoid 9,13,14-orthoesters (Fig. 3) have been isolated from the plants of T. thyrsoideum, T. heterophyllus, T. howii, T. chinensis, T. cherrieri, and T. xyphophylloides. In this class, 16 compounds including trigonosins A (33), B (34) and D (35),9 trigothysoid M (46),10 trigocherrierin A (47),12 trigonothyrin F (48),17 trigoheterins C (49) and E (51),18 trigohownin D (50),16 trigoxyphins A–C (60, 54, and 55, resp.),15 F (52),15 H (62),19 I (53),19 and K (61)20 possessed the same 9,13,14-orthobenzoate moiety at the six-membered C-ring, while the rest of the 14 analogues, namely trigothysoids A–E (42–44, 36–39, resp.),10 trigoheterin D (40),18 trigohownin E (41),16 trigonothyrin G (45),17 trigochinins G–I (56–58),22 and trigoxyphin J (59),20 furnished a common 9,13,14-orthoacetate at the C-ring. For the most of these daphnane diterpenoids, the H-10 was α-configured, but trigoxyphins H (62) and I (53) were the exceptions, where the H-10 was β-directed.
2.1.1.4. Daphnane diterpenoid 12,13,14-orthoesters. Trigonothyrins A–C (63–65) (Fig. 4) were isolated from stems of T. thyrsoideum collected from the Yunnan Province of China by Liu's group.21 Three compounds shared the common characteristics of a 12,13,14-orthoacetate and a unique 4β,6β-oxetanyl moiety. The relative configurations of the 4,6-oxetanyl moiety in the B-ring of 63–65 were first assigned as 4β,6α-oriented, which was indicated to be a wrong assignment shortly afterwards by Yue's group in a related paper.14 Three structures were then revised accordingly by Liu's group.17 Trigothysoid L (66) was isolated from twigs and leaves of T. thyrsoideum collected from the same area by Hao's group quite recently.10
2.1.1.5. Simple daphnane diterpenoids. The rest 24 compounds are the simple daphnane diterpenoids (67–90) without the macrocyclic polyketide appendages and/or orthoester groups (Fig. 5). In this compound category, trigochinins A (67), B (68),14 D–F (69–71)22 were isolated from the twigs and leaves of T. chinensis, a plant growing in the Yunnan Province of China; trigoheterins A (85) and B (86)18 were obtained from the twigs of T. heterophyllus collected from Hainan Province of China, and trigohownins F–I (87–90)16 were from the twigs of a Hainan plant T. howii. Trigolins A–G (73–79)23 were obtained from the stems of T. lii native to Yunnan. Trigonosin E (72)9 and trigothysoids H–J (80–82)10 were isolated from twigs and leaves of T. thyrsoideum, a plant native to Yunnan Province of China, and trigonothyrins D (83) and E (84)17 were isolated from stems of the same plant. From the structural view, compounds 67–86 featured a unique 4β,6β-oxetanyl group at the B-ring.
2.1.2. Norditerpenoid dimers. There was no report on the dimeric diterpenoids from the Trigonostemon genus before the last minireview.3 Recently, 15 norditerpenoid dimers have been isolated from three Trigonostemon plants, T. heterophyllus, T. howii, and T. xyphophylloides (Table 2).
Table 2 Norditerpenoid dimers, phenanthrenones, abietanes, 3,4-seco-cleistanthanes, and tigliane diterpenoids
No. Compound Source Part Ref.
Norditerpenoid dimers
91 Trigoflavidol A T. flavidus Stems 24
92 Trigoflavidol B T. flavidus Stems 24
93 Trigohowilol C T. howii Stems 25
94 Trigohowilol D T. howii Stems 25
95 Trigohowilol E T. howii Stems 25
96 Trigohowilol F T. howii Stems 25
97 Neoboutomannin T. flavidus Stems 24
98 Trigohowilol G T. howii Stems 25
99 Trigoxyphin S T. xyphophylloides Twigs 26
100 Trigoxyphin T T. xyphophylloides Twigs 26
101 Trigoxyphin O T. xyphophylloides Twigs 26
102 Trigoxyphin R T. xyphophylloides Twigs 26
103 Trigoxyphin P T. xyphophylloides Twigs 26
104 Trigoxyphin Q T. xyphophylloides Twigs 26
105 Trigoxyphin J T. xyphophylloides Twigs 27
 
Phenanthrenone diterpenoids
106 Trigoflavidol C T. flavidus Stems 24
107 Trigonochinene E T. flavidus Stems 24
108 Thrigonosomone A T. lii Roots and stems 28
109 Thrigonosomone B T. lii Roots and stems 28
110 Trigonostemone T. reidioides Roots 2
111 6,9-O-Dedimethyl-thrigonosomone A T. lii Roots and stems 28
112 Trigonostemon E T. chinensis Stem bark and wood 29
113 Trigohowilol A T. howii Stems 25
114 Trigohowilol B T. howii Stems 25
115 Trigoxyphin G T. xyphophylloides Twigs 15
116 Trigoxyphin K T. xyphophylloides Twigs 27
117 Trigoxyphin L T. xyphophylloides Twigs 27
118 Trigoxyphin M T. xyphophylloides Twigs 27
119 Trigoxyphin N T. xyphophylloides Twigs 27
 
