© 2018 The Pharmaceutical Society of Japan

Vol. 66, No. 5 493Chem. Pharm. Bull. 66, 493–505 (2018)

New Compounds and Potential Candidates for Drug Discovery from Medicinal Plants of Vietnam

Phan Minh Giang*,a and Hideaki Otsukab

a Faculty of Chemistry, VNU University of Science, Vietnam National University; 19 Le Thanh Tong, Hanoi, Vietnam: and b Faculty of Pharmacy, Division of Natural Product Chemistry, Yasuda Women’s

University; 6–13–1 Yasuhigashi, Asaminami-ku, Hiroshima 731–0153, Japan.Received August 5, 2017

The study of natural products introduces interesting new bioorganic structures and potential candidates for the drug discovery stage in the development of innovative drugs. Vietnam enjoys a broad biodiversity of native plant species, microorganisms, marine organisms, and a long tradition of using herbal remedies. Thus, the study of medicinal plants in determining the basis of their efficacy and safety is an important task for modern researchers in Vietnam. The present review covers literature on new compounds elucidated from the systematic study of medicinal plants within some popular genera in Vietnam, as well as their significant biological activities.

Key words medicinal plant; natural product; biological activity; drug discovery

1. IntroductionPlants and their secondary metabolites have provided im-

portant drugs for modern medicine such as atropine, codeine, digoxin, morphine, quinine, and vincristine. Natural products are also significant as drug precursors, drug prototypes, and pharmacological probes.1) Modern drug discovery and devel-opment process can be divided into two major stages: drug discovery and drug development.2) The drug discovery stage includes target discovery, lead discovery, and lead optimiza-tion. In the lead discovery phase a series of candidate com-pounds has been identified; the candidate compounds undergo lead optimization to identify a single active compound, after which the identified compound progresses into the drug devel-opment stage. The second major stage, drug development, be-gins with a single compound, which then progresses through various studies designed to support its approval as a new drug. The efficiency and selectivity of natural products toward particular molecular targets are related to the complexity and specificity of their three-dimensional structures; in regard to chemical diversity, natural products have no parallel among “pure” synthetic compounds.3) The utility of natural products in drug discovery has been proven to be an outstanding source for innovative drugs.

Terrestrial and marine natural products are some of the most successful sources of drug leads for the treatment of many diseases and illnesses.4) The diversity of living organ-isms is believed to be the cornerstone of success stories of natural biologically active compounds. In terms of opportu-nities for the identification of biologically active substances in relation to a broad biodiversity of species, and the long practice of using herbs to treat numerous diseases, Vietnam is privileged. The flora of Vietnam comprises more than

12000 plant species, about 1/3 of which (3948 species) have been used as medicinal plants in Vietnamese traditional medicine.5–8) The number of known plant genera in Vietnam is 2256, belonging to 305 families. Vietnam’s bioflora features 57% of the global total number of plant families, 15% of plant genera, and 4% of plant species.9)

Medicinal plants are important in drug discovery as they often contain a vast number of biologically active natural products. Clinical trials have been conducted on medicinal plants over many years, and there has often been a correlation between the traditional uses of medicinal plants and the bio-logical activities of their chemical constituents. Vietnam has a vast treasure of traditional medicinal plants. The study of the constituents of these plants, with a focus on medicinal plants used in Vietnam’s traditional medicine, is an important task for researchers in Vietnam. First, researchers have begun to explore the chemical profiles and biological and pharmacologi-cal properties of active constituents of traditional Vietnamese botanical medicines as the basis to understand and prove the purported medical efficacy of many traditional plants in treat-ing a range of diseases and conditions. In addition, during this process, studies have shown many new and/or biologically ac-tive compounds which may be valuable to the drug discovery phase of creating innovative drugs. Due to the occurrence of a large number of scattered publications in recent years, this re-view outlines the most successful research on new compounds from systematic studies of medicinal plants within some popular genera used as herbal medicines in Vietnam, as well as the significance of their biological activities. In particular, this review covers studies on new natural products from six plant genera in Vietnam: Croton, Mallotus, Artemisia, Gonio-thalamus, Garcinia, and Ficus.

* To whom correspondence should be addressed. e-mail: phanminhgiang@yahoo.com

Current Topics

Natural Products Chemistry of Global Tropical and Subtropical Plants

Review

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2. New Compounds from Plants of Vietnam2.1. The Genus Croton Croton is a large genus of the

Euphorbiaceae family, comprising around 1300 species of trees, shrubs, and herbs distributed in the tropical and subtrop-ical regions of both hemispheres.10) More than forty Croton species are listed in Vietnam: C. alpinus A. CHEV. ex GAGNEP., C. argyratus BLUME, C. bonianus GAGNEP., C. budopensis GAGNEP., C. caryocarpus CROIZ., C. cascarilloides RAEUSCH., C. caudatus GEISELER, C. chevalieri GAGNEP., C. crassifolius GEISEL, C. cubiensis GAGNEP., C. dalatensis THIN, C. delpyi GAGNEP., C. dodecamerus GAGNEP., C. dongnaiensis PIERRE ex GAGNEP., C. eberhardtii GAGNEP., C. glandulosus L., C. heterocarpus MUELL.-ARG., C. ignifex CROIZ., C. joufra ROXB., C. kongensis GAGNEP., C. krabas GAGNEP., C. lachnocarpus BENTH., C. laevigatus VAHL, C. lamdongensis THIN, C. langso-nensis THIN, C. laoticus GAGNEP., C. lasianthus PERS., C. latso-nensis GAGNEP., C. limitincola CROIZ., C. longipes GAGNEP., C. maieuticus GAGNEP., C. murex CROIZ., C. phuquocensis CROIZ., C. pontis CROIZ., C. poilanei GAGNEP., C. potabilis CROIZ., C. roxburghii BALAKR., C. salicifolius GAGNEP., C. scopuligenus CROIZ., C. thoii THIN, C. thorelii GAGNEP., C. tiglium L., C. tonkinensis GAGNEP., C. touranensis GAGNEP., and C. yunan-nensis W. W. SMITH.9)

