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Mycobacterium tuberculosis DNA gyrase subunit B (GyrB) has been identified as a promising target for rational drug design against fluoroquinolone drug-resistant tuberculosis. In this study, we attempted to identify the key structural feature for highly potent GyrB inhibitors through 2D-QSAR using HQSAR, 3D-QSAR using CoMSIA and molecular dynamics (MD) simulations approaches on a series of thiazole urea core derivatives. The best HQSAR and CoMSIA models based on IC50 and MIC displayed the structural basis required for good activity against both GyrB enzyme and mycobacterial cell. MD simulations and binding free energy analysis using MM-GBSA and waterswap calculations revealed that the urea core of inhibitors has the strongest interaction with Asp79 via hydrogen bond interactions. In addition, cation-pi interaction and hydrophobic interactions of the R2 substituent with Arg82 and Arg141 help to enhance the binding affinity in the GyrB ATPase binding site. Thus, the present study provides crucial structural features and a structural concept for rational design of novel DNA gyrase inhibitors with improved biological activities against both enzyme and mycobacterial cell, and with good pharmacokinetic properties and drug safety profiles.

Twenty previously unknown compounds and two known metabolites, merulin A and merulin D, were isolated from the endophytic fungus Pseudolagarobasidium acaciicola, which was isolated from a mangrove tree, Bruguiera gymnorrhiza. Structures of the 20 compounds were elucidated by analysis of spectroscopic data. The absolute configuration of seven of these compounds was addressed by a single crystal X-ray analysis using CuKα radiation and an estimate of the Flack parameter. Three compounds also possessed a tricyclic ring system. Terpene endoperoxides isolated exhibited cytotoxic activity, while those without an endoperoxide moiety did not show activity. The endoperoxide moiety of sesquiterpenes has significant impact on cytotoxic activity, and thus is an important functionality for cytotoxicity. One terpene endoperoxide displayed potent cytotoxic activity (IC50 0.28μM), and selectively exhibited activity against the HL-60 cell line.

During functionalization at C2, C3, and C4 of quinoline, we came across a one-step metal free synthesis of C3 quinolinium derivatives of mesomeric betaine dyes. Some mesomeric betaine dyes had solvatochromic properties, and were sensitive to pH and solvates in the water. Certain betaine dyes had different properties in acidic and basic environments; the reversible interconversion between yellow (neutral or basic condition) and colorless (acidic condition) forms of the dye occurs by pH change. The changes in UV absorbance intensities of the dyes in the presence of cyclodextrins indicated the inclusion complex formation between cyclodextrins and dyes. The betaine dyes were partially dissolved in water due to the presence of positive and negative charges in the molecule. These betaine dyes did not exhibit cytotoxic activity, hence may be used in biological research.

A new 22,26

Bacterial strain BAS23 was isolated from rice field soil and identified as

Various classes of natural products and synthetic compounds were tested against reference strains and clinical multidrug resistant isolates of Mycobacterium tuberculosis. Vermelhotin (19), a natural tetramic acid from fungi, was the most active toward clinical MDR TB isolates (MIC 1.5-12.5 μg/mL). Synthetic compounds (i.e. benzoxazocines, coumarins, chromenes, and pyrrolodiquinoline derivatives) were prepared by green chemistry approaches. Under microwave irradiation, a one-pot synthesis of pyrrolodiquinoline 85 was achieved by homocoupling of 1-methylquinolinium iodide; the structure of 85 was confirmed by single-crystal X-ray analysis. Compound 85 and its derivative 86 exhibited potent anti-tubercular activity (MIC 0.3-6.2 μg/mL) against clinical MDR TB isolates, and they displayed weak cytotoxicity toward normal cell line. The scaffold of 85 and 86 is potential for antimycobacterial activity.

Fungal metabolites (1–8) including known compounds, TMC-264 (1), PR-toxin (6) and a sesquiterpene (7), and new natural products 2–5 and 8, were isolated from the mangrove endophytic fungus Penicillium chermesinum. Compound 2 was a novel tetracyclic polyketide uniquely spiro-attached with a γ-lactone ring. Compounds 1 and 6 exhibited comparable cytotoxic activity to that of doxorubicin, and they selectively exhibited activity toward certain cancer cell lines. The cytotoxicity of 1 might be due to the β-chloro substituted α,β-unsaturated ketone functionality, which was reactive toward glutathione and peptides containing a thiol group. The polyketide 1 reacted with glutathione and peptides under physiological conditions, and its thiol-reactive pharmacophore is possibly applicable to the design of glutathione modulation agents, fragment-based drug discovery (for irreversible enzyme inhibitors), bioconjugation, and click reactions. Facile C–S bond formation in water (catalyst-free conditions) inspired by 1 could also be useful for green chemistry.

