© 2018 The Pharmaceutical Society of Japan

Vol. 66, No. 5 469Chem. Pharm. Bull. 66, 469–482 (2018)

Novel Bioactive Natural Products Isolated from Madagascar Plants and Marine Organisms (2009–2017)

Yumin Dai,a Yixi Liu,a and L. Harinantenaina Rakotondraibe*,b

a Department of Chemistry and Virginia Tech Center for Drug Discovery, M/C 0212, Virginia Tech; Blacksburg, VA 24061, U.S.A.: and b Division of Medicinal Chemistry and Pharmacognosy, College of

Pharmacy, The Ohio State University; Columbus, OH 43210, U.S.A.Received May 12, 2017

Madagascar’s rain forests and tropical dry forests are home to numerous endemic plant species and the island is considered a biodiversity hotspot. About 80% of the Madagascan (Malagasy) population relies on traditional medicines that have been proven to contain a variety of biologically active compounds. In the search for bioactive compounds from Madagascan biodiversity, we accessed and collected most of the lit-erature dealing with the isolation, structure elucidation, and biological activities of organic small molecules originating from Madagascan plants and marine organisms. Since we published the first review of this work in 2009 (Curr. Med. Chem., 17, 2010, Hou and Harinantenaina), the present paper covers the isolation, struc-tures, and bioactivity of 182 new secondary metabolites isolated from Malagasy higher plants and marine organisms in the last seven years (2009–2017).

Key words bioactive secondary metabolite; natural product; Madagascar

1. IntroductionMadagascar, the African island nation located 400 km

off the coast of Mozambique, has an area the size of Texas with 80% endemic plant species. The discovery of bioactive compounds from endemic plant species as well as from ma-rine organisms and soil- and marine-derived microorganisms increased the interest of natural product and drug discovery scientists in the island’s biodiversity.1) In this review, papers published in the last seven years (2009–2017) on 182 new and/or bioactive natural products from plants and marine organisms of Madagascar are reviewed. These compounds include alkaloids, terpenoids, steroids, flavonoids, lignans, coumarins, and miscellaneous compounds such as quinones, xanthones, polyketides, macrolides, and peptides. Around half of the investigations published here are the result of one of the cores of the International Cooperative Biodiversity Group (ICBG)/Madagascar research project on the bioassay-guided isolation of antiproliferative (A2780 human ovarian cancer cell line) and antimalarial compounds led by Dr. David Kingston of Virginia Polytechnic Institute and State University. The other bioassay results reported here cover antibacterial activity against Gram-positive/negative strains, antiproliferative activ-ity (against cell lines other than A2780), antiplasmodial (Plas-modium falciparum) activity, and toxicity to brine shrimp.

2. AlkaloidsThree new alkaloids, 8-hydroxyeupolauridine (1), 9-me-

thoxyeupolauridine-1-oxide (2), and 11-methyoxysampangine (3), along with three known alkaloids, eupolauridine N-oxide, eupolauridine, and sampangine, were isolated from a dichlo-romethane (DCM) extract of the roots of Ambavia gerrardii

(Annonaceae) using antiproliferation-guided fractionation. Among the three novel compounds, 3 exhibited strong activity against the H460 human non-small-cell lung cancer cell line, with an IC50 value of 0.57 µM, while compounds 1 and 2 dis-played low activities.2)

Antiproliferative bioassay-guided fractionation of an ethanol extract of the stems of Anisocycla grandidieri (Menisper-maceae) led to the isolation of the four alkaloids stebisimine (4), (+)-1,2-dehydrotelobine (5), (+)-2′-norcocsuline (6), and puetogaline B (7). Although they were reported previously, the full NMR assignments of all four compounds and their single-crystal X-ray crystallography results were reported for the first time. Compounds 5 and 6 displayed moderate anti-proliferative activity against the A2780 human ovarian cancer cell line, with IC50 values of 4.1 and 2.7 µM, respectively.3)

* To whom correspondence should be addressed. e-mail: Rakotondraibe.1@osu.edu

Current Topics

Natural Products Chemistry of Global Tropical and Subtropical Plants

Review

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Two new dibromo proaporphine alkaloids, saldedines A (8) and B (9), were isolated from the DCM fraction of an uniden-tified Didemnidae tunicate collected at Salary Bay, Madagas-car. These two compounds were reported to be the first two marine proaporphine alkaloids. Both compounds displayed modest toxicity against brine shrimp, with LD50 values of 4.4 and 10.9 µM, respectively.4)

Seven new tricyclic alkaloids, netamine H–N (10–16), along with the four known compounds netamine G and mirabilins A, C, and F were isolated from the DCM/methanol (MeOH) extract of the Madagascar sponge Biemna laboutei. The cy-totoxicity of all the compounds against the KB cell line and antiplasmodial activity against P. falciparum strains 3D7 and W2 were evaluated. Netamine M (15) was cytotoxic in the mi-cromolar range (1 µM), while netamine K (13) exhibited mod-erate antiplasmodial activity, with an IC50 value of 2.4 µM.5)

Two novel bisindole alkaloids, goniomedines A (17) and B (18), were isolated from the stem bark of Gonioma malagasy Mgf and P.Bt (Apocynaceae), a tree collected from the forest of Toliara in southwest Madagascar. Their basic carbon skele-ton was formed by two indole moieties fused via a dihydropy-ran unit. These two compounds represented the first examples of an unprecedented class of quebrachamine-pleiocarpamine bisindole alkaloids. Both of the compounds were tested for antiplasmodial activity against chloroquine-resistant strain FcB1 of P. falciparum, and compound 18 displayed moderate activity, with an IC50 value of 2.8 µM, while compound 17 was inactive.6)

The same authors isolated three related new bisindole alka-

loids from the same plant: goniomedinone (19); goniomedine A-methylene chloride (20); and goniomedine A-N-oxide (21). As stated in their report, those three novel compounds may have been artifacts formed through spontaneous oxidation and tertiary amine quaternization during plant extraction.7)