C. tonkinensis GAGNEP. (Euphorbiaceae) is a small plant, native in Northern Vietnam, and grows to 1–1.5 m in height. In Vietnamese traditional medicine, the leaves of C. tonki-nensis are prescribed as a remedy for stomach ache, gas-tric and duodenal ulcers, and many other diseases.7) A vast number of new ent-kaurane diterpenoids and their related compounds (kaurane and grayanane diterpenoids) were iso-lated from the methanol extract of these leaves. NMR and MS techniques were used to determine the structures of the ent-kauranes as ent-18-acetoxy-7β-hydroxykaur-16-en- 15-one (1),11) ent-1α-acetoxy-7β,14α-dihydroxykaur-16-en-15-one (2), ent-18-acetoxy-7β,14α-dihydroxykaur-16-en-15-one (3),12) ent- 1α,14α-diacetoxy-7β-hydroxykaur-16-en-15-one (4), ent-1α,7β- diacetoxy-14α-hydroxykaur-16-en-15-one (5), ent-18-acetoxy- 14α-hydroxykaur-16-en-15-one (6), ent-(16S)-18-acetoxy-7β- hydroxykauran-15-one (7),13) ent-7β-acetoxy-11α-hydroxykaur- 16-en-15-one (8), ent-18-acetoxy-11α-hydroxykaur-16-en-15-one (9), ent-11α-acetoxykaur-16-en-18-oic acid (10), ent-15α,18- dihydroxykaur-16-ene (11), ent-11α,18-diacetoxy-7β-hydroxykaur- 16-en-15-one (12), ent-(16S)-1α,14α-diacetoxy-7β-hydroxy-17- methoxykauran-15-one (13),14) ent-7β,18-dihydroxy-kaur-16- en-15-one (14),15) ent-11α-acetoxy-7β-hydroxykaur-16-en-15-one (15),16) ent-11α-acetoxykaur-16-en-18-ol (16), ent-11β-hydroxy-18-acetoxykaur-16-ene (17), ent-14α-hydroxy-18-acetoxykaur-16-ene (18), and ent-7β-hydroxy-18-acetoxykaur-16-ene (19)17) (Fig. 1). In some examples (compounds 4–11), the circular dichroism (CD) method was used to resolve the absolute configurations of ent-kaurane compounds. An extraction of the whole plant with methanol yielded eight further new ent-kaurane diterpenoids, crotonkinins C–J (20–27).18) A possible biosynthetic coupling of the corresponding precursors 14 and 1 gave two new ent-kaurane dimers crotonkinensins C (28) and D (29).19) The co-occurrence of epimeric kaurane series and rearranged skeletons in C. tonki-nensis was detected. The leaves yielded two new kaurane diter-penes, 14α-hydroxykaur-16-en-7-one (30) (crotonkinin Α) and 14α-acetoxy-17-formylkaur-15-en-18-ol (31) (crotonkinin B),20) and two new grayanane (rearranged ent-kaurane) diterpenoids, 7α,10α-epoxy-14β-hydroxygrayanane-1(5),16-dien-2,15-dione

(crotonkinensin A) (32) and 7α,10α-epoxy-14β-hydroxygrayanane-1(2),16-dien-15-one (crotonkinensin B) (33).21) The gray-anane diterpenoids 32 and 33 comprise a 7α,10α-epoxy-14β-hydroxy-16-en-15-one structure present in the ent-kaurane diter-penoids in C. tonkinensis, suggesting the precursor role of these ent-kaurane diterpenoids in their biosynthesis.

2.2. The Genus Mallotus (Euphorbiaceae) The genus Mallotus is one of the most diverse and rich genera of the Euphorbiaceae family in Vietnam. One hundred fifty Mallo-tus species are mainly distributed in tropical and sub-tropical regions in Asia, and the following 40 species have been found in Vietnam: M. anisopodus (GAGNEP.) AIRY-SHAW, M. apelta (LOUR.) MUELL.-ARG., M. barbatus MUELL.-ARG., M. canii THIN, M. chrysocarpus PAMPAN., M. chuyenii THIN, M. clel-landii HOOK. f., M. contubernalis HANCE, M. cuneatus RIDL., M. muricatus (WIGHT) MUELL.-ARG., M. eberhardtii GAGNEP., M. esquirolii LEVL., M. floribundus (BLUME) MUELL.-ARG., M. glabriusculus (KURZ) PAX & HOFFM., M. hanheoensis THIN, M. hookerianus (SEEM.) MUELL.-ARG., M. kurzii, M. lanceolatus (GAGNEP.) AIRY-SHAW, M. luchenensis METC., M. macrostachy-us (MIQ.) MUELL.-ARG., M. metcalfianus CROIZ., M. microcar-pus PAX & HOFFM., M. mollissimus (GEISEL.) AIRY-SHAW, M. nanus AIRY-SHAW, M. oblongifolius (MIQ.) MUELL.-ARG., M. oreophilus MUELL.-ARG., M. pallidus (AIRY-SHAW) AIRY-SHAW, M. paniculatus (LAM.) MUELL.-ARG., M. peltatus (GEISEL.) MUELL.-ARG., M. philippensis (LAM.) MUELL.-ARG., M. phongn-haensis THIN & KIM THANH, M. pierrei (GAGNEP.) AIRY-SHAW, M. poilanei GAGNEP., M. repandus (WILLD.) MUELL.-ARG., M. resinosus (BLANCO) MERR., M. sathayensis THIN, M. spodo-carpus AIRY-SHAW, M. thorelii GAGNEP., M. ustulatus (GAGNEP.) AIRY-SHAW, and M. yunnanensis PAX & HOFFM.9,22) There are extensive medical records on the use of Mallotus species as medicinal plants in Vietnam and South-East Asian countries. M. apelta, M. barbatus, M. floribundus, M. glabriusculus, M. macrostachyus, M. oblongifolius, M. paniculatus, M. philip-pinensis, and M. poilanei are used to treat such diseases as gastrointestinal disorders, hepatic diseases, fever, and ma-laria.22) The leaves of M. mollissimus are used in the treatment of stomach cramps and together with the bark are used to cure ailments of the spleen. A recent review summarized the chem-ical and pharmacological studies of some Mallotus species in Vietnam through the year 2010.22) Triterpenoids, various types of flavonoids and phenolic compounds, and coumarins are common naturally occurring substances obtained from Mal-lotus species.