Abietane dinorditerpenoids
120 12-Hydroxy-13-methylpodocarpa-9,11,13-trien-3-one T. howii Stems 25
121 Trigonostemon A T. chinensis Stem bark and wood 29
122 Dihydroheudelotinol T. chinensis Stem bark and wood 29
123 Trigonostemon B T. chinensis Stem bark and wood 29
124 5S-Heudelotinone T. chinensis Stem bark and wood 29
125 Trigonostemon C T. chinensis Stem bark and wood 29
126 Trigonostemon D T. chinensis Stem bark and wood 29
 
3,4-Seco cleistanthane diterpenoids
127 Trigonochinene A T. chinensis Stems and leaves 32
128 Trigonochinene B T. chinensis Stems and leaves 32
129 Trigonochinene C T. chinensis Stems and leaves 32
130 Trigonochinene D T. chinensis Stems and leaves 32
131 3,4-Seco-sonderianol T. chinensis Stems and leaves 32
132 3,4-Seco-sonderianic T. chinensis Stems and leaves 32
133 Trigonoheterene T. heterophyllus Stems 33
134 Trigonoheterene B T. heterophyllus Stems 34
135 Trigoflavidone A T. flavidus Stems 35
136 Trigoflavidone B T. flavidus Stems 35
137 Trigoflavidone C T. flavidus Stems 35
138 Trigoflavidone D T. flavidus Stems 35
139 Trigoflavidone E T. flavidus Stems 35
140 Trigoheteric acid methyl ester T. heterophyllus Twigs 18
 
Tigliane diterpenoid
141 Trigowiin A T. howii Bark 36


A chemical study on the stems of Hainan species T. flavidus led to the isolation of two tetranorditerpenoid dimers, trigoflavidols A (91) and B (92), and a homodimeric diterpenoid, neoboutomannin (97) (Fig. 6).24 Four more heterodimers, trigohowilols C–F (93–96), and one diterpenoid homodimer, trigohowilol G (98), were obtained from the stems of T. howii collected in Sanya, Hainan province of China.25 Additionally, seven more degraded diterpenoid dimers, trigoxyphins O–T and J (99–105), were identified from the twigs of a Hainan species of T. xyphophylloides, in which trigoxyphins S (99) and T (100) are homodimers, trigoxyphins O (101) and R (102) belong to heterodimers, and trigoxyphins P, Q, and J (103–105) are the conjugates of a degraded diterpenoid and a phenylpropanoid.26,27


image file: c4qo00161c-f6.tif
Fig. 6 The structures of norditerpenoid dimers.
2.1.3. Phenanthrenone diterpenoids. In the previous minireview, six phenanthrenone diterpenoids, i.e. thrigonosomones A (108) and B (109),28 trigonostemone (110),2 6,9-O-dedimethyl-thrigonosomone A (111),28 trigonostemon E (112),29 and trigoxyphin G (115),15 were included (Fig. 7). Trigonostemone (110), also named 1,1,7-trimethyl-3,6,9-trimethoxy-2-phenanthrenone, was first isolated from roots of the Thai plant T. reidioides, whose absolute structure was determined by X-ray crystallography.2 Recently, a series of phenanthrenone diterpenoids, e.g. trigoflavidol C (106)24 and trigonochinene E (107)24 from the stems of T. flavidus, and trigohowilols A (113) and B (114)25 from the stems of T. howii were isolated, and both plants were collected from Hainan Island. In addition, four degraded diterpenoids, namely trigoxyphins K–N (116–119), were obtained from the twigs of a Hainan species T. xyphophylloides,27 and they were assigned as neoboutomannin derivatives30 and are structurally related to 1,7-dimethyl-9-methoxyphenanthrene.31
image file: c4qo00161c-f7.tif
Fig. 7 The structures of phenanthrenone diterpenoids in the genus Trigonostemon.
2.1.4. Abietane dinorditerpenoids. Seven abietane type dinorditerpenoids were obtained from the plants of T. howii and T. chinensis (Table 2, Fig. 8). An abietane dinorditerpenoid, namely 12-hydroxy-13-methylpodocarpa-9,11,13-trien-3-one (120), was isolated from T. howii, a plant that is native to Hainan Province of China.25 Six compounds, trigonostemons A–D (121, 123, 125, and 126, resp.), dihydroheudelotinol (122), and heudelotinone (124) were identified from the stem bark and wood of T. chinensis, which was collected from Guangxi Province of China.29 The absolute configuration of trigonostemon A (121) was determined by X-ray crystallography. Compounds (121–126) possessed a rearranged skeleton of dinorditerpenoid that was suggested to be biosynthetically originated from 12-hydroxy-13-methylpodocarpa-9,11,13-trien-3-one (120).25
image file: c4qo00161c-f8.tif
Fig. 8 The structures of abietane dinorditerpenoids.
2.1.5. 3,4-Seco cleistanthane diterpenoids. Except for the isolation of six 3,4-seco cleistanthane diterpenoids (Table 2), namely trigonochinenes A–D (127–130), 3,4-seco-sonderianol (131), and 3,4-seco-sonderianic acid (132), from a Hainan species T. chinensis32 as summarized in the previous minireview, eight more 3,4-seco cleistanthane diterpenoids (Fig. 9), i.e. trigonoheterene (133),33 trigonoheterene B (134)34 and trigoheteric acid methyl ester (140)18 from the stems and twigs of T. heterophyllus, and trigoflavidones A–E (135–139)35 from the stems of T. flavidus were isolated, and both plant samples were collected from Hainan Island of China.
image file: c4qo00161c-f9.tif
Fig. 9 The structures of 3,4-seco cleistanthane diterpenoids.
2.1.6. Tigliane diterpenoid. Up to now, only one tigliane diterpenoid, trigowiin A (141, Fig. 10), has been isolated from the bark of T. howii,36 which was collected from Vietnam.
image file: c4qo00161c-f10.tif
Fig. 10 The structure of tigliane diterpenoid.