Three novel alkaloids, isohalitulin (22) and haliclorensins B (23) and C (24), together with the three known compounds halitulin, haliclorensin, and isohalicloresin, were isolated from the chloroform (CHCl3)–MeOH (2 : 1) extract of the Madagas-can sponge Haliclona telearensis (class Demospongiae, order Haplosclerida, family Chalinidae), collected in Salary Bay, north of Tulear, Madagascar. All three new compounds were tested for their toxicity against brine shrimp, and the results indicated that all exhibited moderate activity, with LD50 val-ues of 0.9, 2.2, and 2.1 µM, respectively.8)

Bioassay-guided fractionation of the ethyl acetate (EtOAc) fraction of the stem bark of Muntafara sessilifolia (Apocy-naceae) led to the isolation of four vobasinyl-iboga bisindoles (25–28) and one 2-acyl monomeric indole (29) alkaloid, along with eight known alkaloids (3-oxocoronaridin hydroxyindo-lenine, eglandulosine, eglandine, coronaridine, tabernaemon-tanine, and tabernaelegantines A, B, and D). All the isolated compounds were evaluated for their ability to inhibit the in vitro intraerythrocytic development of the chloroquine-resis-tant strain FcB1 of P. falciparum. Additionally, their cyto-toxicity against human lung cell line MRC-5 and rat skeletal muscle cell line L-6 was also assessed. The antiplasmodial ac-tivity of the monoindole alkaloids ranged from 5.9 to 137 µM, as indicated by their IC50 values, while the bisindoles appeared more active, with IC50 values ranging from 1.2 to 13.3 µM. In particular, compound 26 exhibited selective antiplasmodial activity (IC50 value of 4.4 µM) with very low cytotoxicity (se-lectivity index of about 50).9)

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3. Terpenoids and Steroids3.1. Sesquiterpenoids Bioassay-directed fractionation of

the aerial parts of the DCM fraction of the ethanol extract of Athroisma proteiforme (HUMBERT) MATTF. (Asteraceae) yielded five new sesquiterpene lactones, athrolides A–E (30–34) and the known flavonoid centaureidin. All five lactones were tested for their antiplasmodial and antiproliferative activities, and athrolides C (32) and D (33) displayed moderate antiplas-modial activities, with IC50 values of 6.6 and 7.2 µM against the HB3 strain and 5.5 and 4.2 µM against the Dd2 strain of P. falciparum, respectively. In addition, all six compounds ex-hibited strong antiproliferative activity against A2780 human ovarian cancer cells, with IC50 values ranging from 0.4 to 2.5 µM.10)

Two calamenene-type sesquiterpenoids, tavinin A (35) and epi-tavinin A (36), together with the known sesquiterpenoid mansonone G, were isolated from the DCM fraction of the ethanol extract of the bark of Sterculia tavia BAILL. (Malva-ceae). Tavinin A and epi-tavinin A are a pair of diastereomers. The two novel isolated compounds displayed modest anti-proliferative activities against the A2780 ovarian cancer cell line, with IC50 values of 5.5 and 6.7 µM, respectively.11)

Vanderlandin (37), a novel cadinane-type sesquiterpenoid, along with the known compound 24-methylenecholesterol, was isolated from the methanol extract of the Madagascan soft corals Sinularia vanderlandi (Alcynoiidae).12)

3.2. Diterpenoids Three novel diterpenoids, gravilin (38), dihomoditerpenoid ketone (39), and isodecaryiol (40), along with three known compounds, (+)-(S)-geranyllinalool, (−)-(R)-nephthenol, and 11,12-epoxysarcophytol A, were iso-lated from the methanol extract of the Madagascan soft coral Sinularia gravis. Compound 38 is a spatane-type diterpenoid, while 39 and 40 are dihomo- and scalarane-type diterpenoids,

respectively. Although the crude methanol extract of S. gravis exhibited an IC50 value of 30.8 µg/mL, the three new isolates did not display any activity.12)

Fractionation of an antiplasmodial ethanolic extract from the aerial parts of Vitex cauliflora (Verbenaceae) led to the isolation of a new labdane-type diterpene (41), along with the known compound uvaol. The novel compound did not display any antiplasmodial activity against the multidrug-resistant strain FCM29 of P. falciparum.13)

Antiproliferative-guided isolation of the ethanol ex-tract of bark of Cyphostemma greveana DESC. (Vi-taceae) afforded a new labdane-type diterpenoid, 16,18-di-hydroxykolavenic acid lactone (42), together with four other known compounds (lasiodiplodin, 12-hydroxy-15-oxo-selina-4,1l-diene, 1β,6α-dihydroxyeudesm-4(15)-ene, and (7R*)-opposit-4(15)-ene-1β,7-diol). Compound 42 displayed strong antiproliferative activity against the A2780 human ovarian cancer cell line, with an IC50 value of 0.44 µM.14)

A new diterpenoid, 2″,3″,4″,6′-de-O-acetylcupacinoside (43), together with two known compounds, cupacinoside and 6-de-O-acetylcupacinoside, were isolated by bioassay-directed fractionation from an EtOAc fraction of the roots of Molinaea retusa RADLK. (Sapindaceae). Compound 43 displayed weak antiproliferative activity against A2780 human ovarian cancer cells (IC50 value of 15.4 µM).15)

Two new 3,4-seco-atisane diterpenoids, crotobarin (44) and crotogoudin (45), were identified using bioassay-directed isolation of the EtOAc extracts of the Madagascan plants Croton barorum and Croton goudotii (Euphorbiaceae). Both compounds (44 and 45) showed strong cytotoxic activities, with IC50 values of 0.14 and 0.13 µg/mL, respectively, against the murine P388 cell line used to guide the fractionation, and these activities were confirmed by additional antiprolifera-tive assays in various cell lines, including KB, HT-29, A549, and HL-60. In addition, for the mechanistic study, both of the compounds produced a net progression in the number of cells arrested at the G2/M growth stage in the cell cycle of the K562 human leukemia cell line at 4 µM.16)

Two novel clerodane diterpenoids, antadiosbulbins A (46) and B (47), and two new 19-norclerodane diterpenoids,

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8-epidiosbulbins E (48) and G (49), along with the known compound diosbulbin E, were isolated from the EtOAc-soluble part of the methanolic extract of the tubers of Dioscorea an-taly (Dioscoreaceae), a yam endemic to Madagascar.17)

