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Pure and Applied Chemistry

The Scientific Journal of IUPAC

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Volume 86, Issue 6

Issues

Recent investigations of bioactive natural products from endophytic, marine-derived, insect pathogenic fungi and Thai medicinal plants

Chulabhorn Mahidol
  • Corresponding author
  • Chulabhorn Research Institute, Chulabhorn Graduate Institute, and Center of Excellence on Environmental Health and Toxicology (EHT), Kamphang Phet 6 Road, Laksi, Bangkok 10210, Thailand
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/ Prasat Kittakoop
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/ Vilailak Prachyawarakorn
  • Chulabhorn Research Institute, Chulabhorn Graduate Institute, and Center of Excellence on Environmental Health and Toxicology (EHT), Kamphang Phet 6 Road, Laksi, Bangkok 10210, Thailand
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/ Somsak Ruchirawat
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Published Online: 2014-04-29 | DOI: https://doi.org/10.1515/pac-2013-1206

Abstract

Living organisms in Thailand are very diverse due to the unique geographical location of Thailand. The diversity of Thai bioresources has proven to be a rich source of biologically active compounds. The present review covers bioactive substances from Thai endophytic, marine-derived, insect pathogenic fungi and medicinal plants. Many new compounds isolated from Thai bioresources have diverse skeletons belonging to various classes of natural products. These compounds exhibited an array of biological activities, and some are of pharmaceutical interest. Bioactive compounds from Thai bioresources have not only attracted organic chemists to develop strategies for total synthesis, but also attracted (chemical) biologists to investigate the mechanisms of action. The chemistry and biology of some selected compounds are also discussed in this review.

Keywords: biodiversity; biological activity; fungi; IUPAC Congress-44; Life Chemistry; marine chemistry; medicinal plants; natural products

Article note: A collection of invited papers based on presentations on the Life Chemistry theme at the 44th IUPAC Congress, Istanbul, Turkey, 11–16 August 2013.

Thailand, due to its unique geographical location in the tropics, has long enjoyed the luxury of an innumerable variety of life forms ranging from microorganisms to higher organisms (plants and animals). Mountainous areas in the north and south of Thailand are covered with great diversity of plants. Since the weather in the Northern Thailand is colder than in the Southern Thailand, trees in the northern part are different from those in the southern areas (tropical wet with high humidity). Mountainous areas in the Southern Thailand are furnished with tropical rainforests, however, those in the Northern Thailand, i.e., Doi Inthanon National Park (2565 meters above the sea level) and Doi Huamodluang (2330 meters above the sea level), have tropical-subtropical forests. Moreover, the Southern Thailand has a long coastline approximately 3219 km covering the Gulf of Thailand and the Andaman Sea. Undoubtedly, Thailand has enjoyed the luxury of biodiversity and the bioresources have proved to be rich sources of biologically active compounds, which have diverse skeletons and biological activities. This review covers bioactive compounds from Thai endophytic, marine-derived, insect pathogenic fungi and medicinal plants.

The research on bioactive compounds from Thai microorganisms has focused on fungi, particularly the bioactive metabolites from endophytic, marine-derived, and insect pathogenic fungi. Endophytic fungi live symbiotically within plant living tissues, and they produce bioactive secondary metabolites, some of which are believed to give particular benefits to the host plants [1]. Marine-derived fungi are isolated from tissues of marine organisms, i.e., marine sponges, tunicates, algae, and plants. Insect pathogenic fungi (or entomopathogenic fungi) attach their spores to a body surface of insects, and under approriate temperature and moisture, they can grow and give negative effects (diseases) to insect hosts [2].

A novel tricyclic polyketide, namely dothideomycetide A (1), along with new modified azaphilones, dothideomycetones A (2) and B (3), and a known azaphilone, austdiol (4), was isolated from the endophytic fungus Dothideomycete sp. (Fig. 1). The fungus Dothideomycete sp. was isolated from the root of a Thai medicinal plant, Tiliacora triandra (Colebr.) Diels (Menispermaceae) (known in Thai as “Ya-Nang”) [3]. Dothideomycetide A (1) has a novel terpene-like 6,6,6 ring system, with a close similarity to a terpenoid skeleton. The novel tricyclic polyketide 1 is possibly derived biosynthetically from the azaphilone derivatives 2 and 3, which are in turn derived from a derivative of austdiol (4), as depicted in Fig.1 [3]. Dothideomycetide A (1) exhibited cytotoxic activity against human cancer cell lines with IC50 values of 15–36 μg/mL, and showed antibacterial activity against Staphylococcus aureus ATCC 25923 and ATCC 33591 (methicillin resistant strain) with MIC values of 128 and 256 μg/mL, respectively [3].