Polyketides 1-6 were produced by a one strain-many compounds (OSMAC) approach using the endophytic fungus Dothideomycete sp. CRI7 as a producer. Metabolite production of the fungus Dothideomycete sp. CRI7 was sensitive to sources of potato and malt extract used for the preparation of PDB and Czapek malt media, respectively. Three hitherto unknown metabolites were obtained from the fungus CRI7 grown in PDB medium prepared from a commercial potato powder instead of fresh tubers of potato, while three others were obtained from the fungus cultivated in Czapek malt medium. Moreover, a source of malt extract used in the Czapek malt medium was found to influence metabolite production by the fungus CRI7. Structure elucidation of these compounds was achieved by analysis of spectroscopic data, as well as by single crystal X-ray analysis. Two of the compounds showed weak cytotoxic activity, while the remainders were inactive toward the cell lines tested. One compound exhibited radical scavenging activity with an IC50 value of 21.7 μM, and inhibited aromatase with an IC50 value of 12.3 μM.

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.

Vernonia extensa, known as “Phim Phai Lin” in Thai, is distributed in most regions of Thailand. The plant has been used in Ayurveda and traditionally used to treat malaria and cancer, and possesses several sesquiterpene lactones. This study aimed to investigate and identify the active constituents by bioactivity-based analysis, as well as to evaluate the cytotoxic activity of V. extensa by MTT or XTT assays in ten cancer cell lines (Liver HepG2 and S102; Bile duct HuCCA-1; Leukemia HL-60 and MOLT-3; Lung A549 and H69AR; Breast MDA-MB-231 and T47D; Cervical HeLa). Bioactivity-guided fractionation and semi-preparative HPLC purification were used to separate the bioactive constituents. Apoptosis-inducing activity and cell cycle inhibitory effect of selected active compounds were determined on HepG2 cells by flow cytometric analysis. Bioactivity-guided fractionation of the CH2Cl2 extract and chemical investigation of the cytotoxic fractions led to the isolation of a new sesquiterpenoid pseudo-dimer named vernodalidimer L, together with eight known sesquiterpenoids from the aerial part of V. extensa. The structures of the isolates were elucidated based on spectroscopic analysis, including 1D and 2D NMR and HRMS. Vernolide has potent broad-spectrum cytotoxicity with IC50 values in the range of 0.91–13.84 μM, against all ten cancer cell lines. The annexin-V flow cytometric analysis showed that vernodalin, vernolepin, and vernolide induced apoptosis on HepG2 cells in a dose dependent manner and these effects correlated with G2/M phase cell cycle arrest. Our results indicated that vernodalin, vernolepin, and vernolide have potential to be used as lead compounds in the development of a therapeutic natural product for treatment of liver cancer.

A new concept of catalysts which are prepared from renewable materials is demonstrated. It is known that amino acids (e.g., proline and hydroxyproline) are robust organocatalysts for several reactions. Bovine tendons which are proteins rich in hydroxyproline and proline were used as a source of amino acids. An acid hydrolysate of tendons (a TH catalyst) could catalyze two reactions: (i) the synthesis of coumarins and chromenes under solvent-free conditions and (ii) the synthesis of densely functionalized 4H-chromenes via a three-component reaction. Moreover, an economical and easily accessible TH catalyst is applicable in a multigram scale synthesis of coumarins and chromenes, as well as in the three-component reaction for chromene synthesis. A catalytic activity of hydroxyproline for the synthesis of 4H-chromenes via the three-component reaction was also discovered. The present work demonstrates not only the green catalysts from renewable materials, but also an environmentally benign preparation of coumarins and chromenes.

The endophytic fungus, Dothideomycete sp. CRI7, isolated from the terrestrial plant, Tiliacora triandra, was salt tolerant, capable of growing in the culture medium prepared from seawater; salts in seawater did not have any effects on the fungal growth. Metabolite productions of the fungus CRI7 cultivated in media prepared from seawater (MSW), prepared from deionized water supplemented with potassium bromide (MKBr) or potassium iodide (MKI), and prepared from deionized water (MDW) were investigated. It was found that the cultivation of the fungus CRI7 in MKBr and MSW enabled the fungus to produce nine new metabolites (1–9). The production of an azaphilone, austdiol (10), of the fungus CRI7 grown in MDW was 0.04 g/L, which was much lower than that grown in MSW, MKBr, and MKI media which provided the yields of 0.5, 0.9, and 1.2 g/L, respectively, indicating that halogen salts significantly enhanced the production of the polyketide 10. The cultivation of terrestrial fungi in media containing halogen salts could therefore be useful for the metabolite diversification by one strain-many compounds (OSMAC) approach. Moreover, the isolated polyketides had significant biosynthetic relationship, suggesting that the cultivation of fungi in halogen containing media could provide the insights into certain polyketide biosynthesis. One of the isolated compounds exhibited antibacterial activity with the MIC value of 100 μg/mL.