An ethanol extract of leaves of the plant species Mal-leastrum sp. collected in northern Madagascar afforded a new clerodane diterpene, 18-oxo-cleroda-3,13-dien-16,15-olide (50), together with three other known clerodane diterpenoids, 16,18-dihydroxykolavenic acid lactone, solidagolactone, and (−)-kolavenol, and the known labdane diterpene 3-oxo-ent-Iabda-8(17),13-dien-15,16-olide. The novel compound (50) dis-played moderate antiproliferative activity against the A2780 ovarian cancer cell line, with an IC50 value of 3.0 µM.18)

3.3. Sesterterpenoids Investigation of an antiprolifera-tive EtOAc fraction of the Madagascan sponge Carteriospon-gia sp. led to the isolation of four novel homoscalarane-type sesterterpenoids (51–54), along with two known sesterterpe-noids of the same type. All of the compounds were tested for antiproliferative activity against A2780 ovarian cancer cells, and compounds 51 and 52 displayed submicromolar anti-proliferative activity, with IC50 values of 0.65 and 0.26 µM, respectively, while compounds 53 and 54 exhibited moderate activity (4.5 and 8.7 µM, respectively). The two most active compounds (51 and 52) displayed very similar antiproliferative activities when tested against other cancer cell lines, including H522-T1 non-small cell lung cancer and A2058 human mela-noma lines.19)

3.4. Triterpenoids Bioassay-guided fractionation of an ethanol extract of a Madagascar collection of the leaves and fruit of Cassipourea lanceolata TUL. (Rhizophoraceae) led to the isolation of three euphane triterpenoids (55–57). All three compounds displayed weak antiproliferative activity against the A2780 human ovarian cancer cell line, with IC50 values of 25, 25, and 32 µM, respectively.20)

Two new oleanane-type triterpene saponins, dodoneasides A (58) and B (59), were isolated from the DCM fraction of the roots of the Madagascan plant Dodonaea viscosa (Sapindace-ae) following bioassay-guided fractionation. Both compounds exhibited strong antiproliferative activities against the A2780 human ovarian cancer cell line, with IC50 values of 0.79 and 0.70 µM, respectively.21)

Investigation of an ethanol extract of the leaves of Helmiopsis sphaerocarpa L. C. BARNETT (Ster-culiaceae) led to the isolation of a novel triterpe-noid, 14α,15α-epoxy-3β-hydroxytaraxerane (60), along with four known compounds (taraxerol, stigmast-5-en-3-ol, 5α,8α-epidioxy-24(S)-methylcholesta-6,22-dien-3β-ol, and 24ε-hydroperoxy-24-ethylcholesta-4,28(29) dien-3-one). None of the compounds displayed any inhibition when tested against the A2780 human ovarian cancer cell line.22)

A novel oleanane-type triterpene saponin terminaliaside A (61), together with the two known saponins arjunglucoside and sericoside, was isolated from the MeOH fraction of the roots of the Madagascan plant Terminalia tropophylla H. PERRIER (Combretaceae) following bioassay-guided fractionation. Com-pound 61 exhibited moderate antiproliferative activity against the A2780 human ovarian cancer cell line, with an IC50 value of 1.2 µM.23)

Two new oxygenated oleanane triterpene saponins, 23-hy-droxylongispinogenin 3-O-β-D-glucopyranoside (62) and longispinogenin 3-O-β-D-glycopyranosyl (1->2)-β-D-gluco pyranoside (63), were isolated from the ethanol extract of the endemic Malagasy rubiaceous plant Tarenna grevei follow-ing bioassay-guided fractionation. Both compounds displayed moderate antiproliferative activity against A2780 human ovar-ian cancer cells, with IC50 values of 7.6 and 4.0 µM, respec-tively.24)

Investigation of the endemic Madagascan plant Nemato-stylis anthophylla (Rubiaceae) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of two new bioactive triterpene saponins 2″-O-acetylrandianin (64) and 6″-O-acetylrandianin (65), and the known triterpene

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saponin randianin. The two new saponins displayed moderate but selective antiproliferative activity, with IC50 values of 1.2 and 1.7 µM, respectively, against the A2780 ovarian cancer cell line but only weak inhibition of the proliferation of A2058 melanoma and H522 lung cancer cell lines.25)

A novel pentacyclic triterpene quinone methide (66) was isolated from the acetone extract of the stem bark of Sala-cia leptoclada TUL. (Celastraceae) following bioassay-guided fractionation. The new compound exhibited both in vitro and cytotoxic effects against murine P388 leukemia cells, with an IC50 value of 0.041 µg/mL, and antiplasmodial activity against the chloroquine-resistant strain FC29 of P. falciparum, with an IC50 value of 0.052 µg/mL. Although 66 displayed interest-ing activity, its low therapeutic index (0.788) was discourag-ing.26)

Bioassay-guided fractionation of EtOH extracts obtained from the roots and wood of the Madagascan plant Leptaulus citroides BAILL. (Cardiopteridaceae) resulted in the isolation of ethyl esters of three new triterpenoid saponins (67–69), together with the known compound cinnamosmolide. All the compounds were tested for their antiproliferative activity against A2780 human ovarian cancer cells, with compounds 67 and 68 showing moderate activities, (IC50 values of 2.8 and 10.2 µM, respectively), while compound 69 was inactive. The reduced activity of compound 69 compared with 68 is possibly due to the bulkiness of the 4-coumaroyl group that acylated the C-16 hydroxyl group.27)

Four triterpene saponins (70–73), along with the known apoanagallosaponin IV, were isolated from Polycarpaea cor-ymbosa LAMK. var. eriantha HOCHST (Caryophyllaceae), which is endemic to Madagascar. These compounds were evaluated for their cytotoxicity against three different cancer cell lines (colorectal SW480, prostate DU145, and mammary EMT6). Compound 70 exhibited moderate antiproliferative activity against all three cell lines, with IC50 values ranging from 4.6 to 22.6 µM. Compound 71 was tested only against SW480 and a cardiomyoblast cell line (H9c2), but did not show inhibition of less than 28.7 µM for either line.28)