Biosynthetic relationship among the fungal metabolites 1–4 isolated from Dothideomycete sp.
Fig. 1

Biosynthetic relationship among the fungal metabolites 1–4 isolated from Dothideomycete sp.

Investigation of bioactive compounds from the endophytic fungus, Curvularia geniculata, which was isolated from a Thai medicinal plant, Catunaregam tomentosa (Blume ex DC.) Tirveng. (Rubiaceae) (known in Thai as “Nham-Taeng” or “Ma-Ked”), led to the isolation of new hybrid peptide-polyketides, curvularides A–E (5–9) (Fig. 2) [4]. The structural feature of curvularides A–E (5–9) containing a twelve-carbon polyketide unit linked with L-isoleucine derivative is rare in nature, and to date there have been only two natural compounds, coronatine (10) and (+)-7-iso-jasmonoyl-L-isoleucine (JA-Ile, 11), possessing such feature (Fig. 2). Since coronatine (10) and JA-Ile (11) are critically important for the jasmonate pathway [5, 6], it was postulated that curvularides A–E (5–9) might have phytohormone activity possibly related to the jasmonate pathway. Curvularide B (6) exhibited antifungal activity against Candida albicans with inhibition zone diameter of 12.1 mm; and there was a synergistic activity of curvularide B (6) and antifungal fluconazole drug [4]. Recently, a divergent total synthesis of curvularides A–E (5–9) was successfully established [7].

Structures of curvularides A–E (5–9), coronatine (10), and JA-Ile (11).
Fig. 2

Structures of curvularides A–E (5–9), coronatine (10), and JA-Ile (11).

The endophytic fungus, Phomopsis sp., was isolated from a Thai medicinal plant, Hydnocarpus anthelminthicus Pierre ex Laness. (Flacourtiaceae) (known in Thai as “Kra-Bao”), and the investigation of bioactive metabolites of this fungus led to the isolation of mycoepoxydiene (12), deacetylmycoepoxydiene (13), and 2,3-dihydromycoepoxydiene (14) (Fig. 3) [8]. Compounds 12 and 13 exhibited potent cytotoxic activity, and the α,β-unsaturated lactone moiety in 12 and 13 was possibly responsible for the cytotoxic activity [8]. Because of potent anticancer activity of mycoepoxydiene (12), the culture conditions for the production of 12 by Phomopsis sp. were optimized, leading to the final yield of 354 mg/L [9]. Recently, mycoepoxydiene (12) was found to exhibit interesting biological activities, for example, inducing cell cycle arrest at the G2/M phase and apoptosis in cancer cells [10], suppressing RANKL-induced osteoclast differentiation in vitro and ovariectomy-induced osteoporosis in vivo [11], activating p53 to induce apoptosis and suppressing NF-κB to disrupt cell proliferation [12], inhibiting lipopolysaccharide-induced inflammatory responses through the suppression of TRAF6 polyubiquitination [13], and inhibiting antigen-stimulated activation of mast cells and suppressing IgE-mediated anaphylaxis in mice [14]. Since deacetylmycoepoxydiene (13) has interesting antitumor properties, the antimicrobial-TLC-HPLC method for screening high yield fungal strains for the production of 13 was established [15]. LC-MS/MS method for analysis of deacetylmycoepoxydiene (13) in rat plasma for a preclinical pharmacokinetic study was developed [16], and the formulation of 13 in a nanosuspension form was illustrated for a delivery system for prostate cancer [17].

Structures of mycoepoxydiene (12), deacetylmycoepoxydiene (13), and 2,3-dihydromycoepoxydiene (14).
Fig. 3

Structures of mycoepoxydiene (12), deacetylmycoepoxydiene (13), and 2,3-dihydromycoepoxydiene (14).

The endophytic mitosporic Dothideomycete sp. LRUB20 was isolated from a Thai medicinal plant, Leea rubra Blume ex Spreng. (Vitaceae) (known in Thai as “Stang” or “Ka-Tang-Bai”). The LRUB20 fungus may be useful for “white biotechnology” (or “industrial biotechnology”), a microbial production of building blocks for chemical industry, because it produced a gram scale of 2-hydroxymethyl-3-methyl-cyclopent-2-enone (15) (Fig. 4), an intermediate for organic syntheses [18]. By varying culture media, the fungus Dothideomycete sp. LRUB20 was found to produce many metabolites, for example, dothideopyrones A–D (16–19) and cis,trans-muconic acid (20) (Fig. 4) [19]. The LRUB20 fungus produced large amount of cis,trans-muconic acid (20), which is an intermediate for the environmentally compatible synthesis of adipic acid [20], a monomer of nylon polymer. White biotechnology and green chemistry have recently received great attention from scientists worldwide because these technologies can reduce the use of chemicals that cause global warming.