Graphical abstract, Highlights • Depsidones are aromatase inhibitors in primary human breast adipose fibroblasts. • Depsidones may have pharmacotherapeutical relevance for breast cancer treatment. • Co-cultures of breast tumor and fibroblasts cells create a vivo realistic in vitro model for estrogen dependent breast cancer., Naturally occurring depsidones from the marine fungus Aspergillus unguis are known to have substantial anti-cancer activity, but their mechanism of action remains elusive. The purpose of this study was to examine the anti-aromatase activity of two common depsidones, unguinol and aspergillusidone A, in a co-culture system of human primary breast adipose fibroblasts and hormonal responsive T47D breast tumor cells. Using this in vitro model it was shown that these depsidones inhibit the growth of T47D tumor cells most likely via inhibition of aromatase (CYP19) activity. The IC50 values of these depisidones were compared with the aromatase inhibitors letrozole and exemestane. Letrozole and exemestane had IC50 values of respectively, 0.19 and 0.14 μM, while those for Unguinol and Aspergillusidone A were respectively, 9.7 and 7.3 μM. Our results indicate that among the depsidones there maybe aromatase inhibitors with possible pharmacotherapeutical relevance.

Directed biosynthesis through biohalogenation of depsidones was conducted by cultivating the marine-derived fungus Aspergillus unguis in media containing different halogen salts (i.e., KBr, KI, and KF). The fungus grown in a KBr medium produced new brominated unnatural natural depsidones, while those cultured in KI produced non-halogenated depsidone, unguinol, as a major metabolite. Unexpectedly, the directed biosynthesis through biohalogenation provides insights into depsidone biosynthesis; particular biosynthetic intermediates were co-isolated with brominated depsidones from the fungus cultured in KBr medium. These biosynthetic congeners support that the depsidone biosynthesis in A. unguis operates through the oxidative coupling of depsides, not through the benzophenone-grisadienedione pathway. The isolated depsidones inhibited aromatase, a therapeutic target for the treatment of breast cancer.

Conventional methods generate nitrile oxides from oxime halides in organic solvents under basic conditions. However, the present work revealed that water-assisted generation of nitrile oxides proceeds under mild acidic conditions (pH 4-5). Cycloadditions of nitrile oxides with alkynes and alkenes easily occurred in water without using catalysts, thus yielding isoxazoles and isoxazolines, respectively, with excellent stereoselectivity toward five- and six-membered cyclic alkenes. A double stereoselective cycloaddition of two units of a nitrile oxide with cyclohexene was also achieved, thus yielding 1,2,4-oxadiazole derivatives having a unique hybrid isoxazoline-oxadiazole skeleton. Enantiomerically pure isoxazolines were prepared from monoterpenes with a ring strain. In one case, the isoxazoline with a butterfly-like structure was simply prepared, and it might be used as a ligand in asymmetric catalysis.

New protoberberine alkaloids, namely alangiumkaloids A (1) and B (2), 27-O-trans-caffeoylcylicodiscic acid (3), and β-D-glucopyranos-1-yl N-methylpyrrole-2-carboxylate (5) together with myriceric acid B (4), isoalangiside (6), alangiside (7), 3-O-demethyl-2-O-methylalangiside (8), and demethylalangiside (9) have been isolated from Alangium salviifolium. The cancer chemopreventive properties and cytotoxic activities of the isolated compounds were evaluated. Compounds 3, 4, and 9 scavenged DPPH free radicals with IC50 values of 21.4, 21.8, and 24.0 μM, respectively. Alangisides 7 and 9 inhibited superoxide anion radical formation in the xanthine/xanthine oxidase (XXO) assay with IC50 values of 19.4 and 5.3 μM, respectively. Compounds 6–9 showed excellent antioxidant activity in the oxygen radical absorbance capacity (ORAC) assay with 12.8–24.9 ORAC units. Compounds 3 and 4 inhibited aromatase activity with IC50 values of 4.7 and 6.8 μM, respectively. Although the isolated compounds showed only weak cytotoxicity or were inactive, compounds 3 and 4 exhibited cytotoxic activity towards the MOLT-3 cell line with IC50 values of 5.6 and 3.9 μM, respectively, and compound 8 selectively inhibited the growth of the HepG2 cancer cell line with an IC50 value of 7.1 μM.