2.2. Alkaloids

It is particularly interesting that 36 diverse alkaloids of two major classes, β-carboline and indole (simple indole, bisindole, and flavonoidal indole types), were also isolated from Trigonostemon plants. Among them, 11 alkaloids including four types of carboline, simple indole, bisindole and flavonoidal indole were covered in the previous minireview.3 Thereafter, 25 additional alkaloids with diverse carbon skeletons were further identified from the aforementioned Trigonostemon species. In the present review, all the alkaloids isolated from Trigonostemon species were classified into two major classes, namely β-carboline and indole, and are listed in Table 3.
Table 3 Alkaloids in the genus Trigonostemon
No. Compound Source Part Ref.
β-Carboline alkaloids
142 Trigonostemonine A T. lii Roots and stems 38
143 Trigonostemonine B T. lii Roots and stems 38
144 Trigonostemonine C T. lii Roots and stems 38
145 Trigonostemonine D T. lii Roots and stems 38
146 Trigonostemine E T. lii Leaves 39
147 Trigonostemine F T. lii Leaves 39
148 Trigonostemonine E T. lii Roots and stems 38
149 11-Methoxyrutecarprine T. lii Leaves 39
150 2-Methoxyrutecarprine T. lii Leaves 39
151 Trifiline C T. filipes Plant 40
152 Trigonostemonine F T. lii Roots and stems 38
153 Trifiline A T. filipes Plant 40
154 Trifiline B T. filipes Plant 40
155 Trigonostemine A T. lii Leaves 39
156 Trigonostemine B T. lii Leaves 39
157 Trigonostemine C T. lii Leaves 39
158 Trigonostemine D T. lii Leaves 39
159 Arenarine C T. lii Leaves 39
160 Harmicacid methyl ester T. lii Leaves 39
161 1,2,3,4-Tetrahydro-oxo-β-carboline T. lii Leaves 39
162 Norharmine T. lii Leaves 39
163 Harmine T. lii Leaves 39
164 Trigonoine C T. lii Leaves 40
165 Trigonoine A T. lii Leaves 41
166 Trigonoine B T. lii Leaves 41
 
Indole alkaloids
167 Trigonoliimine A T. lii Leaves 42
168 Trigonoliimine B T. lii Leaves 42
169 Trigonoliimine C T. lii Leaves 42
170 Trigonostemon F T. chinensis Stem bark and wood 29
171 Trigolutesin A T. lutescens Twigs 43
172 Trigolutesin B T. lutescens Twigs 43
173 Trigolute A T. lutescens Twigs 43
174 Trigolute B T. lutescens Twigs 43
175 Trigolute C T. lutescens Twigs 43
176 Trigolute D T. lutescens Twigs 43
177 Lotthanongine T. reidioides Roots 44


2.2.1. β-Carboline alkaloids. β-Carbolines are a class of structurally interesting and biologically important alkaloids possessing a common tricyclic pyrido[3,4-b]indole ring system.37 In addition to six β-carboline alkaloids, trigonostemonines A–D (142–145), E (148), and F (152) presented in the former review,3,38 16 additional β-carboline alkaloids (Fig. 11) were further obtained from the leaves of T. lii, which included 11-methoxyrutecarprine (149),39 2-methoxyrutecarprine (150),39 trigonostemines A–F (155–158, 146, and 147, resp.),39 arenarine C (159),39 harmicacid methyl ester (160),39 1,2,3,4-tetrahydro-oxo-β-carboline (161),39 norharmine (162),39 harmine (163),39 trigonoine C (164),40 trigonoines A (165) and B (166).41 Among them, trigonoine A (165) possessed a 2,8-diazabicyclo[3.3.1]nonane ring system, and trigonoine B (166) formed by a combination of 2,3-dihydroquinolin-4-one and 3H-pyrrolo[2,3-c]quinoline that rearranged from the β-carboline skeleton. In addition, three β-carboline alkaloids, namely trifilines A–C (153, 154, and 151, resp.), were also isolated from the plant T. filipes collected from Guangxi Province of China.40
image file: c4qo00161c-f11.tif
Fig. 11 The structures of β-carboline alkaloids.
2.2.2. Indole alkaloids. 11 indole alkaloids (Fig. 12) including trigonoliimines A–C (167–169),42 trigonostemon F (170),29 trigolutesins A (171) and B (172),43 trigolutes A–D (173–176),43 and lotthanongine (177)44 were identified from Trigonostemon plants. Among them, trigolutesins A (171) and B (172), and trifilines A–D (173–176) were the first examples of bisindole alkaloids with a unique spiro ring system isolated from the twigs of T. lutescens reported by Dai's group.43
image file: c4qo00161c-f12.tif
Fig. 12 The structures of indole alkaloids.