Brine shrimp lethality assay-guided separation of the MeOH extract of leaves of the Madagascan-endemic Capparidaceous plant Physena sessiliflora yielded eight novel oleanane-type triterpene saponins, named physenosides S1–S8 (74–81). This assay was confirmed to be an effective, rapid screening meth-od to determine the cytotoxicity of water-soluble compounds. The results indicated that compounds 80 and 81 displayed moderate toxicities, with LD50 values of 8.5 to 22.1 µg/mL, while the other six compounds were not toxic.29)

A novel triterpene named turranoic acid (82) and a new N-containing nor-triterpene turraenine (83), along with two known compounds, triptocallic acid B and esculentoic acid, were isolated from the leaves of a Turraea sp. Compound 83 was the first known example of a naturally occurring N-linked triterpenoid dimer. Its structure was confirmed by X-ray crys-tallography analysis. Both of the new compounds displayed moderate antiplasmodial activity against the chloroquine-resistant P. falciparum strain FCM29, with IC50 values of 5.2 and 16.6 µM, respectively, while 82 exhibited weak anti-proliferative activity against the non-small lung cancer cell line H522-T1, with an IC50 value of 16.4 µM.30)

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3.5. Steroids Four novel cardenolides, madagascaren-silides A–D (84–87), were isolated from the antiproliferative DCM fraction of the ethanol extract of the roots of the Mada-gascan plant Leptadenia madagascariensis DECNE. (Apocy-naceae). All the novel cardenolides displayed strong activity against the proliferation of A2780 human ovarian cancer and H460 human lung cancer cell lines, with IC50 values ranging from 0.17 to 0.68 µM.31)

Bioassay-directed fractionation of the DCM and butanol fractions of the stem and roots part of Pentopetia androsae-mifolia DECNE (Asclepiadaceae) gave one novel (88) and three known cardenolides. The novel compound exhibited strong antiproliferative activity against the A2780 human ovarian cancer cell line, with an IC50 value of 0.4 µg/mL.32)

4. Flavonoids, Lignans, and Coumarins4.1. Flavonoids Bioassay-guided fractionation of an

ethanol extract of the roots of the endemic Malagasy plant Pongamiopsis pervilleana led to the isolation of three novel flavonoids, (2′R)-4′-hydroxyemoroidocarpan (89), pongavil-leanine (90), and epipervilline (91), together with two known compounds, emoroidocarpan and rotenolone. The novel com-pounds 90 and 91 displayed weak antiproliferative activity against the A2780 human ovarian cancer cell line, with IC50 values of 9.5 and 23.2 µM, respectively, while compound 89 was inactive.33)

Two new hybrid flavonoid glucosides (92, 93) and two new prenylated flavonoids (94, 95), along with the three known compounds β-sitosterol, 3-epi-betulinic acid, and n-pentadec-anyl octa-dec-19-en-oate, were isolated from the methanol ex-tract of the hairy roots of Catharanthus roseus G. DON (Apo-cyanceae), the Madagascar periwinkle. The new flavonoid glucosides revealed no cytotoxicity against the usual cancer cell lines, such as A549, CaSki, DLD-2, and MCF-7, although they inhibited both matrix metalloproteinases activity and tumor necrosis factor-α production in THP-1 cells treated with lipopolysaccharide, suggesting that these new flavonoids may be useful for the treatment of inflammatory diseases.34)

Investigation of the EtOAc extract of the leaves of Dilo-beia thouarsii (Proteaceae) led to the isolation of seven new diprenylated dihydroxyflavonols, named dilobenols A–G (96–102). All of the novel compounds were evaluated for their antibacterial activities against a range of seven strains of Gram-negative bacteria and three strains of Gram-positive bacteria. Most of the compounds exhibited moderate growth-inhibitory activities against Staphylococcus aureus, Vibrio spp., and Bacillus spp. In addition, all of the compounds dis-played weak antiplasmodial activities against the chloroquine-resistant strain FcB1 of P. falciparum, with IC50 values rang-ing from 15 to 30 µM, but no significant cytotoxicity against the rat cell line L-6.35)

Four novel homoisoflavoinoids (103–106) were isolated from the bulbs of Rhodocodon aff. Intermedius (Hyacintha-ceae Sensu APG II). Among the four new compounds, only compound 104 indicated similar cyclooxygenase (COX)-2 in-hibition compared with aspirin as the positive control. At the concentration of 12.5 µM, compound 105 inhibited COX-2 by 10%, while 1 mM of aspirin had an inhibition rate of 12%.36)

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4.2. Lignans Ten new neolignans including the 6′-oxo-8.1′-lignans cymosalignans A (107), B (108), and C (109), an 8.O.6′-neolignan (110), ococymosin (111), didymochlaenone C (112), and the bicyclo[3.2.1]-octanoids 113–116 were isolated, along with the six known compounds 3,4,5,3′,5′-pentamethoxy-1′-allyl-8.O.4′-neolignan, 3,4,5,3′-tetramethoxy-1′-allyl-8.O.4′-neolignan, did-ymochlaenone B, virologin B, ocobullenone, and the unusual 2′-oxo-8.1′-lignan sibyllenone, from the stems and bark of the Madagascan plant Ocotea cymosa. Novel compounds 110, 111, and 113 displayed in vitro insecticidal activity against Aedes aegypti, while compounds 111, 113, and 116 exhibited moderate antiplasmodial activity against the Dd2 strain of P. falciparum, with IC50 values of 0.45, 14.6, and 7.7 µM, respec-tively.37)

Two new lignans, 3α-O-(β-D-glucopyranosyl) desoxypodo-phyllotoxin (117) and 4-O-(β-D-glucopyranosyl) dehydropodo-phyllotoxin (118), were isolated from Cleistanthus boivinianus, together with the known lignans deoxypicropodophyllotox-in, (±)-β-apopicropodophyllin, (−)-desoxypodophyllotoxin, (−)-yatein, and β-peltatin-5-O-β-D-glucopyranoside. Both of the novel compounds exhibited strong antiproliferative activ-ity against the A2780 human ovarian cancer cell line, with IC50 values of 0.033 and 2.1 µM, respectively. In addition, compound 117 also displayed potent antiproliferative activity against the HCT-116 human colon carcinoma cell line, with an IC50 value of 0.021 µM.38)