In continuation of the study of Mallotus species in Vietnam, two new megastigmane sulphonoglucosides, anisoposides A (34) and B (35), were isolated from the leaves of M. anisopo-dus.23) A new megastigmane glycoside, malloluchenoside (36), was also obtained from water-soluble fractions of a methanol extract from the leaves of M. luchenesis.24) Two new 2-C-β-D-glucopyranosyl benzoic acid derivatives, mallonanosides A (37) and B (38), were isolated from the methanol extract of the leaves of M. nanus.25) A new lignan dimer, bilariciresinol (39), was isolated from the leaves of M. philippensis.26) The methanol leaf extract of M. macrostachyus yielded two new cycloartanes, macrostachyosides A (40) and B (41).27) (2S)-Prenylflavanones and taraxerane triterpenoids were isolated from the leaves of M. mollissimus, including a pair of new diastereomeric prenylflavanones, (2″S)- and (2″R)-(2S)-5,7-dihydroxy-4′-methoxy-6-(2″-hydroxy-3″-methylbut-3-enyl)-

Vol. 66, No. 5 (2018) 495Chem. Pharm. Bull.

flavanones (42 R/S)28) (Fig. 2).2.3. The Genus Artemisia (Asteraceae, syn. Composi-

tae) The large Asteraceae (syn. Compositae) family compris-es 1000 genera and 20000 species worldwide. The genus Arte-misia is a member of the Asteraceae family, widely distributed in the warmer temperate zones of Europe, Asia, and North America. Artemisia comprises more than 500 species world-wide, with sixteen species described in the flora of Vietnam: A. absinthium L., A. annua L., A. apiacea HANCE ex WALP, A. campestris L., A. capillaris THUNB., A. carvifolia [BUCH.-HAM. ex ROXB.] BESS., A. dracunculus L., A. dubia var. longerac-emosa forma tonkinen PAMP., A. indica WILLD., A. japonica THUNB., A. lactiflora WALL. ex DC., A. maritima L., A. palus-tris L., A. roxburghiana BESS., A. scoparia WADLST. & KIT., and A. vulgaris L.9,29) These species are perennial, biennial,

and annual herbs or small shrubs. Artemisia is an economical-ly important plant genus because many Artemisia species have been known for their curative properties and have been used in the treatment of various ailments such as malaria, inflam-mation, cancer, and infections by fungi, bacteria, and viruses. A. annua and A. apiacea have been used as remedies for various fevers including malaria.7) A. dubia WALL. ex BESSER is recorded as a remedy for the treatment of gastric problems, intestinal worms, and skin infections in China, India, Japan, and Thailand.30,31) A. japonica is used in Vietnam and China to treat fever, headache, malaria, hypertension, and tuberculo-sis.9) A. roxburghiana is a subshrub and is used to treat fever and intestinal worms.32) A. vulgaris has been used as an anti-inflammatory, an antispasmodic, an anthelmintic, and in the treatment of painful menstruation.7) A huge interest has been

Fig. 1. New Compounds from C. tonkinensis

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observed in the genus Artemisia, with 260 Artemisia species investigated; their secondary metabolites and pharmacological activities have been summarized in several reviews.33–36)

Sesquiterpene lactones eudesmanolides, guaianolides, and rarely, germacranolides, have been considered chemi-cal makers of the Artemisia species.35) In contrast to the common occurrence of 5α,11βH-guaian-12,6α-olides and 11,13-guaiaen-12,6α-olides in many Artemisia species, 11αH-guaianolides were obtained from A. roxburghiana. Three new sesquiterpene lactones of this type, roxbughianin A (11-epiar-borescin) (43), roxbughianin B (1β,4β,10β-trihydroxy-5α,11αH- guai-2-en-12,6α-olide) (44), and 11-epi-8α-hydroxyarborescin (45) were isolated from the leaves of A. roxburghiana37,38) (Fig. 3). The configuration of roxbughianin A was deter-

mined using an X-ray crystallographic method37) (Fig. 4). Eudesmane sesquiterpenes are chemotaxonomic compounds of A. japonica; three new eudesmanes, named artemisidiols A–C (46–48) with an unusual 1α,6α,8α-oxygenated pattern, were obtained from the leaves of A. japonica in Vietnam.39) Oxygenated guaianolides and dicaffeoylquinic acids were ob-tained as main constituents from A. dubia WALL. ex BESS. in China and Korea, but its Vietnamese variety, A. dubia WALL. ex BESS. var. longeracemosa PAMP. forma tonkinensis PAMP., yielded natural 6-methoxy-1H-indole-3-methylcarboxylate (49) together with oleanene and ursane triterpenoids, acyl glycer-ols, and sterols40) (Fig. 3).