Highlights • Unguinol and Aspergillusidone D inhibit cell viability at low μM concentrations. • These depsidones increase the amount of apoptotic cells in the MDA-MB-231 cell line. • Unguinol causes cell cycle arrest of MDA-MB-231 cells in the G2/M-phase. • Apoptosis and cell cycle arrest were seen at clinically high concentrations (>60 μM)., There is an ongoing search for new compounds to lower the mortality and recurrence of breast cancer, especially triple-negative breast cancer. Naturally occurring depsidones, extracted from the fungus Aspergillus, are known for their wide range of biological activities such as cytotoxicity, aromatase inhibition, radical scavenging, and antioxidant properties. Research showed the potential of depsidones as a treatment option for hormone receptor-positive breast cancer treatment, yet its effects on hormone receptor-negative breast cancer are still unkown. This study, therefore, investigated the potential of two depsidones (Unguinol and Aspergillusidone D) to induce apoptosis, cell cycle arrest and cytotoxicity, and reduce cell proliferation in the triple-negative MDA-MB-231 breast cancer cell line. Results were compared with the effects of the cytostatic drug doxorubicin, antimitotic agent colchicine and endogenous hormones 17β-estradiol, testosterone and dihydrotestosterone. The cytostatic drugs and hormones affected the MDA-MB-231 cell line comparable to other studies, showing the usefulness of this model to study the effects of depsidones on a triple-negative breast cancer cell line. At sub μM levels, Unguinol and Aspergillusidone D did not influence cell proliferation, while cell viability was reduced at concentrations higher than 50 μM. Both depsidones induced apoptosis, albeit not statistically significantly. In addition, Unguinol induced cell cycle arrest in MDA-MB-231 cells at 100 μM. Our research shows the potential of two depsidones to reduce triple-negative breast cancer cell survival. Therefore, this group of compounds may be promising in the search for new cancer treatments, especially when looking at similar depsidones.

Five new hybrid peptide-polyketides, curvularides A-E (1-5), were isolated from the endophytic fungus Curvularia geniculata, which was obtained from the limbs of Catunaregam tomentosa. Structure elucidation for curvularides A-E (1-5) was accomplished by analysis of spectroscopic data, as well as by single-crystal X-ray crystallography. Curvularide B (2) exhibited antifungal activity against Candida albicans, and it also showed synergistic activity with a fluconazole drug.

Crude extracts (CH 2 Cl 2 and MeOH) of 20 plants in the family Acanthaceae were screened for their antiplasmodial, cytotoxic, antioxidant, and radical scavenging activities. These plants included ASYSTASIA NEMORUM, BARLERIA CRISTATA, B. STRIGOSA, DICLIPTERA BURMANNI, ERANTHEMUM TETRAGONUM, HYGROPHILA RINGENS, JUSTICIA BALANSAE, J. PROCUMBENS, LEPIDAGATHIS INCURVA, PERISTROPHE LANCEOLARIA, PHAULOPSIS DORSIFLORA, RUELLIA KERRII, STROBILANTHES AURICULATA, S. CORRUGATA, S. CUSIA, S. DIMORPHOTRICHA, S. KARENSIUM, S. MAXWELLII, S. PATERIFORMIS, and S. BRANDISII. CH 2 Cl 2 extracts of A. NEMORUM, S. CORRUGATA, S. CUSIA, S. MAXWELLII, S. PATERIFORMIS, and S. BRANDISII, as well as MeOH extracts of J. BALANSAE and J. PROCUMBENS, showed antiplasmodial activity with IC 50 values of 10-100 μg/mL. CH 2 Cl 2 extracts of nine plants including D. BURMANNI, H. RINGENS, J. BALANSAE, J. PROCUMBENS, L. INCURVA, P. LANCEOLARIA, P. DORSIFLORA, S. CORRUGATA, and S. MAXWELLII showed cytotoxic activity with IC 50 values of 3.5-46.0 μg/mL. MeOH extracts (at 100 μg/mL) of R. KERRII and S. AURICULATA could effectively scavenge DPPH free radicals (82-83 % inhibition) and superoxide anion radicals (79 % and 88 % inhibition). In the ORAC antioxidant assay, MeOH extracts of B. CRISTATA, J. PROCUMBENS, R. KERRII, and S. AURICULATA exhibited activity with ORAC units of 3.1-3.9.

New naphthalene derivatives (1 and 2) and a new isomer (3) of ventilagolin, together with known anthraquinones, chrysophanol (4), physcion or emodin 3-methyl ether (5), and emodin (6), were isolated from vines of Ventilago denticulata. The isolated compounds exhibited cytotoxic activity with IC50 values of 1.15 - 40.54 μg/ml. Compounds 1 - 3 selectively exhibited weak antibacterial activity (MIC values of 200.0 - 400.0 μg/ml), while emodin (6) displayed moderate antibacterial activity with MIC value of 25.0 μg/ml. The isolated compounds showed nitric oxide and DPPH radical scavenging activities. Compounds 1 - 3 and 6 exhibited weak xanthine oxidase inhibitory activity, while emodin (6) acted as an aromatase inhibitor with the IC50 value of 10.1 μm. Compounds 1 and 2 exhibited phosphodiesterase 5 inhibitory activity with IC50 values of 8.28 μm and 6.48 μm, respectively.

Binding energy calculations of flurbiprofen to the binding pocket of the cyclooxygenase (COX) enzyme were performed based on quantum chemical calculations. The interaction energies between flurbiprofen and two types of COX binding sites were studied. Quantum chemical calculations were used, based on the B3LYP hybrid functional and the MP2 method, with 6-31G(d) and 6-31G(d,p) basis sets. The results show that the main interaction between flurbiprofen and two COX isozymes (COX-1 and COX-2) is due to Arg120. In addition, selective SC558 COX-2 inhibitor was also compared. It was found that repulsive interaction plays a significant role in its inhibition of COX-2. ONIOM2(B3LYP/6-31G(d):PM3) calculations indicate that flurbiprofen interacts via moderate hydrogen bonding with Arg120 in the COX-2 binding site, while no hydrogen bond was detected with either Tyr355 or Val523. The ONIOM2 method can be used to describe the specific interaction of the inhibitor and is helpful in designing a specific COX inhibitor.