4.3. Coumarins Investigation of the MeOH fraction of the roots of the Madagascan plant Terminalia tropophylla H. PERRIER (Combretaceae) led to the isolation of a novel lignan derivative of coumarin, 4′-O-cinnamoyl cleomiscosin A (119), together with three triterpene saponins (terminaliaside A, arjunglucoside, and sericoside), which were reviewed in the previous section. Unfortunately, the novel lignin did not show significant antiproliferative activity against the A2780 human ovarian cancer cell line.23)

The novel coumarin 3-(4′-hydroxy-2′,3′-dihydropen-prenyl)-4,6-dimethoxy-5-methylcoumarin, named astrotricou-marin (120), was isolated from the EtOAc faction of the stems of Astrotrichilia sp. following bioassay-guided fractionation. It displayed moderate antiproliferative activity against the A2780 human ovarian cancer cell line, with an IC50 value of 6.8 µM.39)

Two novel coumarins, 8-hydroxy-7-methoxy-6-(2R-hy-droxy-3-methylbut-3-enoxy)-2H-1-benzopyran-2-one (121) and 7-hydroxy-6-(2R-hydroxy-3-methylbut-3-enoxy)-2H-1-benzo-pyran-2-one,5,6,7-trimethoxy-2H-1-benzopyran-2-one (122), were isolated from the bark of the Malagasy plant Cedre-lopsis rakotozafyi CHEEK & LESCOT (Rutaceae), along with four known compounds, scoparone, scopoletin, lupeol, and β-amyrin. However, no activity data were reported for these two new compounds.40)

5. Miscellaneous Compounds5.1. Phenolic Compounds Four novel diphenylpropanes,

bussealines A–D (123–126), together with the new cyclohepta-dibenzofuran, bussealin E (127), were isolated from the DCM fraction of the roots of Bussea sakalava DU PUY & R. RABEV. (Fabaceae), which is endemic to Madagascar. The skeleton of compound 127 was not previously reported. All five of these new compounds were evaluated for their antiproliferative ac-tivity against the A2780 human ovarian cancer cell line but exhibited only weak activities, with IC50 values ranging from 24 to 45 µM, respectively.41)

Investigation of an endemic Malagasy plant identi-fied as Symphonia pauciflora BAKER (Clusiaceae) for anti-proliferative activity against the A2780 ovarian cancer cell line led to the isolation of a new compound identi-fied as 2-(3,3-dimethylallyl)-1,5,6-trihydroxy-7-methoxy-2″,2″-

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dimethylpyrano (6″,5″:3,4) xanthone (128) and the two known guttiferones A and I. The novel compound displayed moderate antiproliferative activity, with an IC50 value of 3.8 µM.42)

Bioassay-directed fractionation of the leaf and root extracts of the antiproliferative Madagascar plant Stuhlmannia moavi afforded 6-acetyl-5,8-dihydroxy-2-methoxy-7-methyl-1,4-naph-thoquinone (stuhlmoavin, 129) as the most active compound, with an IC50 value of 8.1 µM against the A2780 human ovarian cancer cell line, as well as six known compounds, includ-ing the homoisoflavonoid bonducellin and the stilbenoids 3,4,50-trihydroxy-30-methoxy-trans-stilbene, piceatannol, res-veratrol, rhapontigenin, and isorhapontigenin.43)

Two new dimeric phloroglucinols, mallotojaponins B (130) and C (131), along with the known compound mallotophe-none, were isolated from the leaves and inflorescence of Mal-lotus oppositifolius (GEISELER) MÜLL. ARG. following bioassay-guided fractionation. The two novel compounds displayed strong antiplasmodial activities against the chloroquine-resis-tant Dd2 strain of P. falciparum, with IC50 values of 0.75 and 0.14 µM, respectively. In addition, they also exhibited strong antiproliferative activity against the A2780 human ovarian cancer cell line (IC50 values of 1.1 and 1.3 µM, respectively).44)

Three novel bioactive compounds, TR-21 (132), TR-22 (133), and TR-23 (134), were isolated from the root bark of Disopyros quercina (Baill.) G. E. SCHATZ & LOWRY (Ebena-ceae) following bioassay-guided fractionation. All three novel compounds displayed strong antiproliferative activity against the murine P388 leukemia cell line, with IC50 values of 0.0175, 0.089, and 1.027 µg/mL, respectively.45)

Bioassay-guided fractionation using an antimicrobial assay of the crude acetonic extract of Garcinia goudotiana leaves and of its five partitions led to the isolation of two new pre-nylated benzoylphloroglucinol derivatives, goudotianone 1 (135) and goudotianone 2 (136), in addition to two known

compounds including one xanthone, 1,3,7-trihydroxy-2-iso-prenylxanthone, and one triterpenoid, friedelin. Both of the new compounds isolated demonstrated significant selective antimicrobial activities against Gram-positive bacteria, in particular Staphylococcus lugdunensis, Enterococcus faecalis, and Mycobaterium smegmatis, with minimum inhibition con-centration (MIC) values as low as 39 µg/mL. In addition, the potential cytotoxicity of these two compounds was evaluated against HT-29 human colon cancer cells and MRC5 human fetal lung fibroblast cells, and both novel compounds showed weak cytotoxicity, with IC50 values of 65 and 55 µg/mL, re-spectively.46)

Six new phenolic glucosides, named flacourtosides A–F (137–142), along with five known compounds, the phenolic glycosides itoside H, xylosmin, scolochinenoside D, polio-thrysoside, and betulinic acid 3β-caffeate, were isolated from the stem bark of Flacourtia ramontchi using a bioassay-guided isolation process. All of the novel compounds moder-ately inhibited dengue (DENV) RNA polymerase, with IC50 values ranging from 9.3 to 71 µM. Compounds 137 and 141 were the most active compounds among the six, showing IC50 values of 9.3 and 13.4 µM, respectively.47)