Structures of fungal metabolites 15–20 produced by Dothideomycete sp. LRUB20.
Fig. 4

Structures of fungal metabolites 15–20 produced by Dothideomycete sp. LRUB20.

The endophytic fungus Corynespora cassiicola L36 was iolated from a Thai medicinal plant, Lindenbergia philippensis (Cham.) Benth. (Scrophulariaceae) (in Thai “Yha-Dub-Fia”), and chemical investigation of this fungus yielded new depsidones and diaryl ethers, i.e., corynesidones A (21) and B (22), corynether A (23), and compound 24 (Fig. 5) [21]. Compounds 21–24 exhibited potent antioxidant activity, and corynesidone A (21) also inhibited the activity of aromatase enzyme, a targeted therapy for the treatment of breast cancer [21]. New depsidones, namely aspergillusidones A–C (25–27), a diaryl ether 28, and a new natural but synthetically known pyrone (29), together with known depsidones, nidulin (30), nornidulin (31), and 2-chlorounguinol (32) (Fig. 5), were isolated from the marine-derived fungus Aspergillus unguis CRI282-03 [22]. Depsidones 25–27 and 30–32 inhibited aromatase with the IC50 values of 0.74–11.2 μM; among the isolated depsidones, aspergillusidone C (27) exhibited the most potent aromatase inhibitory activity with the IC50 value of 0.74 μM. It is interesting to note that while depsidones inhibited aromatase, diaryl ethers did not inhibit this enzyme, therefore the structural features of depsidones are possibly important for the inhibition of aromatase.

Structures of depsidones 21, 22, 25–27, and 30–32, diaryl ethers 23, 24, and 28, and a pyrone 29.
Fig. 5

Structures of depsidones 21, 22, 25–27, and 30–32, diaryl ethers 23, 24, and 28, and a pyrone 29.

Depsidones exhibit a broad spectrum of biological activities [23]. Recently, few landmark discoveries on bioactivity of depsidones have been reported, for example, as inhibitors of the enzyme Rab geranylgeranyl transferase (a target for the treatment of cancer and osteoporosis) [24], as inhibitors of anthrax lethal factor [25], and being potent inhibitors of microsomal prostaglandin E2 synthase-1 (potent anti-inflammatory agents) [26]. The biological activities of depsidones mentioned above, together with our finding that a depsidone core structure is necessary for the inhibition of aromatase, encouraged us to produce new depsidone derivatives. Since we have the marine-derived fungus capable of producing depsidones [22], we then used this fungus (A. unguis CRI282-03) as a producer of new depsidone derivatives using the technique “directed biosynthesis through biohalogenation” [27]. Normally, there are enzymes, e.g., FADH2-dependent halogenases and haloperoxidases, responsible for halogenation of natural products, and these enzymes can incorporate halogens (bromine and iodine) other than chlorine into natural product molecules [28–30]. Accordingly, we cultivated A. unguis CRI282-03 in media containing different halogen salts, and found that the fungus produced new depsidone derivatives (Fig. 6) in the media containing KBr and KI [27]. However, the CRI282-03 fungus could not grow in the KF medium, probably due to the toxicity of KF to the fungus. New “unnatural” natural products obtained from the fungus cultivated in the KBr-containing medium were depsidones, namely aspergillusidones D–F (33–35), phenol derivatives, aspergillusphenols A and B (36 and 37), and 3,5-dibromo-2,4-dihydroxy-6-methyl-benzoic acid methyl ester (38) (Fig. 6); compound 38 was a new natural product, but synthetically known [31]. Known fungal metabolites, unguinol (39) and 3-ethyl-5,7-dihydroxy-3,6-dimethylphthalide (40), were also obtained from the KBr medium (Fig. 6). In the KI containing medium, the CRI282-03 fungus produced a new depsidone, 2,4-dichlorounguinol (41) (Fig. 6), and known compounds including unguinol (39) (Fig. 6), nidulin (30), nornidulin (31), 2-chlorounguinol (32) (Fig. 5), and agonodepside A (42) (Fig. 6) [27]. It should be noted that there is a trace amount of chloride in the commercial KI used for the preparation of KI-containing medium; the enzymes of the CRI282-03 fungus prefer trace chloride to iodide as substrates. The fungal cultivation in seawater (1.5 L) produced gram scale of nidulin (30), while those in KBr and KI gave aspergillusidone D (33) (0.7 g) and unguinol (39) (0.28 g), respectively, as major components. These results implied that the fungal metabolites could be produced in a controlled fashion; chlorinated metabolites from seawater, brominated derivatives from the KBr medium, and non-halogenated compounds from the KI medium [27]. In addition, the directed biosynthesis through biohalogenation gave insights into the depsidone biosynthesis, which is through the oxidative coupling of depsides [27]. Aspergillusidones D–F (33–35) and unguinol (39) inhibited aromatase with IC50 values of 0.5–1.0 μM [27].