2.3. Miscellaneous

Except for the two major and most important ingredients of diterpenoids and alkaloids in the Trigonostemon plants, a number of diverse compound classes, including steroids, triterpenoids, sesquiterpenoids, lignans, flavonoids and coumarins, were also isolated. All these compounds are summarized in Table 4.
Table 4 Miscellaneous compound classes in the genus Trigonostemon
No. Compound Source Part Ref.
Steroids
178 Stigmasterol T. reidioides Roots 7
179 5α-Stigmastane-3,6-dione T. reidioides Roots 45
180 Δ8,22-Ergostadien-3β-ol-11-one T. xyphophylloides Twigs 46
181 Mangdesisterol T. xyphophylloides Twigs 47
182 Ergosterol peroxide T. xyphophylloides Twigs 46,47
 
Triterpenoids
183 3-O-Benzoylpluricostatic acid T. xyphophylloides Stems 20
184 Pluricostatic acid T. xyphophylloides Stems 20
185 Ursolic acid T. xyphophylloides Stems 20
186 24(R)-25-Dihydroxy-5α-dammar-20-en-3-one T. xyphophylloides Stems 20
 
Sesquiterpenoids
187 Trigohetone T. heterophyllus Twigs 18
188 Trigonoheterone T. heterophyllus Stems 33
 
Lignans
189 Syringaresinol T. xyphophylloides Twigs 46
190 Pinoresinol T. lutescens Twigs 47
191 Episyringaresinol T. xyphophylloides Twigs 46
192 Aviculin T. heterophyllus Stems 48,49
193 Trigonoheteran T. heterophyllus Stems 48
 
Flavaloid
194 Afzelechin-(4α→8)-afzelechin T. reidioides Roots 44
 
Coumarins
195 Scopoletin T. reidioides Roots 7
196 Tomenti T. reidioides Roots 7
197 5,7-Dihydroxy-6-methoxycoumarin T. reidioides Roots 45
198 1-(2-Hydroxy-4,5-dimethoxyphenyl)-propan-1-one T. xyphophylloides Stems 50
199 4-Hydroxy-3,5-dimethoxybenzaldehyde T. lutescens Twigs 47
200 6-Deoxyjacareubin T. xyphophylloides Twigs 46


2.3.1. Steroids. Five steroids (Table 4, Fig. 13) were obtained in the previous research on Trigonostemon plants. Stigmasterol (178)7 and 5α-stigmastane-3,6-dione (179)45 were discovered from roots of T. reidioides, and Δ8,22-ergostadien-3β-ol-11-one (180),46 mangdesisterol (181),46 and ergosterol peroxide (182)46,47 were obtained from twigs of a Hainan plant T. xyphophylloides.
image file: c4qo00161c-f13.tif
Fig. 13 The structures of steroids.
2.3.2. Triterpenoids. In 2013, four triterpenoids (Table 4, Fig. 14), namely 3-O-benzoylpluricostatic (183), pluricostatic acid (184), ursolic acid (185), and 24(R)-25-dihydroxy-5α-dammar-20-en-3-one (186), were isolated from the stems of T. xyphophylloides, a plant native to Hainan Island of China.20
image file: c4qo00161c-f14.tif
Fig. 14 The structures of triterpenoids and sesquiterpenoids.
2.3.3. Sesquiterpenoids. Trigohetone (187) was the first prenylated bisabolane sesquiterpenoid isolated from the air-dried twigs of a Hainan species T. heterophyllus.18 A sesquiterpenoid, trigonoheterone (188), with a naphthoquinone skeleton (Table 4, Fig. 14) was then isolated from the stems of T. heterophyllus, which was also collected from Hainan Island of China.33
2.3.4. Lignans. Three lignans (Fig. 15), syringaresinol (189) and episyringaresinol (191) from the twigs of a Hainan plant T. xyphophylloides,46 and pinoresinol (190) from the twigs of a Guangxi plant T. lutescens,47 were reported. Recently, two lignan glycosides (Fig. 15), namely aviculin (192) and trigonoheteran (193), were further isolated from the stems of T. heterophyllus, a plant native to Hainan Island of China.48,49
image file: c4qo00161c-f15.tif
Fig. 15 The structures of lignans.
2.3.5. Flavaloid. One flavaloid dimer, afzelechin-(4α→8)-afzelechin (194), was obtained from the roots of a Thai medicinal plant T. reidioides (Fig. 16).44
image file: c4qo00161c-f16.tif
Fig. 16 The structure of flavaloid.
2.3.6. Coumarins and other phenolics. Scopoletin (195),7 tomenti (196),7 and 5,7-dihydroxy-6-methoxycoumarin (197)45 are coumarins isolated from the roots of a Thai plant T. reidioides (Fig. 17). Besides, three other phenolics, 1-(2-hydroxy-4,5-dimethoxyphenyl)-propan-1-one (198) from the stems of T. xyphophylloides,50 4-hydroxy-3,5-dimethoxybenzaldehyde (199) from the twigs of a Guangxi species of T. lutescens,47 and 6-deoxyjacareubin (200) from the twigs of a Hainan species of T. xyphophylloides,46 were isolated recently.
image file: c4qo00161c-f17.tif
Fig. 17 The structures of coumarins and other phenolics.

3. Biosynthetic origin proposed for some isolated compounds

3.1. Phenanthrenone diterpenoids

A possible biosynthetic origin for thrigonosomone A (108) and 6,9-O-demethylthrigonomone A (111) is proposed (Scheme 1). A biogenetic precursor of phenanthrenone diterpenoid 111i subjected to a cascade of methylation, isomerization, and oxidation would produce a ring-expended heptacyclic anhydride, thrigonosomone A (108). A simple methylation of 111i would give 6,9-O-demethylthrigonomone A (111).28
image file: c4qo00161c-s1.tif
Scheme 1 Plausible biogenetic pathways for thrigonosomone A (108) and 6,9-O-demethylthrigonosomone A (111).