The two novel compounds tanikolide seco-acid (143) and tanikolide dimer (144) were isolated from the Madagascar ma-rine cyanobacterium Lyngbya majuscula. The stereochemistry of compound 144 was determined to be exclusively the R,R-isomer rather than a mixture of meso-compounds based on the total synthesis. The novel compounds were tested in the SIRT2 inhibitory assay, a mammalian cell sodium channel-blocking assay, as well as in a cytotoxicity assay. Compound 144 displayed strong inhibition against SIRT2, with an IC50 value of 176 nM, while compound 143 was inactive at the highest concentration tested (50 µM). In the sodium channel-blocking assay, compound 144 induced 54% inhibition at 5.2 µM, while compound 143 was still inactive at the highest concentration tested (10 µM). Cytotoxicity assays revealed that compound 143 at 9.9 µM was moderately toxic to the human lung H-460 cell line, but compound 144 did not have any ac-tivity at 10 µM.48)

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NPTX-594 (145) is a neurotoxic acylpolyamine isolated from the venom of a Madagascar Joro spider, Nephila mada-gascariensis. The initial structure was proposed based on the mass spectroscopic data, but the structure was confirmed by total synthesis. Paralytic assay data revealed the novel com-pound had strong activity against crickets (Gryllus bimacula-tus), with an LD50 value of 0.175 nmol/g.49)

Investigation of the endemic Madagascan plant Uvaria sp. (Annonaceae) for antiproliferative activity against the A2780 ovarian cancer cell line led to the isolation of two new ace-togenins, uvaricin A (146) and uvarican B (147) following bioassay-guided fractionation. The two acetogenins displayed moderate antiproliferative activites against the A2780 ovarian cancer cell line, with IC50 values of 6.4 and 8.8 µM, respec-tively.50)

Four new beilschmiedic acid derivatives, cryptobeilic acids A–D (148–151), along with the known compound tsangibeilin B, were isolated from the bark of Beilschmiedia cryptocary-oides collected from Madagascar. The novel compounds dis-played moderate antibacterial activity against Escherichia coli 6r3, Acinetobacter calcoaceticus DSM 586, and Pseudonamas stutzeri A1501, with MIC values ranging from 10 to 50 µM. In addition, the compounds exhibited antiplasmodial activ-ity against erythrocytic stages of chloroquine-resistant P. falciparum strain NF54 and weak cytotoxicity against L6 cell lines.51)

The novel butanolide macrocarpolide A (152) and the two new secobutanolides macrocarpolides B (153) and C (154), along with the two known butanolides linderanolide B and isolinderanolide, were isolated from the ethanol extract of the roots of Ocotea macrocarpa (Lauraceae) following bioassay-directed fractionation. All the novel compounds displayed moderate antiproliferative activity against A2780 ovarian cancer cells, with IC50 values of 2.57, 1.98, and 1.67 µM, re-spectively.52)

Antimalarial bioassay-guided fractionation of an EtOH extract of the root wood of Cryptocarya rigidifolia (Laura-ceae) led to the isolation of the five new 5,6-dihydro-α-pyrone cryptorigidifoliols A–E (155–159) and the six novel bicy-clic tetrahydro-α-pyrone derivatives cryptorigidifoliols F–K (160–165). The bicyclic tetrahydro-α-pyrone derivatives were identified as products of acid-catalyzed intramolecular Michael additions of the 5,6-dihydro-α-pyrones in the pres-ence of silica gel. All the compounds were evaluated for their antiplasmodial activity against the chloroquine/mefloquine-resistant Dd2 strain of P. falciparum, and compounds 155–161 exhibited moderate activities, with IC50 values ranging from 4.0 to 9.2 µM, while compounds 162–165 showed less activity (IC50 values >10 µM), suggesting that the presence of an α,β-unsaturated carbonyl moiety is not essential for potent antima-larial activity.53)

Two novel polyketides, PM050489 (166) and PM060184 (167), were isolated from the DCM/MeOH extract of the Mad-agascan sponge Lithoplocamia lithistoides. Both of the new compounds displayed strong antiproliferative activity against a panel of three human cancer cell lines, comprising A549 lung, HT-29 colon, and MDA-MB-231 breast cancer cell lines, with 50% growth inhibition (GI50) values ranging from 0.38 to 0.61 nM. Compound 167 displayed strong antimitotic activity (IC50=26.4 nM) when tested in a modified cell-based immuno-assay using the specific mitotic marker MPM-42, suggesting that it may target microtubules by an unusual mechanism.54)

Langaside (168), a secoiridoid lactone glucoside possessing a novel skeleton formed by a [2+2] cycloaddition reaction be-tween the secoiridolactone glucoside 1,9-trans-9,5-cis-swero-side and p-coumaric acid, was isolated from the fruits and flowers of Malagasy Tachiadenus longiflorus GRISEB. (Genti-anaceae), along with seven known compounds. However, the novel compound did not display significant activity against an

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NCI 59 human tumor cell line panel.55)

Seven new nitrogenous macrolides, named salarins D–J (169–175), were isolated from the Madagascar sponge Fasca-plysinopsis sp., collected from the west coast of Madagascar in Salary Bay. All the compounds were evaluated for their cytotoxicity against K562 and UT-7 human leukemia cells. Compounds 169, 170, 173, and 175 displayed dose- and time-dependent inhibition of proliferation, while compounds 171 and 174 were inactive in these assays.56)

A novel nitrogenous bismacrolide, named tausalarin C (176), was isolated from the Madagascar sponge Fascaplysin-opsis sp. It was suggested that tausalarin C is assembled from the known macrolide salarin and pretaumycin A. The effect of the new compound on cell proliferation was determined using the K562 human leukemia cell line, and the results showed that tausalarin C at 1 µM inhibited 25, 65, and 74% of K562 growth after 24, 48, and 72 h, respectively.57)