Aim of study This study screened for anthelmintic and/or antitumour bioactive compounds from Thai indigenous plants and evaluated effectiveness against three different worm species and two cancer cell lines. Materials and methods Methylene chloride and methanol extracts of 32 plant species were screened for in vitro anthelmintic activity against three species of worms, the nematode Caenorhabditis elegans, the digeneans Paramphistomum epiclitum and Schistosoma mansoni (cercariae). Cytotoxicity of the extracts was evaluated against two cancer cell lines: human amelanotic melanoma (C32) and human cervical carcinoma (HeLa) by the SRB assay. Anthelmintic and anticancer activities were evaluated by the inhibiting concentration at 50% death (IC50) and the selectivity index (SI) relative to human fibroblasts. Results and conclusions None of the extracts were active against Paramphistomum epiclitum. Plumbagin, a pure compound from Plumbago indica, had the strongest activity against Caenorhabditis elegans. The methylene chloride extract of Piper chaba fruits had the strongest activity against schistosome cercariae. Strong cytotoxicity was shown by the methylene chloride extract of Michelia champaca bark and the methanol extract of Curcuma longa rhizome against C32 and HeLa, respectively. These extracts had higher SI (>100) than positive controls in relation to either the worms or the cell lines. The methanol extract of Bouea burmanica had a slightly lower activity towards C32 cells than did Michelia champaca but had a much higher SI (>27,000). Ethnopharmacological relevance The plant species screened in this research was recorded by several indigenous medicinal practitioners as antiparasitic, anticancer and/or related activities to the human major organ system.

A new 10-membered ring meroterpene (1), named globiferin, was isolated from root extracts of Cordia globifera. Biomimetic transformations of 1 and its derivatives, either by acid cyclization or by Cope rearrangement, provided information relating to the biogenesis of cordiachromes A-C. Globiferin (1) underwent Cope rearrangement upon refluxing in xylene and DMSO-d(6) to yield cordiachrome C (3) and cordiaquinol C (4), respectively. Heating in DMSO-d(6) resulted in an unexpected reduction of a quinone moiety. Globiferin diacetate (1b) cyclized under acidic conditions to give compounds 10 and 11, respective derivatives of natural cordiachromes B (2) and A (12). The present study indicates that globiferin (1) is a genuine intermediate for the biosynthesis of cordiachromes in Cordia species. Compounds 1 and 3 exhibited significant antimycobacterial activity, with MIC values of 6.2 and 1.5 mug/mL, respectively. Antimalarial, antifungal, and cytotoxic activities of 1 and its derivatives were also evaluated.

The endophytic mitosporic Dothideomycete sp. LRUB20 was found to produce pyrone derivatives, dothideopyrones A-D (1, 3, 4, and 5), together with seven known compounds, including questin (9), asterric acid (10), methyl asterrate (11), sulochrin (12), and eugenitin (13), 6-hydroxymethyleugenitin (14), and cis, trans-muconic acid (15). Dothideopyrone D (5) and its acetate derivative 6 exhibited moderate cytotoxic activity. This is the first report on a naturally occurring muconic acid, which is commonly known as a biomarker in environments after exposure to benzene and phenol (or derivatives). Interestingly, the LRUB20 fungus could produce muconic acid in relatively high yield (47.8mg/L). The utility of endophytic fungi in the field of white biotechnology is discussed.

Five metabolites, ( Z)-6-benzylidene-3-hydroxymethyl-1,4-dimethyl-3-methylsulfanylpiperazine-2,5-dione ( 1), (3S,3'R)-3-(3'-hydroxybutyl)-7-methoxyphthalide ( 2), ( S)-3-butyl-7-methoxyphthalide ( 3), (3R,6R)-bisdethiodi(methylthio)hyalodendrin ( 4), and bis- N-norgliovictin ( 5), were isolated from the culture broth of the marine derived fungus of the order Pleosporales strain CRIF2. Compounds 1 and 2 are new fungal metabolites, while 3 was isolated for the first time as a natural product. Compounds 1, 3, and 4 exhibited only weak cytotoxic activity, while 5 was inactive at 50 microg/mL.

Two new clerodane diterpenes, methyl 15,16-epoxy-3,13(16),14- ENT-clerodatrien-18,19-olide-17-carboxylate ( 1) and dimethyl 15,16-epoxy-12-oxo-3,13(16),14- ENT-clerodatriene-17,18-dicarboxylate ( 2), together with seven known compounds ( 3 - 9), were isolated from the roots of Croton oblongifolius. The isolated compounds showed only mild cytotoxic activity against HuCCA-1, KB, HeLa, MDA-MB231, and T47D cell lines with IC (50) values ranging from 10 to 50 microg/mL.