3.2. 3,4-Seco cleistanthane diterpenoids

Trigochinenes A–D (127–130), 3,4-seco-sonderianol (131), 3,4-seco-sonderianic (132), trigonoheterene (133), trigonoheterene B (134), trigoflavidones A–E (135–139), and trigoheteric acid methyl ester (140) belonged to the compound class of 3,4-seco cleistanthane diterpenoids, which were likely originated from the cleavage of the C-3–C-4 bond of the 3-keto precursors.35 In Scheme 2, trigoflavidone A (135) would be readily modified by involving a [1,3]-sigmatropic shift of the vinyl group and ring contraction rearrangement to form the trigoflavidones D (138) and E (139). Epoxidation of the 8,14 double bond of 135 would produce trigoflavidones B (136) and C (137).
image file: c4qo00161c-s2.tif
Scheme 2 Plausible biogenetic pathway of trigoflavidones A–E (135–139).

3.3. β-Carboline alkaloids

The biosynthetic origin of trigonoine A (165), a carboline alkaloid featuring a 2,8-diazabicyclo[3.3.1]nonane ring system, is proposed as shown in Scheme 3. The key intermediate 165iii would be formed via the Mannich reaction of tryptamine (165i) and quinoline-4-carbaldehyde (165ii). Followed by dehydrogenation and intramolecular nucleophilic reaction, alkaloid 165 would be yielded. Trigonoine B (166) is an adduct of 2,3-dihydroquinolin-4-one (166i) and 3H-pyrrolo[2,3-c]quinolone rearranged from the precursor β-carboline alkaloid (166ii), which was first oxygenated to 166iii, and was then converted to 166iv by an intramolecular condensation. The condensation of 166iv and 166i would yield intermediate 166v, which was finally converted to 166 by dehydrogenation (Scheme 4).41
image file: c4qo00161c-s3.tif
Scheme 3 Plausible biogenetic pathway of trigonoine A (165).

image file: c4qo00161c-s4.tif
Scheme 4 Plausible biogenetic pathway of trigonoine B (166).

3.4. Indole alkaloids

Three indole alkaloids, trigonoliimines A–C (167–169), were proposed to be originated from 201 (Scheme 5), which would yield 202 by oxidation. The key intermediate 202 underwent two alternative acidic catalysis pathways and modifications would give alkaloids trigonoliimine A (167) or B (168), and trigonoliimine C (169), respectively.51
image file: c4qo00161c-s5.tif
Scheme 5 Plausible biogenetic pathway of trigonoliimines A–C (167–169).

The plausible biogenetic pathways for alkaloids 171 and 174 are proposed as shown in Scheme 6,43 where trigonostemon F (170) was supposed to be the biogenetic precursor of two bisindole alkaloids trigolutesin A (171) and trigolute B (174).


image file: c4qo00161c-s6.tif
Scheme 6 Plausible biogenetic pathway of trigolutesins A (171) and B (174).

4. Biological activities

The former review summarized the biological activities of the compounds isolated from Trigonostemon plants previously, which included insecticidal, insect antifeedant, antimicrobial, cytotoxic, antitumor, anti-HIV-1, and antivenom activities and inhibition of MET tyrosine kinase.3 In addition, it was found that the methanolic extract of the roots of T. reidioides shows anticandidal activity against Candida krusei.52 We described herein only the biological activities of the newly obtained compounds from Trigonostemon species, which were not included in the last review.

4.1. Cytotoxic activity

The cytotoxic activities of the daphnane diterpenoids from Trigonostemon plants against different human tumor cell lines were evaluated. Nine daphnane diterpenoids from twigs of T. howii were evaluated for cytotoxic activity against tumor cell lines HL-60 (human premyelocytic leukemia) and A-549 (human lung adenocarcinoma) using the MTT method and the SRB method, respectively, and the results showed that trigohownins A (30) and D (50) exhibit moderate activities against the HL-60 cell line with the IC50 values of 17.0 and 9.3 μM, respectively.16 Trigoheterin E (51) exhibited moderate cytotoxic activity against both HL-60 and A-549 cell lines with IC50 values of 1.8 and 10.0 μM, respectively.18 Trigoxyphin I (53) showed modest cytotoxicity against SPCA-1 (human lung cancer) and BEL-7402 (human hepatocellular carcinoma) cancer cell lines with IC50 values of 11.07 and 8.73 μM, respectively, and trigoxyphin H (62) exhibited weak activities with IC50 values of 37.30 and 16.13 μM, respectively.19