Metabolites obtained from the directed biosynthesis through biohalogenation by the fungus A. unguis CRI282-03.
Fig. 6

Metabolites obtained from the directed biosynthesis through biohalogenation by the fungus A. unguis CRI282-03.

The marine derived fungus of the order Pleosporales strain CRIF2 was isolated from tissues of an unidentified sponge; this fungus produced a new diketopiperazine 43 and a new phthalide derivative 44 (Fig. 7) [32]. The phthalide 45 was also obtained as a new natural product but synthetically known [33, 34]) (Fig. 7). Compounds 43 and 45 exhibited cytotoxic activity with IC50 values of 25.8–44.0 μg/mL [32]. The new phthalide, colletotrialide (46), together with known isocoumarins, i.e., monocerin (47) and derivative 48, together with fusarentin derivative 49, were isolated from the endophytic fungus Colletotrichum sp. (Fig. 7), which was isolated from a Thai medicinal plant, Piper ornatum N.E. Br. (Piperaceae) [35]. Compound 48 could scavenge 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals with the IC50 value of 23.4 μM, and inhibit superoxide anion radical formation with the IC50 value of 52.6 μM [35]. Colletotrialide (46) and isocoumarins 4749 exhibited potent antioxidant activity [35]. A new phthalide, acremonide (50), and several isocoumarin derivatives, i.e., acremonones 51–55, were isolated from the endophytic fungus Acremonium sp. (Fig. 7), which was isolated from a mangrove plant, Rhizophora apiculata Blume (Rhizophoraceae) [36]. It should be noted that the structure of phthalide is of great pharmaceutical interest, therefore there have been several synthetic methodologies recently reported for the synthesis of phthalides [37–41].

Fugal metabolites 43–55 isolated from fungi including the fungus of the order Pleosporales strain CRIF2, Colletotrichum sp., and Acremonium sp.
Fig. 7

Fugal metabolites 43–55 isolated from fungi including the fungus of the order Pleosporales strain CRIF2, Colletotrichum sp., and Acremonium sp.

A new tetronic acid, nodulisporacid A (56), was isolated from the marine-derived fungus Nodulisporium sp. (Fig. 8), which was isolated from an unidentified soft coral [42]. Nodulisporacid A (56) existed as equilibrium E/Z mixtures. Nodulisporacid A (56) exhibited antimalarial activity with the IC50 value in the ranges of 1–10 μM [42]. The absolute configuration of nodulisporacid A (56) was later defined, through the total synthesis, as 4R,4′R,6′R by Watanabe and co-workers [43]. A tetramic acid, vermelhotin (57) (Fig. 8), was isolated from an unidentified marine-derived fungus CRI247-01 (a member of the Order Pleosporales) [42]. Although vermelhotin (57) was previously isolated as a single E-isomer from an unidentified fungus by a Japanese group [44], we found that vermelhotin (57) obtained from the fungus CRI247-01 spontaneously underwent inter-conversion between E- and Z-isomers to give an equilibrium ratio of 1:2. Vermelhotin (57) exhibited cytotoxic and antimalarial activities [42]. Recently, vermelhotin (57) was found to be an inhibitor of calmodulin, an important drug target [45]. Calmodulin is a cellular Ca2+-binding protein, modulating many enzymes and ion channels necessary for several cellular functions. Moreover, we recently found that vermelhotin (57) exhibited potential anti-inflammatory activity through the inhibition of nitric oxide production [46]. Vermelhotin (57) suppressed expression of inducible nitric oxide synthase (iNOS), and selectively inhibited p38 phosphorylation [46]. Aspergillusidone D (33) (Fig. 6) and 2-chlorounguinol (32) (Fig. 5) also exhibited anti-inflammatory activity through the inhibition of nitric oxide production [46].

Structures of nodulisporacid A (56) and vermelhotin (57).
Fig. 8

Structures of nodulisporacid A (56) and vermelhotin (57).