2.4. The Genus Goniothalamus (Annonaceae) The large Annonaceae family consists of 120 genera and more than

Fig. 3. New Compounds from Artemisia Species

Fig. 2. New Compounds from Mallotus Species

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2000 species. The genus Goniothalamus comprises about 160 species of shrubs and trees in tropical and subtropical Asia. Goniothalamus species are used as medicines for abortion, anti-aging, body pains, rheumatism, skin complaints, typhoid fever, stomach ache, and fever.41) Twenty-two Goniothalamus species have been recorded in Vietnam: G. albiflorus BAN, G. banii B. H. QUANG, R. K. CHOUDHARY & V. T. CHINH, G. chartaceus P. T. LI, G. chinensis MERR. & CHUN, G. donnaien-sis FIN. & GAGNEP., G. elegans AST, G. expansus CRAIB, G. flagellistylus TAGANE & V. S. DANG, G. gabriacianus (BAILL.) AST, G. gracilipes BAN, G. leiocarpus (W. T. WANG) P. T. LI, G. macrocalyx BAN, G. multiovulatus AST, G. ninhianus BAN, G. takhtajanii BAN, G. tamirensis PIERRE ex FIN. & GAGNEP., G. tenuifolius KING, G. touranensis AST, G. undulatus RIDL., G. vietnamensis BAN, G. wightii HOOK. f. & THOMS., and G. yunnanensis W. T. WANG.9) Phytochemical studies report the isolation of compounds from forty species of Goniothalamus out of the 160 known species.41) Important constituents are styryllactones, alkaloids, and acetogenins. Styryllactones are divided into several subtypes such as styryl-pyrones, furano-pyrones, furano-furones, and pyrano-pyrones, whose chem-istry and biological activities have been described in several reviews.42,43) According to the size of the lactone rings, styryl-lactones are grouped into five-, six- and eight-membered ring lactones, or unusual styryllactones. Study of the leaves of G. tamirensis of Vietnam isolated a new alkaloid gonitamirine (50) together with goniotamiric acid (51) and 3,5-deme-thoxypiperolide (52).44) The latter two compounds, 51 and 52, were isolated for the first time from natural sources. Further work on the leaves of G. tamirensis yielded two new pyrano-pyrone styryllactones, (+)-8-epi-9-deoxygoniopypyrone (53) and (+)-9-deoxygoniopypyrone (54).45) Two new styryllac-tones, macrocalactone (55) and 3-deoxycardiobutanolide (56), were isolated from the fruits of G. macrocalyx46) (Fig. 5). Depending on the structures and physical appearance of the isolated styryllactones, their absolute configurations have been determined by X-ray crystallographic analysis or Mosher’s modified method.

2.5. The Genus Garcinia (Clusiaceae, syn. Guttiferae) Plants of the Clusiaceae (syn. Guttiferae) family grow mainly in the tropics and number more than 1000 species. Garcinia is a large genus of polygamous trees or shrubs, distributed in tropical Asia, Africa, and Polynesia.47) More than fifteen known Garcinia species have been recorded in Vietnam, in-cluding G. cochinchinensis (LOUR.) CHOISY, G. cowa ROXB., G. fagraeoides A. CHEV, G. ferrea PIERRE, G. gaudichaudii PLANCH. & TRIANA, G. hanburyi HOOK. f., G. lanessanii PIERRE, G. mangostana L., G. merguensis WRIGHT, G. multiflora

CHAMPION ex BENTHAM, G. oblongifolia CHAMPION ex BENTHAM, G. oligantha MERR., G. oliveri PIERRE, G. poilanei GAGNEP., G. schomburgkiana PIERRE, and G. tinctoria (CHOISY) W. F. WIGHT.9) Species of the genus Garcinia have been used in traditional medicine to treat different illnesses and ailments such as vomiting, swelling, tapeworms, dysentery, chronic diarrhea, piles, pains, and heat complaints. The bark of G. cochinchinensis is a crude drug used in Vietnam to cure al-lergy, itches, and skin disease, while the buds are used for the treatment of threatened abortion.8) The pericarp of G. mangostana is used in Southeast Asian countries for the treat-ment of abdominal pain, diarrhea, dysentery, infected wound, suppuration, and chronic ulcer.7) The bark of G. oblongifolia is used for the treatment of allergy, itching, and hemoptysis.7) G. schomburgkiana is used in the folk medicine of Vietnam for the treatment of cough and menstrual disturbances.6) Xan-thones and polyisoprenylated benzophenones are compounds of interest from the genus Garcinia because of their complex chemical structures and potent biological responses. New xan-thones and a series of new polyisoprenylated benzophenones, named guttiferones or schomburgkianones, were isolated from the Garcinia species of Vietnam. New xanthones, 1-O-methylglobuxanthone (57) from the bark of G. vilersiana,48) merguenone (58) from the bark of G. merguensis,49) man-goxanthone (59) from the heartwood of G. mangostana,50) 6-O-demethyloliverixanthone (60) and schomburgxanthone (61) were isolated from the bark of G. schomburgkiana,51) pedunxanthones A–C (62–64) from the bark and pedunx-anthones D–F (65–67) from the pericarp of G. peduncu-lata,52,53) oblongixanthones F–H (68–70) from the twigs of G. oblongifolia,54) planchoxanthone (71) from the pericarp of G. planchonii,55) and xanthochymusxanthones A (72) and B (73) from the bark of G. xanthochymus56) (Fig. 6). New gut-tiferones Q–S (74–76) were isolated from the pericarp of G. conchinchinensis,57) guttiferone I (77) from the stem bark of G. griffithii,50) and guttiferone T (78) from the bark of G. con-chinchinensis.58) Guttiferone Q may be the biogenetic precur-