Two tetranorditerpenoid dimers trigoflavidols A (91) and B (92) and a phenanthrenone diterpenoid trigonochinene E (106) from T. flavidus showed weak cytotoxicities against five human tumor lines, HL-60, SMMC-7721 (human hepatocellular carcinoma), A-549, MCF-7 (human breast cancer), and SW480 (human colon adenocarcinoma).24 Three degraded diterpenoids trigohowilols E (95), F (96), and G (98) from T. howii showed moderate cytotoxic activities against five human tumor cell lines HL-60, SMMC-7721, A-549, MCF-7, and SW480 with IC50 values in the range of 2.33–17.75 μM.25 Trigoxyphin T (100) showed moderate cytotoxicities against SPCA-1 and K-562 tumor cell lines with IC50 values of 1.70 and 2.24 μM, respectively; trigoxyphin O (101) showed significant cytotoxic activities against K-562 (human myelogenous leukaemia) with an IC50 value of 0.37 μM, and exhibited moderate activities against SPCA-1 and SGC-7901 (human gastric cancer) with IC50 values of 1.42 and 2.88 μM, respectively; trigoxyphin R (102) showed significant cytotoxic activity against SPCA-1 with an IC50 value of 0.24 μM and moderate activities against BEL-7402 and SGC-7901 with IC50 values of 3.89 and 5.59 μM, respectively.26 In addition, trigoxyphins J–N (105, 116–119) were evaluated for the cytotoxicities in vitro against the BEL-7402, SPCA-1, and SGC-7901 tumor cell lines, and only trigoxyphin N (119) showed activities against SPCA-1 and SGC-7901 with IC50 values of 4.08 and 5.00 μM, respectively.27

Trigonostemines A–F (155–158, 146, and 147, resp.) are β-carboline alkaloids from T. lii, and were tested against the HL-60, SMMC-7721, A-549, MCF-7 and SW480 tumor cell lines. Trigonostemine A (155) displayed cytotoxic activities against MCF-7 and SW480 cells with IC50 values of 5.30 and 4.86 μM, respectively; trigonostemine B (156) exhibited cytotoxicities against SMMC-7721, A-549, MCF-7, and SW480 cells, with IC50 values of 4.78, 8.67, 2.98, and 3.55 μM, respectively; trigonostemine D (158) showed inhibitory activity against the MCF-7 cell line with the IC50 value of 13.75 μM.39 In addition, three indole alkaloids trigonoliimines A–C (167–169) showed weak activities (10–50 μM) against tumor cell lines (U-937, human lymphoma, and HeLa, human cervical cancer).53

4.2. Antimicrobial activity

Trigoflavidols A–C (91, 92, and 106, resp.) and trigonochinene E (107) were screened for antimicrobial activities against six microbes, Monilia albicans, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, 8# MRSA (MRSA, methicillin-resistant Staph. aureus), and 82# MRSA, in which trigoflavidols A (91) and B (92) displayed moderate activities against Staph. aureus, 8# MRSA, and 82# MRSA with MIC (minimum inhibitory concentration) values ranging from 1.56 to 6.25 μg mL−1.24 Trigohowilols A–F (113, 114, and 93–96, resp.) showed weak activities against Staph. aureus, 92# MRSA, and 98# MRSA with MIC values ranging from 6.25 to 25 μg mL−1.25 Trigonostemone (110) and trigonochinene (128) showed moderate antibacterial activities against Staphylococcus aureus with MICs of 2.5 and 5.0 mg mL−1, respectively.34

4.3. Antivirus activity

Trigocherriolides A–C (15–17), and trigocherrins A (20), B (21), and E (25) were evaluated in a virus-cell-based assay against three members of the genus Alphavirus (CHIKV; Sindbis virus: SINV; Semliki forest virus: SFV), and in an enzymatic assay against the NS5 RNA-dependent RNA polymerase (RdRp) of dengue virus (DENV) of the genus Flavivirus.11,13 All the tested compounds showed strong anti-CHIKV activities as shown in Table 5, and the selectivity indices (SI) of 20, 21, and 25 (SI = 23, 36, and 8, respectively) are better than those of 15–17 (SI = 2–3).11 Trigocherriolide (19) and trigocherrierin A (47) also showed strong anti-CHIKV activities with EC50 values of 0.6 ± 0.1 and 0.7 ± 0.1 μM, respectively.12 A tigliane diterpenoid, trigowiin A (141), was tested for the antiviral activity in a CHIKV virus-cell-based assay, showing weak antiviral activity with an EC50 value of 43.5 ± 12.8 μM.36
Table 5 Antiviral activities of compounds 15–17, 20, 21, and 25 in Vero cell, against CHIKV, SINV, SFV, and in a DENV RdRp assay (data in μM)a
Compd. Cellular assay DENV RdRp IC50
Vero cells CC50 CHIKV EC50 SINV EC50 SFV EC50
a n.d. = not determined.
15 4.6 ± 0.8 1.9 ± 0.6 3.2 ± 0.1 4.0 3.1 ± 0.2
16 5.3 ± 0.2 2.5 ± 0.3 3.3 ± 0.2 4.2 16.0 ± 1.3
17 10.5 ± 0.1 3.9 ± 1.0 5.3 ± 2.1 5.1 ± 0.4 n.d.
20 35 ± 8 1.5 ± 0.6 7.7 ± 1.8 16 ± 3 12.7 ± 0.2
21 93 ± 3 2.6 ± 0.7 21 ± 3 45.0 ± 0.6 n.d.
25 23.1 ± 0.6 3.0 ± 1.2 5.6 ± 0.6 18 n.d.
Chloroquine 100 ± 25 10 ± 5 11.0 ± 2.1 13.8 ± 2.3 n.d.
3′-Deoxy-GTP n.d. n.d. n.d. n.d. 0.02


In particular, 32 daphnane diterpenoids were tested for anti-HIV activity by an assay of the inhibition of cytopathic effects of HIV-1, in which rediocides A (1), C (2), and F (4), trigonosin F (8), and trigothysoids N (9) and M (46) showed potent anti-HIV-1 activities with the EC50 values at the nanomolar level, and excellent therapy index (TI) as shown in Table 6; trigothysoids O (5), J (82) and L (66) showed very strong anti-HIV-1 activities with EC50 values of 0.358, 2.3, and 4.0 nM (TIs of 80.8, 101.2, and 74.0), respectively;10 trigonothyrin F (48) showed significant activity to prevent the cytopathic effect of HIV-1 with an EC50 value of 0.13 μg mL−1 (TI = 75.1);17 trigolins C (75) and G (80) showed modest anti-HIV-1 activity with EC50 values of 2.04 and 9.17 μg mL−1 (TI = 26.49 and >21.81), respectively.23 It was observed that the presence of macro-lactone moieties in the structurally modified daphnane diterpenoids will significantly enhance the anti-HIV-1 activity of this compound class.