New 14-membered resorcylic macrolides, aigialomycins A–E (58–62) (Fig. 9), were isolated from the marine mangrove fungus Aigialus parvus. Among the isolated macrolides, aigialomycin D (61) exhibited antimalarial activity (IC50 value of 6.6 μg/mL) and cytotoxic activity (IC50 values of 1.8–3.0 μg/mL) [47]. The first total synthesis of aigialomycin D (61) was achieved by Danishefsky group [48], and aigialomycin D (61) was found to be an inhibitor of heat shock protein 90 (Hsp90) [49], one of the drug targets for the treatment of cancers. Aigialomycin D (61) was also found to be protein kinase inhibitors, inhibiting CDK1/cyclin B and CDK5/p25 with respective IC50 values of 5.7 and 5.8 μM [50]. Because of these interesting bioactivities, few alternative routes for the total syntheses of aigialomycin D (61) were subsequently established [51–54]. Recently, aigialomycin D (61) was tested against a panel of kinases, and MNK2 protein kinase was found to be a promising target for aigialomycin D (61) [55].

Structures of aigialomycins A–E (58–62).
Fig. 9

Structures of aigialomycins A–E (58–62).

The marine-derived fungus Aspergillus aculeatus CRI323-04 was isolated from a marine sponge, Xestospongia testudinaria. The fungus A. aculeatus CRI323-04 produced a new tyrosine-derived metabolite, aspergillusol A (63), and known compounds, a methyl ester of 4-hydroxyphenylpyruvic acid oxime (64) (Fig. 10) and secalonic acid A [56]. Aspergillusol A (63) was optically inactive because it had a plane of symmetry (or meso form) and it was obtained on a gram scale from a fungal cell extract. Aspergillusol A (63) inhibited α-glucosidase, a therapeutic target for the treatment of type 2 diabetes, and it exhibited cytotoxic activity against cancer cell lines (IC50 19-74 μM) [56]. Aspergillusol A (63) has similar structure to that of psammaplin A (65) (Fig. 10), a metabolite of marine sponges [57]. Hydroxyphenylpyruvic acid oxime is often found in tyrosine-derived metabolites produced by many marine sponges, for example, Ianthella basta [58, 59], Verongia aerophoba [60, 61], Hymeniacidon sanguine [62], Aplysinella rhax [63], Suberea clavata [64], and Pseudoceratina verrucosa [65]. Although few tyrosine derivatives were found in fungi, i.e., gymnastatins from a marine-derived fungus Gymnasella dankaliensis [66] and OF4949 from Penicillium rugulosum [67], none has an oxime unit in the molecules; aspergillusol A (63) is the first fungal metabolite having the same hydroxyphenylpyruvic acid oxime moiety as those in marine sponges [58–65]. It was previously demonstrated that some metabolites in marine sponges originated from associated microorganisms, i.e., cyanobacteria, bacteria, and dinoflagellates [68]. We therefore speculated that marine sponges may use microbial tyrosine-derived metabolites, i.e., aspergillusol A (63), for the transformation into toxic tyrosine-derived compounds, probably using as chemical defences in sponges [58–65]. The total synthesis of aspergillusol A (63) was accomplished by Ullah and Haladu [69]. In addition to aspergillusol A (63), a novel sesquiterpenoid, asperaculin A (66) (Fig. 10), was also isolated from A. aculeatus CRI323-04 [70]. Asperaculin A (66) has a novel [5, 5, 5, 6] fenestrane ring system, and its skeleton is named as “aspergillane” [70]. A method for the synthesis of a molecular framework of asperaculin A (66) was recently developed, using iterative intramolecular Pauson–Khand reaction [71]. A novel chemistry inspired by aspergillusol A (63) was serendipitously discovered while exploring the chemistry of 63. Aspergillusol A (63) reacted with ketone/aldehyde to yield nitrones (i.e., compound 67) (Fig. 10), and this reaction proceeded in phosphate buffer and aqueous solutions with pH ranges of 6.8–8.6, resembling physiological conditions [72]. This reaction could possibly be applied for click chemistry and bioorthogonal chemistry with the experiments performing under physiological conditions. The reaction of aspergillusol A (63) with 1-substituted cyclohexanones diastereoselectively yielded the (1′S*,2′R*)-isomer, for example, a nitrone 68 (Fig. 10) [72]. We previously proposed that aspergillusol A (63) had an Z,Z-oxime geometry, however, a fungal metabolite (known as JBIR-25) having an E,E-oxime isomer of 63 was also reported [73]. Recently, we found that aspergillusol A (63) actually contained more than one isomer, but only one isomer that is responsible for the nitrone formation; these results will be communicated in the near future.