Fig. 4. X-Ray Crystal Structure of 43 Fig. 5. New Compounds from Goniothalamus Species

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sor of guttiferones R and S. The latter two may be synthesized from guttiferone Q by cyclization of the 3-methylbut-2-enyl side chain at C-8 to the oxygen atom at C-1 or by cycliza-tion of the 4-methylpent-3-enyl group at C-5 to the oxygen atom at C-3.57) The fruits of G. schomburgkiana yielded eight new schomburgkianones A–H (79–86).59) The absolute con-figuration at C-40 of 78 and 79 was determined by Mosher’s modified method.58,59) The absolute configuration of the bicyclo[3.3.1] nonane core of the schomburgkianones was as-signed by comparison of their experimental electronic circular dichroism (ECD) spectra with those of related compounds.59) New non-isoprenylated benzophenones, benthaphenone (87) and 3′,6-dihydroxy-2,4,4′-trimethoxybenzophenone (88) were isolated from the bark of G. benthami and the heartwood of G. mangostana,50,60) respectively (Fig. 7). Other new compounds include a megastigmane sulphoglycoside, friedolanostane, a friedocycloartane, protostane, and lanostane triterpenoids. The megastigmane 4-O-sulpho-β-D-glucopyranosyl abscis-ate (89) was isolated from the pericarp of G. mangostana.61) The friedolanostanes (22Z,24E)-3β-acetoxy-9α-hydroxy-17,14-friedolanosta-14,22,24-trien-26-oic acid (90), (22Z,24E)-3β,9α-dihydroxy-17,14-friedolanosta-14,22,24-trien-26-oic acid (91), (22Z,24E)-9α-hydroxy-3-oxo-17,14-friedolanosta-14,22,24- trien-26-oic acid (92), (24E)-3-oxo-17,14-friedolanosta-8,14,24-trien-26-oic acid (93), (22Z,24E)-9α-hydroxy-3-oxo-17,13-friedolanosta-12,22,24-trien-26-oic acid (94), (22Z,24E)-3-oxo-17,14-friedolanosta-8,14,22,24-tetraen-26-oic acid (95), (22Z,24E)-9α-hydroxy-3-oxo-13α,30-cyclo-17,13-friedolanosta- 22,24-dien-26-oic acid (96), and a friedocycloartane (22Z, 24E)-3α-hydroxy-17,13-friedocycloarta-12,22,24-trien-26-oic acid (97) were isolated from the leaves and bark of G. ben-thami and from the bark of G. celebica.60,62) New protostane (22Z,24E)-3-oxoprotosta-12,22,24-trien-26-oic acid (98) and lanostane triterpenoids garciferolides A (99) and B (100) were obtained from the bark of G. ferrea,63) while (E)-3β,9α-dihydroxylanosta-24-en-26-oic acid (101) and 3,23-dioxo-9,16-lanostadien-26-oic acid (102) were isolated from the bark of G. celebica.62) Five new prenylated depsidones, garcinisidone H (103) and oliveridepsidones A–D (104–107), were isolated from the bark of G. celebica and G. oliveri 62,64) (Fig. 8).

2.6. The Genus Ficus (Moraceae Family) The genus Ficus belongs to the family Moraceae and is the largest genus within this family, with more than 800 species.65) Ficus spe-cies are deciduous trees, hemi-epiphyte shrubs, creepers, and climbers. Many Ficus species grow in the tropical and sub-tropical forests of both hemispheres and are used medicinally by local populations. The fruits, roots, and leaves of F. carica are used in traditional medicine to treat gastrointestinal, respi-ratory, and cardiovascular disorders, and as anti-inflammatory and antiplasmodic remedies.65) The leaves of F. drupacea are used to treat malaria, paragonimiasis, nasosinusitis, sinusitis, and anasarca. Leaf extracts of F. elastica are used as remedies for skin infections and skin allergies, and as a diuretic agent. The leaves, roots, and bark of F. microcarpa are used as herbs in Vietnam for perspiration, alleviating fever, and relieving pain. F. religiosa has been extensively used for a wide range of ailments of the central nervous system, endocrine system, gastrointestinal tract, reproductive system, respiratory system, and infectious disorders.66) F. deltoidea (Moraceae) is used in Malaysia to alleviate and heal ailments such as sores, wounds, and rheumatism, and as an after-birth tonic and an antidiabet-