Eleven new secondary metabolites (1-11), together with two known flavanones (12 and 13) and five known bibenzyls (14-18), were isolated from the root extract of Bauhinia purpurea. New compounds include eight dihydrodibenzoxepins (1-8), a dihydrobenzofuran (9), a novel spirochromane-2,1'-hexenedione (10), and a new bibenzyl (11). Antimycobacterial, antimalarial, antifungal, cytotoxic, and anti-inflammatory activities of the isolated compounds are reported, and biosynthetic pathways of these compounds are also discussed.

Conventional methods generate nitrile oxides from oxime halides in organic solvents under basic conditions. However, the present work revealed that water-assisted generation of nitrile oxides proceeds under mild acidic conditions (pH 4-5). Cycloadditions of nitrile oxides with alkynes and alkenes easily occurred in water without using catalysts, thus yielding isoxazoles and isoxazolines, respectively, with excellent stereoselectivity toward five- and six-membered cyclic alkenes. A double stereoselective cycloaddition of two units of a nitrile oxide with cyclohexene was also achieved, thus yielding 1,2,4-oxadiazole derivatives having a unique hybrid isoxazoline-oxadiazole skeleton. Enantiomerically pure isoxazolines were prepared from monoterpenes with a ring strain. In one case, the isoxazoline with a butterfly-like structure was simply prepared, and it might be used as a ligand in asymmetric catalysis.

Together with three known sesquiterpenes, the new tricyclic (I) and spirocyclic norsesquiterpenes (II), and the new nor-chamigrane endoperoxide (III) are isolated from the title fungus.

Aims: The aim of this work was to optimize the production of a novel antimaralial menisporopsin A by the seed fungus Menisporopsis theobromae BCC 4162. Methods and Results: Fungal cultures were grown in shake flasks at 25°C in the basal medium with varying carbon and nitrogen sources, aeration rates and initial pH levels. The optimal carbon and nitrogen sources that improved the production of menisporopsin A were 1% fructose and 2·5% meat extract respectively. The production was further enhanced when the culture incubated on a shaker at 200 rev min−1 with an initial pH of 8. The yield of menisporopsin A cultured under the optimized conditions was increased from 348·30 (obtained from basal medium) to 889·02 mg l−1, and the cultivation time was reduced from 28 to only 4 days. As a result, the productivity of menisporopsin A was greatly enhanced to 222·26 mg l−1 day−1 which is 18-fold higher than that of basal conditions. Larger scale production in a fermenter was also achieved, yielding menisporopsin A at a maximal level of 594·32 mg l−1 in 4 days. Conclusions: The optimized culture conditions for menisporopsin A production by M. theobromae BCC 4162 was the cultivation under shaking or agitation at 25°C in fructose–meat extract medium with an initial pH of 8. Significance and Impact of the Study: The production of menisporopsin A in a fermenter with a relatively short incubation period could be valuable for further utilization for chemical structure modification and derivatization.

The amino acid residues serine at position 213 (S213) and lysine at position 218 (K218), which are present in close proximity to the histidine-rich motif II of Mucor rouxii fatty acid Delta(6)-desaturase isoform II, were targeted for studying structure-function relationships using site-directed mutagenesis. The mutants were functionally characterized in a heterologous host, Saccharomyces cerevisiae. Substrate specificity and preference studies revealed that S213 and K218 are involved in substrate recognition. K218 plays a role in substrate preference by involvement in the binding of substrates, particularly C15-C18 monoene fatty acids. Modification of the M. rouxii Delta(6)-desaturase therefore has potential in specifically altering substrate utilization for production of desired fatty acids.

The total synthesis of antimalarial and cyclooxygenase inhibitors, racemosol and de- O -methylracemosol, is described. The key steps involved the lateral lithiation reaction of ortho -methyl tolulate and the pyran formation via a tandem demethylation–cyclization reaction.

Racemosol (I) and 10-O-demethylracemosol (2). natural products from Bauhinia malabarica ROXB., exhibit potent in vitro anti-inflammatory activities against cyclooxygenase-1 and -2 (COX-1 and -2) enzymes. To investigate the structure- activity relationship (SAR) of these molecules, we prepared and fully characterized 17 derivatives by functionalizing one, tow, or all three OH group(s) of 2 (Scheme). Both the size and polarity of the substituents as well as the substitution pattern in compounds 3a-q were found to he critical for anti-inflammatory activity. The orientation of the drugs and their mode of binding were studied by molecular docking based on the known 3D structure of the complex between COX-2 and the drug SC-558. Whereas the monoacetoxy derivative 3h exhibited an equally potent inhibitory activity towards both COX-1 and -2 (Table 1). its diacetoxy congener 3i was slightly more selective toward ( OX-2, In vivo anti-inflammatory tests showed that 3i and 2 are slightly more active than the reference compound phenylbutazone (Table 2).