Structures of aspergillusol A (63), oxime derivative 64, psammaplin A (65), and asperaculin A (66); and a scheme displaying the reaction of 63 with ketones to give nitrones 67 and 68.
Fig. 10

Structures of aspergillusol A (63), oxime derivative 64, psammaplin A (65), and asperaculin A (66); and a scheme displaying the reaction of 63 with ketones to give nitrones 67 and 68.

While A. aculeatus CRI323-04 produced aspergillusol A (63) and asperaculin A (66) [56, 70], another strain of A. aculeatus (strain CRI322-03) produced a new diketopiperazine, pre-aurantiamine (69) and itaconic acid derivatives 70 and 71 (Fig. 11) [74]. These suggest that Thai marine-derived fungi are rich sources of bioactive compounds. It is worth mentioning that pre-aurantiamine (69) may be a biosynthetic precursor of aurantiamine (72) (Fig. 11), a potent anticancer agent [75, 76]. Thai endophytic fungi are also rich in bioactive agents, since recent investigation showed that 69 percent of 160 endophytic fungi exhibited antimicrobial activity against human pathogenic microorganisms [77]. Fusaric acid (73) and dehydrofusaric acid (74) (Fig. 11) were isolated from the endophytic fungus, Fusarium sp., and they exhibited potent acanthamoebicidal activity towards Acanthamoeba trophozoites [78]. A new tetrahydroanthraquinone derivative, phomopsanthraquinone (75), from the endophytic fungus, Phomopsis sp., exhibited cytotoxic and antibacterial activities [79]. Nor-chamigrane and chamigrane endoperoxides, i.e., merulins A (76), C (77), and D (78) (Fig. 11), were isolated from the endophytic fungus of the family Meruliaceae [80, 81]. Merulins A (76) and C (77) exhibited cytotoxic activity [80], and 77 also exhibited potent antiangiogenic activity [81]. Merulins are also known as steperoxides, which are metabolites isolated from a Chinese fungus [82]. Recently, merulin A (76) and its semi-synthetic derivatives were found to exhibit potent antiparasitic activity, and thus being drug candidates for the treatment of African sleeping sickness [83].

Structures of fungal metabolites 69–78.
Fig. 11

Structures of fungal metabolites 69–78.

Insect pathogenic fungi collected in Thailand have proven to be a rich source of bioactive compounds, and they were previously reviewed in 2005 [84]. The present review covers the compounds recently isolated from insect pathogenic fungi. Hirsutellones, i.e., hirsutellones A (79), B (80), and F (81) (Fig. 12) are tyrosine nonaketides isolated from insect pathogenic fungus Hirsutella nivea and the seed fungus Trichoderma sp.; they exhibited antitubercular and antimalarial activities [85, 86]. Strategies toward the total synthesis of hirsutellones were developed [87, 88], and the first total synthesis of hirsutellone B (80) was accomplished by Nicolaou group [89]. Few synthetic routes for the total synthesis of hirsutellones were recently reported [90–92]. Cordycommunin (82) (Fig. 12), a new cyclodepsipeptide, and dihydroisocoumarins were isolated from the insect pathogenic fungus Ophiocordyceps communis; the peptide 82 exhibited antitubercular activity [93]. New pyridone and tetramic acid alkaloids, i.e., torrubiellone A (83) (Fig. 12), were isolated from the fungus Torrubiella sp.; compound 83 exhibited antimalarial activity [94]. Hopane triterpenoids (i.e., 84), a cyclohexadepsipeptide, bioxanthracenes, and a new isocoumarin glycoside were isolated from the insect pathogenic fungus Conoideocrella tenuis (Fig. 12), and a hopane 84 and bioxanthracenes exhibited antimalarial activity [95]. Hopane triterpenoids, as well as dihydronaphthopyrones, i.e., aschernaphthopyrone B (85) (Fig. 12), were isolated from the fungus Aschersonia paraphysata; these metabolites exhibited antimalarial activity [96].

Structures of fungal metabolites 79–85 obtained from insect pathogenic fungi.
Fig. 12

Structures of fungal metabolites 79–85 obtained from insect pathogenic fungi.

New lanostane-type triterpenes (i.e., 86) and hopane triterpenoids (i.e., 87–89) were isolated from the insect pathogenic fungus Hypocrella sp. (Fig. 13); lanostane 86 and hopanes 87 and 88 exhibited antimalarial and antimycobacterial activities [97]. New dimeric anthraquinones, i.e., torrubiellin B (90) (Fig. 13), were isolated from the insect pathogenic fungus Torrubiella sp., and a metabolite 90 exhibited a broad spectrum of bioactivities [98].