A new member of the tartrolon series, tartrolon D (177), along with the known compound ikaragamycin, was isolated from Streptomyces sp. MDG-04-17-069 fermentation broths, which was isolated from marine sediment at a depth of 30 m collected off the east coast of Madagascar. Cytotoxicity as-says were performed with the novel compound against a panel of three human cancer cell lines, comprising A549 lung, HT-29 colon, and MDA-MB-231 breast cancer cell lines. The compound displayed GI50 values in the submicromolar range against all the lines tested, making it a promising anticancer drug candidate.58)

Two new cyclic depsipeptides, pipecolidepsins A (178) and B (179), were isolated from the sponge Homophymia lamellosa collected off the coast of Madagascar. In addition to several

Table 1. List of Higher Plants, Marine Organisms, and Bacterial Strains Studied

Higher plants

Ambavia gerrardii (Annonaceae)Anisocycla grandidieri (Menispermaceae)Astrotrichilia sp. (Meliaceae)Athroisma proteiforme (Asteraceae)Beilschmiedia cryptocaryoides (Lauraceae)Bussea sakalava (Fabaceae)Cassipourea lanceolate (Rhizophoraceae)Catharanthus roseus (Apocyanceae)Cedrelopsis rakotozafyi (Rutaceae)Cleistanthus boivinianus (Phyllanthaceae)Croton barorum (Euphorbiaceae)Croton goudotii (Euphorbiaceae)Cryptocarya rigidifolia (Lauraceae)Cyphostemma greveana (Vitaceae)Dilobeia thouarsii (Proteaceae)Dioscorea antaly (Dioscoreaceae)Disopyros quercina (Ebenaceae)Dodonaea viscosa (Sapindaceae)Flacourtia ramontchi (Salicaceae)Garcinia goudotiana (Clusiaceae)Gonioma malagasy (Apocynaceae)Helmiopsis sphaerocarpa (Sterculiaceae)Leptadenia madagascariensis (Apocynaceae)Leptaulus citroides (Cardiopteridaceae)Malleastrum sp. (Meliaceae)Mallotus oppositifolius (Euphorbiaceae)Molinaea retusa (Sapindaceae)Muntafara sessilifolia (Apocynaceae)Nematostylis anthophylla (Rubiaceae)Ocotea cymosa (Lauraceae)Ocotea macrocarpa (Lauraceae)Pentopetia androsaemifolia (Asclepiadaceae)Physena sessiliflora (Physenaceae)Polycarpaea corymbosa (Caryophyllaceae)Pongamiopsis pervilleana (Fabaceae)Rhodocodon aff. Intermedius (Hyacinthaceae)Salacia leptoclada (Celastraceae)Sterculia tavia Baill. (Malvaceae)Stuhlmannia moavi (Fabaceae)Symphonia pauciflora (Clusiaceae)Tachiadenus longiflorus GRISEB. (Gentianaceae)Tarenna grevei (Rubiaceae)Terminalia tropophylla (Combretaceae)Turraea sp. (Meliaceae)Uvaria sp. (Annonaceae)Vitex cauliflora (Lamiaceae)

Marine organisms

Biemna laboutei (Desmacellidae, sponge)Fascaplysinopsis sp. (Thorectidae, sponge)Haliclona telearensis (Chalinidae, sponge)Homophymia lamellose (Neopeltidae, sponge)Lithoplocamia lithistoides (Raspailiidae, sponge)Sinularia gravis (Alcyoniidae, soft coral)Sinularia vanderlandi (Alcyoniidae, soft coral)Theonella aff. Swinhoei (sponge)Unidentified Carteriospongia sp. (sponge)Unidentified tunicate (Didemnidae, soft coral)

Bacteria and animals

Lyngbya majuscula (Oscillatoriaceae, cyanobacteria)Nephila madagascariensis (Nephilidae, spider)

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common amino acids, these peptides contain unusual residues, including 2-amino-3-hydroxy-4,5-dimethylhexanoic acid, 3-ethoxyasparagine, 3,4-dimethylglutamine, 4,7-diamino-2,3-dihydroxy-7-oxoheptanoic acid, and 3-hydroxyaspartic acid, as well as a terminal 3-hydroxy-2,4,6-trimethylheptanoic acid residue. Cytotoxicity assays were performed with the novel compound against a panel of three human cancer cell lines, including A549 lung, HT-29 colon, and MDA-MB-231 breast cancer cell lines. Both of the novel compounds displayed GI50 values in the submicromolar range against all the lines tested, while compound 179 was significantly more potent, with GI50 values of 0.04, 0.01, and 0.02 µM against the three different cell lines, respectively.59)

Three novel cyclic peptides, cyclotheonellazoles A–C (180–182), were isolated from the marine sponge Theonella aff. Swinhoei collected in Madagascar. These three new com-pounds contain six unusual nonproteinogenic amino acids,

among which the two most novel were 4-propenoyl-2-tyrosyl-thiazole and 3-amino-4-methyl-2-oxohexanoic acid. All three peptides inhibited chymotrypsin activity, with IC50 values of 0.62, 2.8, and 2.3 nM, respectively, and elastase with IC50 val-ues of 34, 100, and 99 pM, respectively.60)

6. ConclusionOur previous review discussed 262 new active compounds

identified before July 2009, while here we present 182 com-pounds identified in the past 8 years. Compared with the num-ber of new active compounds reported in our previous review, more activity was described during the more recent time pe-riod (2009–2017). This can be attributed to hard work by the isolation and structure elucidation core of the ICBG/Madagas-car research project and the growing interest in searching for potential drug candidates from the natural resources of Mada-

Table 2. List of Cytotoxic Compounds Isolated with IC50 Values of ≤1 µM

Compound Bioassay Activity (µM) Origin Reference

11-Methyoxysampangine (3) H460 human non-small-cell lung cancer cell line 0.57 Ambavia gerrardii 2Isohalitulin (22) Brine shrimp 0.9 Haliclona telearensis 8

Athrolides C (32) A2780 human ovarian cancer cells 0.57 Athroisma proteiforme 10Athrolides D (33) A2780 human ovarian cancer cells 0.38 Athroisma proteiforme 10

42 A2780 human ovarian cancer cell line 0.44 Cyphostemma greveana 1344 Murine P388 leukemia cell line 0.35a) Croton barorum 1645 Murine P388 leukemia cell line 0.41a) Croton goudotii 1651 A2780 ovarian cancer cell line 0.65 Carteriospongia sp. 1952 A2780 ovarian cancer cell line 0.26 Carteriospongia sp. 19