ic drug.67) There are about 511 Ficus species existing in Asia, Malaysia, the Pacific islands and Australia; 132 Ficus species occur in central and south America; and 112 Ficus species occur in Africa (South Sahara) and in Madagascar. The fol-lowing 65 Ficus species have been listed in a Vietnam plant database: F. abelii MIQ., F. altissima BLUME, F. amplissima SM., F. annulata BLUME, F. ashday, F. aurata (MIQ.) MIQ., F. auricularia LOUR., F. balansae GAGNEP., F. benjamina L., F. binnendijkii MIQ., F. callophylla BLUME, F. callosa Willd., F. capillipes GAGNEP., F. chartacea (WALL. ex KURZ) WALL. ex KING, F. curtipes CORNER, F. drupacea THUNB., F. elastica ROXB. ex HORNEM, F. erecta THUNB., F. fistulosa REINW. ex BLUME, F. formosana MAXIM., F. fulva REINW. ex BLUME, F. geniculata KURZ, F. glaberrima BLUME, F. glandulifera (WALL. ex MIQ.) KING, F. henryi WARB. ex DIELS, F. heterophylla L. f., F. heteropleura BLUME, F. hirta VAHL., F. hispida L. f., F. is-chnopoda MIQ., F. lacor BUCH.-HAM, F. laevis BLUME, F. lang-kokensis DRAKE, F. microcarpa L. f., F. nervosa B. HEYNE ex ROTH, F. obscura BLUME, F. oligodon MIQUEL, F. orthoneura H. LÉV. & VANIOT, F. pisocarpa BLUME, F. prostrata (WALL. ex MIQ.) BUCH.-HAM. ex MIQ., F. pumila L., F. racemosa L., F. religiosa L., F. retusa L., F. rhododendrifolia (MIQ.) MIQ., F. rumphii BLUME, F. sagittata VAHL, F. sarmentosa BUCH.-HAM., F. semicordata BUCH.-HAM., F. simplicissima LOUR., F. spathu-lifolia CORNER, F. stenophylla HEMSL., F. stricta MIQ., F. sub-cordata BLUME, F. subtecta CORNER, F. sumatrana MIQ., F. sundaica BLUME, F. superba MIQ., F. tinctoria G. FORST., F. tuphapensis DRAKE, F. variegata BLUME, F. variolosa LINDL. ex BENTH., F. vasculosa WALL. ex MIQ., F. villosa BLUME, and F. virens AITON.9) Megastimane glycosides were isolated from the polar fractions of several Ficus plants of Vietnam. Fractionation of a methanol extract from the leaves of F. mi-crocarpa yielded a new C-glucosylflavone, ficuflavoside (108), and a new megastigmane glycoside, ficumegasoside (109).68) Megastigmane dihydroalangionoside A (110) was also isolated for the first time from natural sources.68) The isolation of a megastigmane, sodium 4′-dihydrophaseate (111) was reported from F. drupacea, together with a new benzenediol glucoside, 1,4-di-O-β-glucopyranosyl-2-(1,1-dimethylporpenyl) benzene (112).69) Another new megastigmane glycoside, ficalloside (113) was isolated from a methanol extract of the leaves of F. callosa.70) New compounds obtained from F. elastica include sodium (1′S,6′R)-8-O-β-D-glucopyranosyl abscisate (114) and ficuselastic acid (115).71) New ursane (3β-acetyl urs-14(15)-en-16-one (116)) and new lanostane (lanosterol-11-one acetate (117)) triterpenoids were obtained in an early work on F. fistulosa of Vietnam, along with five known triterpenoids72) (Fig. 9).

3. Potential Candidates for Drug Discovery3.1. Antimicrobial Activity Staphylococcus aureus is

a virulent pathogen that is currently the most common cause of infections in hospitalized patients. The increase in the resistance of S. aureus to antibiotics, coupled with its in-creasing prevalence as a nosocomial pathogen, is of major concern. Of eleven tested ent-kaurane diterpenoids from C. tonkinensis, compounds 1, 3, and 9 showed the lowest mini-mum inhibitory concentration (MIC) values at 500, 125, and 32 µg/mL against the methicillin-resistant Staphylococcus aureus (MRSA) strain. All three active diterpenoids possess an α,β-unsaturated cyclopentanone moiety in the D ring of the

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ent-kaurane skeleton.73)

3.2. Antiplasmodial Activity Ethanol and water ex-tracts from the leaves of C. tonkinensis showed antiplasmo-dial activity against Plasmodium falciparum. Bioassay-guided fractionation of the ethanol extract resulted in the isolation of the active ent-kaurane 1. Compound 1 showed activity against the chloroquine-sensitive Plasmodium falciparum T966 strain with an IC50 value of 16.47 µg/mL, and against the chloro-quine-resistant Plasmodium falciparum K1 strain with an IC50

value of 17.34 µg/mL.74)

3.3. Antiinflammatory Activity The dimeric tran-scription factor nuclear factor kappa B (NF-κB) activates the expression of genes involved in the inflammatory pro-cess. Therefore, NF-κB inhibitors are considered potential anti-inflammatory and anti-cancer compounds. Bioactivity-guided fractionation using NF-κB and Griess assay led to the isolation of new ent-kauranes 1–3 and ent-7β,14α-dihydroxykaur-16-en-15-one from the leaves of C. tonki-

Fig. 6. New Xanthones from Garcinia Species

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nensis. They showed strong inhibitory activity of NF-κB activation (IC50 values of 0.10±0.01, 0.42±0.07, 0.07±0.01, and 0.11±0.02 µM, respectively) and nitric oxide (NO) pro-duction (IC50 values of 0.21±0.04, 0.47±0.03, 0.15±0.02, and 0.26±0.02 µM, respectively) in RAW264.7 cells.12) Kuo et al. demonstrated the inhibition of new ent-kauranes 1, 2, 14, 30, ent-7β,14α-dihydroxykaur-16-en-15-one, ent-7β-hydroxykaur-16-en-15-one, and ent-kaur-16-en-15-one 18-oic acid from C. tonkinensis on NO production with IC50 values <5 µM.20) Reduced nicotinamide adenine dinucleotide phos-phate (NADPH) oxidase (NOX) is the major reactive oxygen species (ROS)-inducing enzyme in activated inflammatory cells. Compounds 1, 2, 14, ent-7β-hydroxykaur-16-en-15-one, and ent-7β,14α-dihydroxykaur-16-en-15-one potently inhibited NOX, with the maximum inhibition of NOX activity at 50 µM ranging from 20 to 29%.20) The strong inhibition of superox-

ide anion generation and elastase release by human neutro-philes in response to FMLP/CB by diterpenoids 1, 2, 12, and 32 with IC50 values ranging from 1.12±0.06 to 2.64±0.12 µM demonstrated the potential use of these diterpenoids from C. tonkinensis in the development of antiinflammatory agents.18) The activity of the inflammatory enzyme cyclooxygenase (COX-2) was also inhibited by grayanane diterpenes crotonki-nensins A (32) and B (33), with IC50 values of 7.14±0.2 and 5.49±0.2 µM, respectively.21)