Table 6 Anti-HIV activities of compounds 1, 2, 4, 8, 9, and 46 (data in nM)
Compd. Anti-HIV-1 EC50 Cytotoxicity CC50 TI CC50/EC50
1 0.004 ± 0.11 × 10−2 22.9 ± 0.64 6077.3
2 0.008 ± 0.98 × 10−3 27.9 ± 0.02 3245.9
4 0.001 ± 0.60 × 10−3 15.2 ± 13.76 15[thin space (1/6-em)]242
8 0.015 ± 0.85 × 10−3 23.8 ± 1.49 1618.8
9 0.001 ± 0.76 × 10−3 22.2 ± 0.42 17[thin space (1/6-em)]619
46 0.358 ± 0.50 × 10−2 28.9 ± 5.91 80.8
Azidothymidine (AZT) 0.0008 ± — 1317.4 ± — 1[thin space (1/6-em)]646[thin space (1/6-em)]762.5


Some alkaloids isolated from the genus Trigonostemon also showed antiviral activity. Trifilines A (153) and B (154) displayed weak anti-HIV-1 activities with EC50 values of 54.61 and 9.75 μg mL−1 (TI = 1.52 and 1.42), respectively;40 trigonoines A (165) and B (166) also showed weak anti-HIV activities with EC50 values of 13.1 and 17.6 μg mL−1 (TI = 1.28 and 4.48), respectively.41

4.4. Other activities

Rediocide A (1) was reported to have versatile biological functions, such as an antitoxin against cobra venom, acaricidal activity against D. pteronyssinus, insecticidal activities against mosquito larvae (Aedes aegypti) and ectoparasitic flea (Ctenocephalides felis), and cytotoxic effects against tumor cell lines.3–7,54 Recently, it was reported that rediocide A activates conventional PKC (protein kinase C), which induces GPCR (G-protein-coupled receptors) desensitization and internalization, and possibly modulate other cellular events.55 In addition, trigolutesin A (171) showed weak AChE (acetylcholinesterase) inhibitory activity (14.56% inhibition) at 50 μg mL−1.43

5. Chemical synthesis

5.1. Synthesis of daphnane and tigliane diterpenoids

The daphnane and tigliane diterpenoids possess a basic carbon skeleton of the tricyclo[9.3.0.02,7]tetradecane ring system.56 These two compound classes have long been the synthetic topics, and great efforts have been made on the total synthesis of daphnane and tigliane skeletons. In 1989, Wender's group carried out the first total synthesis of a precursor of a tigliane diterpenoid of phorbol ester,57 which involved a 23-step sequence that gave 10% overall yield and 93% overall stereoselectivity. In 1991, the same research group reported a new [5 + 2] cycloaddition method to construct the B, C rings of the daphnane diterpenoids.58 Several years later, they conducted the first asymmetric total synthesis of a daphnane diterpenoid in 1997.59 In 2006, they developed a stereoselective intramolecular oxidopyrylium-alkene [5 + 2] cycloaddition route to furnish the B,C-ring system of 12-hydroxy daphnetoxins.60 One year later, they reported an efficient synthesis of the ABC tricyclic core of macrocyclic daphnane diterpenoids, namely 1α-alkyldaphnanes.61 In the same time period, Page's,56,62,63 Carreira's,64 West's,65 and Evan's66 groups also made tremendous contributions toward the total synthesis of daphnane and tigliane diterpenoids.

Wender's group also made efforts to synthesize bioactive DDOs, which are among the major metabolites of Trigonostemon plants.67 In 2011, they reported a gateway synthesis of daphnane diterpenoid 9,13,14-orthoesters as shown in Schemes 7 and 8. This strategy employed a novel Claisen rearrangement to transfer tartrate-derived chirality to a pro-C11 centre, which in turn controlled the selectivity in [5 + 2] oxidopyrylium cycloaddition. The oxygen-bridged B-ring cycloadduct was then used to control the introduction of C10 and C4 stereochemistry.68


image file: c4qo00161c-s7.tif
Scheme 7 Synthesis of the daphnane skeleton.

image file: c4qo00161c-s8.tif
Scheme 8 Synthesis of the daphnane diterpeniod 9,13,14-orthoester.