Dodoneasides A (58) A2780 ovarian cancer cell line 0.79 Dodonaea viscosa 21Dodoneasides B (59) A2780 ovarian cancer cell line 0.70 Dodonaea viscosa 21

66 Murine P388 leukemia cell line 0.08 Salacia leptoclada 26Madagascarensilide A (84) A2780 ovarian cancer cell line 0.18 Leptadenia madagascariensis 31Madagascarensilide B (85) A2780 ovarian cancer cell line 0.21 Leptadenia madagascariensis 31Madagascarensilide C (86) A2780 ovarian cancer cell line 0.17 Leptadenia madagascariensis 31Madagascarensilide D (87) A2780 ovarian cancer cell line 0.29 Leptadenia madagascariensis 31

88 A2780 ovarian cancer cell line 0.57a) Pentopetia androsaemifolia 32117 A2780 ovarian cancer cell line HCT-116 human

colon carcinoma cell line0.033 Cleistanthus boivinianus 380.021

TR-21 (132) Murine P388 leukemia cell line 0.048a) Disopyros quercina 45TR-22 (133) Murine P388 leukemia cell line 0.2a) Disopyros quercina 45

PM050489 (166) HT-29 colon cancer cell line 0.46c) Lithoplocamia lithistoides 54PM060184 (167) HT-29 colon cancer cell line 0.42 Lithoplocamia lithistoides 54

Pipecolidepsin A (178) MDA-MB-231 breast cancer cell line 0.7 Homophymia lamellosa 59Pipecolidepsin B (179) MDA-MB-231 breast cancer cell line 0.02 Homophymia lamellosa 59

a) These values were converted from µg/mL to µM; b) activity in nM/g and c) in nM.

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

gascar. In this review, the isolated compounds cover various types of natural products, including alkaloids, terpenoids, and steroids, aromatic compounds such as flavonoids and lignans, quinones, polyketides, and peptides and depsipeptides.

Forty-six Malagasy higher plant species from 30 families (Annonaceae, Apocyanceae, Asclepiadaceae, Asteraceae, Cardiopteridaceae, Caryophyllaceae, Celastraceae, Clusiaceae,

Combretaceae, Dioscoreaceae, Ebenaceae, Euphorbiaceae, Fa-baceae, Gentianaceae, Hyacinthaceae, Lamiaceae, Lauraceae, Malvaceae, Meliaceae, Menispermaceae, Phyllanthaceae, Physenaceae, Proteaceae, Rhizophoraceae, Rubiaceae, Ruta-ceae, Salicaceae, Sapindaceae, Sterculiaceae, Vitaceae) and 10 marine organisms, including seven sponge species and three soft coral species, were investigated (Table 1) during this time

C: Cytotoxic (µM unless otherwise noted), amurine P388 leukemia cell line, bA2780 ovarian, cHCT-116 human colon, dHT-29 colon cancer cell line; A: antimalarial (µM); Ins: activity against crickets (Table 4).

Chart 1. Selected Compounds with Strong Antiplasmodial and/or Cytotoxic Activity

Table 3. List of Antimalarial Compounds Isolated with IC50 Values of ≤1 µM

Compound Bioassay Activity (µM) Origin Reference

Netamine M (15) P. falciparum strain 3D7 1.0 Biemna laboutei 566 P. falciparum 0.1a) Salacia leptoclada 26

Ococymosin (111) P. falciparum strain Dd2 0.45 Ocotea cymosa 37130 P. falciparum strain Dd2 0.75 Mallotus oppositifolius 44131 P. falciparum strain Dd2 0.14 Mallotus oppositifolius 44

a) This value was converted from µg/mL to µM.

Table 4. Insecticide Compound Isolated

Compound Bioassay Activity (µM) Origin Reference

NPTX-594 (145) Crickets (Gryllus bimaculatus) 0.175a) Nephila madagascariensis 49

a) This value was converted from µg/mL to µM.

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period.6.1. Cytotoxicity Activity As shown in Table 2 and

Chart 1, among the compounds tested in the cytotoxicity assays, five (66, 117, 132, 166, and 179) displayed activity against cancer cell lines with ED50 values of <100 nM. Com-pound 66, a tritepene-quinone seemingly biosynthesized by the migration of three methyl groups of an oleanane followed by oxidation, exhibited cytotoxicity against the murine P388 leukemia cell line with an ED50 value of 80 nM. Another qui-none (132) dimer isolated from Disopyros quercina showed an ED50 value of 48 nM against the murine P388 leukemia cell line. The presence of the quinone moiety, unsaturated ring, and ester group may contribute to its activity. Compound 117, a derivative of the well-known topoisomerase inhibitors podophyllotoxin and etoposide, confirmed the strong activ-ity of these types of compounds against the A2780 ovarian cancer cell line (ED50 value of 33 nM). The polyketide 166 and the depsipeptide 179 are the most promising cytotoxic com-pounds, with ED50 values of 56 nM against HT 29 colon cancer and GI50 of 20 nM against MDA-MB-231breast cancer cell line, respectively. The mechanism of action of the polyketide 166, a chlorinated unsaturated δ-lactone with amide functionalities isolated from the sponge Lithoplocamia lithistoides is believed to target microtubules. The potential target of the strongly ac-tive depsipeptide 179 has not been elucidated.

6.2. Antimalarial Activity As shown in Table 3 and Chart 1, four compounds (66, 111, 130, and 131) demonstrated antiplasmodial activity (P. falciparum) with IC50 values of ≤1 µM. Among these active compounds, 66 and 131 were found to display very strong activity with IC50 values of 0.1 and 0.14 µM, respectively. It is obvious that the strong cytotox-icity of these two compounds interferes with their antiplasmo-dial activity. Recently, 131 and related compounds have been synthesized and evaluation of the antiplasmodial activity of the synthetic compounds confirmed the observed antimalarial activity properties of phloroglucinols.61,62)

Conflict of Interest The authors declare no conflict of interest.

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