3.4. Anticancer Activity The cytotoxicity of ent-kaurane diterpenoids against various human cancer cell lines was tested as an anticancer primary screen. The importance of the 16-en-15-one moiety in the ent-kaurane D-ring was demonstrated in all cytotoxicity tests of the ent-kaurane diter-penoids and their related compounds from C. tonkinensis. The functional groups (hydroxyl or acetoxy groups) at C-7, C-11,

Fig. 7. New Benzophenones from Garcinia Species

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C-14, and C-18 may modulate the potency of this cytotoxicity. New ent-kaurane 1 and ent-7β,14α-dihydroxykaur-16-en-15-one showed the highest potency against four human cancer cell lines, A459 (lung cancer), MCF-7 (breast adenocarcinoma), KB (epidermoid carcinoma), and KB-Vin (vinblastin-resis-tant KB cell line), with EC50 values ranging from 0.61 to 1.45 µg/mL.20) New ent-kaurane diterpenoids 2, 3, 14, and ent-7β-hydroxykaur-16-en-15-one showed strong cytotoxic-ity against MCF-7, KB, and KB-Vin (EC50<2 µg/mL). ent-

Kaurane diterpenoids 1–4, 7, 8, and 12 showed cytotoxicity against LU (lung adenocarcinoma), RD (rhabdocarcoma), and Hep-G2 (hepatocellular carcinoma) human cancer cell lines with IC50<2 µg/mL.75) ent-Kaur-16-en-15-one diterpenoids (1–5, 7, 9, 14, 16, 30, 32), ent-7β,14α-dihydroxykaur-16-en-15-one, ent-18-hydroxykaur-16-en-15-one, and ent-1α,7β,14α-tri-acetoxykaur-16-en-15-one were also active against MCF-7, adryamicin-resistant MCF-7 (MCF-7/ADR), and against tamox-ifen-resistant MCF-7 (MCF-7/TAM) human cancer cell lines.

Fig. 8. New Triterpenoids, Depsidones, and Megastigmane from Garcinia Species

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Compounds 1–5 and ent-7β,14α-dihydroxykaur-16-en-15-one showed the highest activity, with IC50 values <5 µg/mL. The preferential cytotoxicity of 29 to MCF-7 and MCF-7/ADR as compared to MCF-7/TAM, and of 15 to MCF-7 as compared to MCF-7/ADR and MCF-7/TAM, was disclosed. Grayanane diterpenoid 32 showed cytotoxicity against the three human cell lines with IC50 values ranging from 7.9 to 8.1 µg/mL, while its congener 33 did not show this inhibitory activity (IC50>10 µg/mL).76) Crotonkinensin D (29) showed potent cyto-toxic activity against MCF-7, MCF-7/TAM, MCF-7/ADR, and MDA-MB-231 breast human cancer cell lines with IC50 values of 9.4±1.7, 2.6±0.9, 18.9±0.6, and 22.0±0.9 µM, respectively.18) Human hepatocellular carcinoma is the most common type of liver cancer. The structural requirement of the 16-en-15-one moiety was observed in the cytotoxicity of ent-kauranoid against both human HepG2 and Hep3b cell lines. This cy-totoxicity was closely correlated to apoptosis, as evidenced by concentration-dependent subG1 cell accumulation, and to increased annexin V expression. In addition, subtoxic concen-trations of the active diterpenoids dramatically enhanced the sensitivity of human hepatocellular carcinoma cells to doxo-rubicin.77) AMP-activated protein kinase (AMPK) is a biologic sensor for cellular energy status that acts as a tumor suppres-sor and as a potential cancer therapeutic target. ent-Kaurane 1 blocked proliferation in dose- and time-dependent manners in human hepatocellular carcinoma SK-HEP1 cells. AMPK

activation induced by 1 regulated cell viability and apoptosis. The study demonstrated that 1 is a novel AMPK activator, and that AMPK activation in SK-HEP1 cells is responsible for anticancer activity, including apoptosis.78) ent-Kauranes with a 15-oxo-16-ene moiety also induced the apoptosis of colorectal cancer cell lines, Caco-2 and LS180, and enhanced the genera-tion of intracellular ROS in both cell types.79) The new cyclo-artanes 40 and 41 from M. macrostachyus showed cytotoxic-ity against the human cancer cell lines KB and LU-1 (lung adenocarcinoma) with IC50 values ranging from 4.31±0.09 to 7.12±0.07 µg/mL.27) 3-Deoxycardiobutanolide (56) from G. macrocalyx was found to have potent cytotoxicity (IC50 value of 0.09 µM) against HL-60 (human promyelocytic leukemia) cell lines, but no inhibitory activity against the KB cell line (IC50>20 µM).46) Xanthones and polyisoprenylated benzophe-nones are mainly present in the genus Garcinia, and have been demonstrated to have significant cytotoxic activity in in vitro assay.47) 6-O-Demethyloliverixanthone (60) from G. schomburgkiana showed weak cytotoxic activity against HeLa (human cervical cancer) cell lines (IC50 16.7±1.9 µg/mL).51) Pedunxanthone D (65) is an active compound against HeLa and NCI-H460 (human lung cancer) cells, with IC50 values of 24.9±0.4 and 26.1±1.5 µg/mL, respectively.53) The new poly-isoprenylated benzophenones guttiferones Q–S (74–76) were tested for three human cancer cell lines: MCF-7, HeLa, and NCI-H460. Guttiferone Q (74) showed strong activity, with