Deoxypreussomerin derivatives, palmarumycins JC1 (1) and JC2 (2), and two dimeric naphthoquinones, isodiospyrin (3) and its new derivative isodiospyrol A (4), were isolated from dried fruits of Diospyros ehretioides. Structures of the isolated compounds were elucidated by spectroscopic analyses. Palmarumycins were not found in the extract of freshly collected fruits; however, they were present in dried fruit extract. The absence of palmarumycins in fresh fruits of D. ehretioides, together with the chemotaxonomic point of view, we proposed that palmarumycins JC1 (1) and JC2 (2) are more likely to be fungal metabolites, i.e., endophytes or epiphytes. The isolation of palmarumycins 1 and 2 from dried D. ehretioides fruits could be reproducible; both plant samples collected in the years 2002 and 2004 provided the same result, and, therefore, symbiont fungal strains should be specific to the plant host, D. ehretioides, and they can grow on the fruits during drying the sample. Palmarumycin JC1 (1) did not exhibit antimalarial, antifungal, antimycobacterial, and cytotoxic activities. Palmarumycin JC2 (2) exhibited antimalarial (IC50 4.5 microg/ml), antifungal (IC50 12.5 microg/ml), antimycobacterial (MIC 6.25 microg/ml), and cytotoxic (IC50 11.0 microg/ml for NCI-H187 cell line) activities. In our bioassay systems, isodiospyrin (3) did not exhibit antimycobacterial, antifungal, antimalarial, and cytotoxic activities. Isodiospyrol A (4) exhibited antimalarial (IC50 2.7 microg/ml) and antimycobacterial (MIC 50 microg/ml) activities, but was inactive towards Candida albicans. Compound 4 also exhibited cytotoxicity against BC cells (IC50 12.3 microg/ml), but not towards KB and Vero cell lines.

Production of red pigments (naphthoquinones) by the insect pathogenic fungus Cordyceps unilateralis BCC 1869 was investigated in this study. Cultivation conditions, including temperature, intitial pH of medium, and aeration, were optimised to improve the yield of total naphthoquinones in shake-flask culture of C. unilateralis. The highest yield of total naphthoquinones (3 g L-1) was obtained from a 28-day culture grown in potato dextrose broth with an initial pH of 7.0, at 28 degrees C with shaking-induced aeration at 200 rpm. An extraction process for isolation of the targeted naphthoquinone, 3,5,8-trihydroxy-6-methoxy-2-(5-oxohexa-1,3-dienyl)-1,4-naphthoquinone (3,5,8-TMON), from a culture of C. unilateralis, was also developed. The yield of 3,5,8-TMON obtained was about 1.2 g L-1 or 40% of total naphthoquinones. The stability of 3,5,8-TMON was very high, even upon exposure to strong sunlight (70,000 lx), high temperature up to 200 degrees C, and acid and alkali solutions at concentrations of 0.1 M.

Azaphilone pigments, monascusones A (1) and B (2), together with two known azaphilones, monascin (3) and FK17-P2b2 (4), were isolated from the CH2Cl2 extract of a yellow mutant of the fungus M. kaoliang grown on rice. Structures of the isolated compounds were elucidated by analyses of spectroscopic data. Monascusone A (1), the major metabolite of M. kaoliang, showed no antimalarial (against Plasmodium falciparum), antitubercular (against Mycobacterium tuberculosis H37Ra), and antifungal (toward Candida albicans) activities. Compound 1 exhibited no cytotoxicity against BC (breast cancer) and KB (human epidermoid carcinoma of cavity) cell lines.

Four new cyclohexadepsipeptides, enniatins L (1), M1 (2), M2 (3), and N (4), have been isolated from an unidentified fungus (BCC 2629), together with the known enniatins B (5), H (6), and I (7), MK1688 (8), and enniatin B4 (9). Compounds 1–4 are the first enniatin analogs with an OH group at the side chain of one of the 2-hydroxycarboxylic acid residues. The structures of 1–4 were elucidated by spectroscopic means and by X-ray crystallography.

A novel 24-membered polyene lactam macrolide, micromonosporin A (=(3E,5E,7Z,15E,17E,19E,21E)-9,11,13-trihydroxy-14,19,24-trimethyl-1-azacyclotetracosa-3,5,7,15,17,19,21-heptaen-2-one; 1) was isolated from the actinomycete, Micromonospora sp. strain TT1-11, which was isolated from a very acidic peat swamp forest.

Aigialone (1) and aigialospirol (2), two structurally unique compounds, were isolated from the mangrove fungus Aigialus parvus BCC 5311. The structure of the new ketene acetal 1 was elucidated by spectral analysis, and its relative stereochemistry was determined by X-ray crystallography. The stereochemistry of aigialospirol (2), elucidated by NMR spectral analysis, suggested that this compound is possibly derived from hypothemycin (3), a metabolite previously isolated from this same fungus.