Bioactive metabolites 86–90 from insect pathogenic fungi.
Fig. 13

Bioactive metabolites 86–90 from insect pathogenic fungi.

As mentioned earlier in the Introduction, Thailand has a great variety of plant species, and some are sources of foods and medicines. Thai herbal medicine has long been used for centuries; examples of popular Thai herbs include Croton stellatopilosus Ohba (Euphorbiaceae) as a source of commercially available drug “plaunotol”, an acyclic diterpenoid for the treatment of gastric ulcers; Andrographis paniculata Nees. (Acanthaceae) (its crude extract is commercially available as an alternative medicine); and Pueraria mirifica Airy Shaw & Suvat. (Fabaceae) (known in Thai as “Kwao Keur”) with potent activity of phytoestrogen has been used in various preparations for cosmetics and dietary supplements. Bioactive compounds from Thai plants have been extensively investigated. New protoberberine alkaloids, alangiumkaloids A (91) and B (92), triterpene caffeate 93, and β-D-glucopyranosyl-1-N-methylpyrrole carboxylate (94), together with myriceric acid B (95) and alkaloid glycosides (i.e., 96–98) (Fig. 14), were isolated from Alangium salviifolium Wangerin (Alangiaceae) [99]. Some of these metabolites inhibited aromatase activity, and exhibit antioxidant and radical scavenging activities.

Bioactive compounds 91–98 from A. salviifolium.
Fig. 14

Bioactive compounds 91–98 from A. salviifolium.

New dihydroflavonols, longeracemosones A–F (99–104) (Fig. 15), and known flavonoids (i.e., 105) were isolated from Dunbaria longeracemosa Craib (Fabaceae) [100]. Compounds 101, 102 and 105 inhibited aromatase with IC50 values of 0.3–1.2 μM. Hybrid flavan-chalcones, i.e., desmosflavan A (106) (Fig. 15), and known compounds, cardamonin, pinocembrin, and chrysin, were isolated from the leaves of Desmos cochinchinensis Lour. (Annonaceae) [101]. Desmosflavan A (106), pinocembrin, and chrysin inhibited aromatase (IC50 0.8–3.3 μM); compound 106 also inhibited lipoxygenase (IC50 4.4 μM) [101]. Recently, we found that flavans 107–112 (Fig. 15) from the roots of D. cochinchinensis exhibited potent aromatase inhibitory activity at nanomolar levels; IC50 values of the flavans 107, 110, and 111 were 40.0, 90.0, and 80.0 nM, respectively [102]. It should be noted that letrozole, an anti-aromatase drug for the treatment of breast cancer, inhibited aromatase with the IC50 value of 1.1 nM.

Bioactive compounds 99–112 from Dunbaria longeracemosa and Desmos cochinchinensis.
Fig. 15

Bioactive compounds 99–112 from Dunbaria longeracemosa and Desmos cochinchinensis.

Siphonodon celastrineus Griff. (Celastraceae) is rich in bioactive compounds, and recently, twenty-one new triterpenes, i.e., a lupane 113, friedelanes 114 and 115, an oleanane 116, and an ursane 117 (Fig. 16), were isolated from this plant [103]. Among the isolated compounds, compound 117 was most active against cancer cell line. Cordia globifera W.W. Sm. (Boraginaceae) is also rich in bioactive metabolites; many bioactive compounds, i.e., 118–123 (Fig. 16), were isolated from C. globifera [104, 105]. The substances from C. globifera exhibited a broad spectrum of bioactivities including antimycobacterial, antimalarial, antifungal, cytotoxic, radical scavenging activities [104, 105]. Interestingly, upon refluxing in xylene and DMSO, globiferin (118) biomimetically transformed, via Cope rearrangement, to cordiachrome C (120) and cordiaquinol C (121) [104]. Coumarins (i.e., 124 and 125) and a quinolinone derivative, as well as 33 known compounds, were isolated from Citrus hystrix DC. (Rutaceae) (Fig. 16), and some metabolites exhibited anti-HIV-1 protease, radical scavenging, and antibacterial activities [106]. Several plants of the family Acanthaceae collected from Thailand were found to possess antimalarial, cytotoxic, radical scavenging, and antioxidant activities [107], while many Thai ethnomedicinal plants exhibited anthelmintic and anticancer activities [108].