Fig. 9. New Compounds from Ficus Species

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IC50 values of 2.74±0.12, 3.03±0.15, and 4.04±0.22 µg/mL, respectively, while guttiferones R (75) and S (76) were not ac-tive.57) Guttiferone T (78) showed weak activity, with IC50 val-ues of 19.88±0.14 and 14.31±0.94 µg/mL, respectively, against HeLa and MCF-7 human cancer cell lines.58)

3.5. SIRT1 Inhibitory Activity Silent information regulator two ortholog 1 (SIRT1) is a member of the sirtuin deacetylase family of enzymes that removes acetyl groups from lysine residues in histones and other proteins. It has been suggested that SIRT1 inhibitors might be beneficial in the treatment of cancer and neurodegenerative diseases. New ent-kauranes 1–5, 14, ent-7β,14α-dihydroxykaur-16-en-15-one, and ent-1α,7β,14α-triacetoxykaur-16-en-15-one from C. tonki-nensis inhibited SIRT1 activity with IC50 values ranging from 16.08±0.11 to 44.34±2.32 µg/mL, respectively.17) The ent-kaur-16-en-15-one moiety has been shown to be the struc-tural requirement for the inhibitory activity and functional groups at C-7 and C-11 that reinforce SIRT1 inhibitory activ-ity.

3.6. Antioxidant Activity Mallonanosides A (37) and B (38) from M. nanus showed antioxidant activities in an oxygen radical absorbance capacity (ORAC) test. The ORAC assay measures the oxidative degradation of the fluorescent molecule in vitro after being mixed with a free radical gen-erator. Antioxidants are considered to protect the fluorescent molecule from oxidative generation. The peroxyl radical-scavenging activity of 37 was stronger than that of 38, and the increase of antiradical activity was explained by the presence of a hydroxyl group at C-4.25) Ficuflavoside (108) exhibited potent peroxyl radical-scavenging activity at the concentra-tions of 2.0 µM compared with the positive control, Trolox.68)

3.7. Osteoblast Differentiation Assay Direct stimulato-ry effect on osteoblast differentiation is an assay used to iden-tify potential therapeutic molecules against bone diseases such as osteoporosis. New bone formation is primarily a function of the osteoblasts, agents that regulate bone formation, either by increasing the proliferation of cells in the osteoblastic lin-eage or inducing osteoblast differentiation. Bioactivity-guided fractionation using an in vitro osteoblast differentiation assay resulted in the isolation of ent-kaur-16-enes 16–18, and ent-7α-hydroxy-18-acetoxykaur-16-ene from C. tonkinensis. All ent-kaur-16-enes significantly increased alkaline phosphatase activity and osteoblastic gene promoter activity. Compounds 16–18 also increased the levels of alkaline phosphatase (ALP) and collagen type I alpha mRNA in C2C12 cells in a dose-dependent manner.17) At concentrations of 2.67 µM, compounds 53 and 54 from G. taminensis significantly increased the growth of osteoblastic MC3T3-E1 cells and increased collagen synthesis, alkaline phosphatase activity, and nodule mineral-ization in the cells. 53 and 54 increased the proliferation and differentiation of osteoblastic MC3T3-E1 cells.45)

3.8. Antimycobacterial Activity ent-Kaurane, kaurane, and grayanane diterpenoids from C. tonkinensis were sub-jected to an antituberculosis activity test against both suscep-tible and resistant strains of Mycobacterium tuberculosis. All of the compounds showed high to moderate activity against Mycobacterium. The highest antituberculosis activity was observed for ent-1α,7β,14α-triacetoxykaur-16-en-15-one, with MIC values of 0.78, 1.56, and 3.12–12.5 µg/mL against H37Ra, H37Rv and all other resistant strains of M. tuberculosis tested. ent-Kaurane diterpenoids with an α,β-unsaturated ketone in

the D ring 1 (IC50 3.12–6.25 µg/mL), 2 (IC50 3.12–6.25 µg/mL), 4 (IC50 3.12–6.25 µg/mL), and 14 (IC50 1.56 µg/mL) showed high activities against Mycobacterium.80)

3.9. Anti-diabetic Activity Oblongixanthones G (69) and H (70) displayed potent α-glucosidase inhibitory activity (IC50 9.4±1.8 and 21.2±9.7 µM, respectively) but weak PTP1B (protein-tyrosine phosphatase 1B) inhibitory activity (IC50 94.8±12.0 and 82.4±6.8 µM, respectively). Oblongixanthone F (68) inhibited PTP1B with an IC50 value of 33.1±4.7 µM and α-glucosidase with an IC50 value of 36.7±20.0 µM. Xantho-chymusxanthone B (73) exhibited strong inhibition towards PTP1B with an IC50 value of 8.0±0.6 µM.56)

4. ConclusionMedicinal plants are rich sources of biologically active

compounds. There are many unexplored medicinal plants in Vietnam that may offer a huge library for compounds of dif-ferent structural types and biological potency in the process of drug discovery. Variations of skeleton architecture of such a compound library, through medicinal chemistry and chemical synthesis of analogs, greatly expands the complexity, diver-sity, and therapeutic efficacy of available natural compounds. The present review shows the importance of systematic phyto-chemical studies of plant materials, as well as multi-targeted activity tests of natural compounds from some popular groups of medicinal plants of Vietnam, as exemplified by the study of C. tonkinensis. With the advancement of separation and isola-tion techniques, and the inclusion of new bioassays, many new and/or biologically active compounds from medicinal plants in Vietnam are expected to be found.

Conflict of Interest The authors declare no conflict of interest.

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