Two new antimycobacterial dibenzo[b,f]oxepins, bauhinoxepins A (=3,3,5-trimethylbenzo[b]pyrano[g][1]benzoxepin-6,11-diol; 1) and B (=6-methoxy-7-methyl-2-(3-methylbut-2-enyl)dibenzo[b,f]oxepine-1,8-diol; 2), were isolated from the roots of Bauhinia saccocalyx, and their structures were elucidated by analysis of spectroscopic data. Bauhinoxepins A and B exhibited antimycobacterial activities with respective minimum-inhibitory concentrations (MIC) of 6.25 and 12.5 μg/ml. They were inactive (at 20 μg/ml) against the malarial parasite, and also inactive (at 20 μg/ml) towards the Vero, KB, and BC cell lines.

Nitrones are formed from the reaction of aspergillusol A ( 1 ) and a ketone/aldehyde in phosphate buffer and aqueous solutions with pH ranges of 6.8–8.6, resembling physiological conditions. The reaction of 1 with 1-substituted cyclohexanones gave the (1′ S ∗ ,2′ R ∗ )-isomer, diastereoselectively.

Natural products are recognized as a rich source of bioactive compounds for modern medicine, particularly those for the treatment of cancer. Since natural products are metabolites of living organisms, they have a tendency to bind or interact with biomolecules in living cells such as proteins, enzymes, DNA, RNA, and receptors, some of which are drug targets. This special property makes natural compounds to be the ideal sources for the drug development. Cancer is a serious health threat, and it is known as the leading cause of death worldwide. Recent anticancer drug development is heavily based on drug targets, that is, proteins, enzymes, and receptors, and this mechanism-based drug discovery would significantly shorten the drug development process. This chapter covers the recent development of anticancer drugs, which are from natural products or inspired by natural products. Recently, several new anticancer drugs and potential anticancer leads have been discovered through the rational drug design on different drug targets. This chapter highlights natural anticancer drugs and leads, as well as derivatives of natural products, which are discovered through the most recently employed anticancer drug targets, for example, tubulin/microtubule interaction, tyrosine kinases, cyclin-dependent kinases, heat shock protein 90, Hedgehog signaling pathway, and histone deacetylase.

Structurally unique isocoumarin glucosides, named halorosellins A (1) and B (2), were isolated from the EtOAc extract of a broth of the marine fungus Halorosellinia oceanica. Other new minor metabolites including 4,8-dihydroxy-6-methoxy-4,5-dimethyl-3-methyleneisochroman-1-one (3), 3-acetyl-7-hydroxy-5-methoxy-3,4-dimethyl-3H-isobenzofuran-1-one (4) and an ophiobolane sesterterpene, 17-dehydroxyhalorosellinic acid (5), were also isolated. Structures of these compounds were elucidated by analyses of spectroscopic data. Compound 4 exhibited mild antimycobacterial activity (MIC value of 200 µg mL−1).

Precursor-directed biosynthesis of beauvericin analogs, cyclohexadepsipeptide antibiotics, was investigated using the insect pathogenic fungus Paecilomyces tenuipes BCC 1614. Feeding l -isoleucine or d -alloisoleucine in liquid medium led to the enhanced production of beauvericin A and beauvericin B together with beauvericin and a missing analog, beauvericin C. Feeding experiments with d -isoleucine or l -alloisoleucine resulted in the production of diastereomers of beauvericins A, B and C, named allobeauvericins A, B and C, respectively.

The C-4 sulfated isoflavonoid, torvanol A (1), and the steroidal glycoside, torvoside H (3), together with the known glycoside, torvoside A (2), were isolated from a MeOH extract of Solanum torvum fruits. Upon enzymatic hydrolysis with beta-glucosidase, torvoside A (2) and torvoside H (3) yielded the corresponding acetal derivatives 4 and 5, respectively. Torvanol A (1), torvoside H (3) and compound 5 exhibited antiviral activity (herpes simplex virus type 1) with IC(50) values of 9.6, 23.2 and 17.4 microg/ml, respectively. Compounds 1-5 showed no cytotoxicity (at 50 microg/ml) against BC, KB and Vero cell lines.

A novel sesquiterpenoid, asperaculin A (1), possessing a novel [5,5,5,6]fenestrane ring system, was isolated from the marine-derived fungus Aspergillus aculeatus CRI323-04. The structure of asperaculin A (1) was established by analysis of spectroscopic data. The name aspergillane is proposed for the sesquiterpene skeleton in asperaculin A (1).

Three new isoflavanones (1–3) and thirteen known compounds (4–16) were isolated from the roots of Mucuna pruriens. The absolute configurations of isoflavanones 1–3 and parvisoflavanone (4), lespedeol C (5), and uncinanone C (6) were addressed by a circular dichroism technique. Isoflavanones, isoflavones, and pterocarpans of M. pruriens were found to be α-glucosidase inhibitors. Medicarpin (7) and parvisoflavone B (9) were potent α-glucosidase inhibitors (twofold less active than the standard drug acarbose). The production of bioactive metabolites in M. pruriens seems to be season-dependent.