Bioactive compounds 113–125 from S. celastrineus, Cordia globifera, and Citrus hystrix.
Fig. 16

Bioactive compounds 113–125 from S. celastrineus, Cordia globifera, and Citrus hystrix.

New 5-formylfurfuryl esters, i.e., 126–128 (Fig. 17), and several known compounds were isolated from Duabanga grandiflora (Roxb. ex DC.) Walp. (Lythraceae), and some substances exhibited cytotoxic activity [109]. New unprecedented furan-2-carbonyl C-glycosides (i.e., 129 and 130) (Fig. 17) and a few phenolic glycosides were isolated from Scleropyrum pentandrum (Dennst.) Mabb. (Santalaceae) [110]. Metabolites of S. pentandrum exhibited antioxidant and radical scavenging activities. Eleven new bioactive compounds, i.e., 131–134 (Fig. 17), were isolated from Bauhinia purpurea Linn. (Fabaceae), and some metabolites exhibited antimalarial, antimycobacterial, antifungal, anti-inflammatory (COX-2 inhibition), and cytotoxic activities [111]. A dihydrodibenzoxepin, bauhinoxepin J (133), was synthesized by three different methods, intramolecular radical cyclizations onto quinones [112], DDQ-promoted oxidative dearomatization-cyclization [113], and an internal nucleophilic addition/elimination sequence [114]. Bisbenzylisoquinoline alkaloids (i.e., 135), as well as its semi-synthetic analog (136), from Tiliacora triandra (Colebr.) Diels (Menispermaceae) exhibited potent antimycobacterial activity against multidrug-resistant isolates of Mycobacterium tuberculosis, which were isolated from patients [115].

Bioactive compounds 126–136 from D. grandiflora, S. pentandrum, B. purpurea, and T. triandra.
Fig. 17

Bioactive compounds 126–136 from D. grandiflora, S. pentandrum, B. purpurea, and T. triandra.

Croton stellatopilosus Ohba (Euphorbiaceae) is a rich source of an acyclic diterpenoid, plaunotol, which is widely used for the treatment of gastric ulcers. Recently, plaunotol was found to promote oral cell proliferation and wound healing [116], and it also exhibited anti-inflammatory activity [117]. Andrographis paniculata (Burm.f.) Wall. ex Nees (Acanthaceae) produces a gram-scale of a labdane diterpenoid, collectively called “andrographolide”. In Thailand, a crude extract of A. paniculata is commercially available for the treatment of fever, sore throat, upper respiratory tract infection, diarrhea, and sinusitis. The following recent landmark discoveries of andrographolide have supported the traditional use of A. paniculata. Andrographolide was found to be a promising therapeutic agent for the treatment of osteoclast-related bone diseases, as it could suppresses RANKL-induced osteoclastogenesis in vitro, and thus preventing inflammatory bone loss in vivo [118]. Andrographolide could be a potential supplement for the control of hepatitis C virus by up-regulating heme oxygenase-1 via the p38 MAPK/Nrf2 pathway [119]. Combination of andrographolide and cis-platin had significant anti-proliferative and pro-apoptotic effects on ovarian cancer cell lines [120]. Kaempferia parviflora Wall. ex Baker (Zingiberaceae) is widely used as a traditional medicine in Thailand, and its rhizomes have been extensively studied. Germacrene D, β-elemene, α-copaene, and E-caryophyllene in K. parviflora rhizomes were possibly adaptogenic agents [121]. A flavonoid, 3,5,7,3′,4′-pentamethoxyflavone, from K. parviflora rhizomes was found to cause relaxation of human cavernosum through voltage-dependent Ca2+ channels and the mechanisms associated with calcium mobilization [122].

In conclusion, Thailand has great biodiversity of organisms (plants, animals, and microorganism), which are rich sources of biologically active natural products. Several classes of natural products have been isolated from Thai bioresources, and many compounds have novel skeletons. These natural products exhibit an array of diverse biological activities, some of which are of pharmaceutical interests.

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About the article

Corresponding author: Chulabhorn Mahidol, Chulabhorn Research Institute, Chulabhorn Graduate Institute, and Center of Excellence on Environmental Health and Toxicology (EHT), Kamphang Phet 6 Road, Laksi, Bangkok 10210, Thailand, e-mail:


Published Online: 2014-04-29

Published in Print: 2014-06-18


Citation Information: Pure and Applied Chemistry, Volume 86, Issue 6, Pages 979–993, ISSN (Online) 1365-3075, ISSN (Print) 0033-4545, DOI: https://doi.org/10.1515/pac-2013-1206.

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