5.2. Synthesis of indole alkaloids: trigonoliimines A–C (167–169)

Shortly after the isolation of trigonoliimines A–C (167–169), a number of synthetic studies on the total synthesis of this class of alkaloids were reported. A retrosynthetic analysis of trigonoliimines was put forward by Movassaghi's group, in which the tryptamine heterodimer (210) (Scheme 9) was served as a common biosynthetic precursor to these alkaloids. The enantioselective total syntheses of trigonoliimines A (167) and B (168) were thus accomplished in seven steps from commercially available materials (Scheme 10), while the total synthesis of trigonoliimine C (169) was completed in eight steps by applying venerable Wagner–Merrwein rearrangement of the hydroxyindolenines (+)-212 (Scheme 11).69 In their next paper in 2014, Movassaghi's group gave full account of the syntheses of the trigonoliimine alkaloids, which remains currently the only solution to access all trigonoliimines in the enantiomerically enriched form.53
image file: c4qo00161c-s9.tif
Scheme 9 Retrosynthetic analysis for (−)-trigonoliimines A–C (167–169).

image file: c4qo00161c-s10.tif
Scheme 10 Movassaghi's synthesis of (−)-trigonoliimines A (167) and B (168).

image file: c4qo00161c-s11.tif
Scheme 11 Movassaghi's synthesis of (−)-trigonoliimine C (169).

In 2011, Tambar's group completed the first convergent total synthesis of (±)-trigonoliimine C (169) in 10 steps from tryptamine and 6-methoxytryptamine (Scheme 12). They developed methods to oxidize either the electron-poor or electron-rich indole system in an unsymmetrical conjugated binary indole, which may have a broader impact on the construction of other structurally complex indole alkaloids.70


image file: c4qo00161c-s12.tif
Scheme 12 Tambar's synthesis of (±)-trigonoliimine C (169).

In 2011, Shi's group developed a new strategy to construct the hexacyclic skeleton of trigonoliimines A (167) and B (168) (Scheme 13). The key step involves a carbanion-triggered intramolecular cyclization of a seven-membered ring and a subsequent tetrahydropyrimidine ring formation in one pot. The five-membered imine of 218a and 218b was formed via an aza-Wittig reaction.71


image file: c4qo00161c-s13.tif
Scheme 13 Shi's synthesis toward trigonoliimines A (167) and B (168).

One year later, Zhu's group reported a seven-step synthetic route to trigonoliimine B (168) (Scheme 14), in which they started with the functionalization of commercially available α-isocyanoacetate (219) and 2-fluoronitrobenzene (220), and ended with the unprecedented Bischler–Napieralski reaction implemented for the construction of a seven-membered ring with an overall yield of 12%.72 Further to this, Zhu's group successfully developed a catalytic enantioselective cinchona-alkaloid-catalyzed Michael addition of 222 to 223b for the synthesis of the enantiomerically enriched α,α-disubstituted α-isocyanoacetate 224 and the enantioselective total syntheses of both (+)- and (−)-trigonoliimine A (167) with an overall yield of 7.5% and 6.8%, respectively (Scheme 15).73


image file: c4qo00161c-s14.tif
Scheme 14 Zhu's synthesis of (±)-trigonoliimine B (168).

image file: c4qo00161c-s15.tif
Scheme 15 Zhu's synthesis of (±)-trigonoliimine A (167).

In 2011, Hao's group also reported the biomimetic oxidative rearrangement of the bistryptamine framework into the ring system of trigonoliimine C (169) (Scheme 16) after their discovery of these alkaloids.51 Two years later, they delivered a six-step modified synthetic route based on Zhu's work to construct the skeleton of trigonoliimines A (167) and B (168) (Scheme 17).74 Meanwhile, they further reported the total synthesis of trigonoliimine A (167), in which the Houben–Hoesch cyclization for closing the seven-membered ring and the Strecker-type reaction for assembling the precursor were involved (Scheme 18).75


image file: c4qo00161c-s16.tif
Scheme 16 Hao's biomimetic synthesis toward trigonoliimine C (169).

image file: c4qo00161c-s17.tif
Scheme 17 Hao's two alternative synthetic paths toward trigonoliimines A (167) and B (168).

image file: c4qo00161c-s18.tif
Scheme 18 Hao's rapid total synthesis of (±)-trigonoliimine A (167) via a Strecker/Houben–Hoesch sequence.

Recently, Ramana's group reported the total synthesis of (±)-trigonoliimine C (169) which effectively used three catalytic reactions in sequence, including the [Pd]-catalyzed Sonogashira and nitroalkyne cycloisomerization reactions, and the [Au]-catalyzed C2 addition of protected tryptamine to isatogen (Scheme 19).76


image file: c4qo00161c-s19.tif
Scheme 19 Ramana's catalytic total synthesis of (±)-trigonoliimine C (169).

6. Conclusions

In conclusion, a total of 200 structurally diverse compounds, including terpenoids, alkaloids, phenolics, and steroids, have been isolated from the plant genus of Trigonostemon in the last two decades. Among them, daphnane diterpenoids, norditerpenoid dimers, phenanthrenone diterpenoids, abietane dinorditerpenoids, 3,4-seco cleistanthane deterpenoids, and alkaloids were the major and important components. The biological activities of the diterpenoids and alkaloids were extensively evaluated, and a number of components exhibited promising cytotoxic, antimicrobial, and antivirus activities. Particularly, the anti-HIV macrocyclic daphnane diterpenoid 9,12,14-orthoesters and some alkaloids are noteworthy, and they need to be paid more attention for in-depth studies. Meanwhile, the structurally interesting daphnane diterpenoids and some alkaloids with potent biological activities have also attracted considerable interest from synthetic chemists. All these taken together will make the research on the metabolites of Trigonostemon plants a hot topic for the relevant scientific communities in the future.

Acknowledgements

Financial support from the National Natural Science Foundation (no. U1302222; 81273398) and the Foundation from the MOST (no. 2012CB721105) of the P. R. China is gratefully acknowledged.

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