Biomedical subjects
Publications and source records attributed to Y Thebtaranonth.
Nucleophilic additions of lithium keto and ester enolates and mono- and bifunctional Grignard reagents to artemisitene provided C-16-derived artemisinin monomers, dimers, trimers, and tetramers whose antimalarial and cytotoxic activities have been evaluated.
Three known compounds, 2-hexylidene-3-methylsuccinic acid (1), cytochalasin Q (2), and 5-carboxymellein (3), together with two new derivatives, 2-hexylidene-3-methylsuccinic acid 4-methyl ester (4) and an ophiobolane sesterterpene named halorosellinic acid (5), were isolated from culture broth of the marine fungus Halorosellinia oceanica BCC 5149. Compounds 1-3 exhibited moderate cytotoxicity against KB and BC-1 cell lines with IC(50) values of 1-13 microg/mL, while compounds 2, 3, 5, and 6 showed antimalarial activity with respective IC(50) values of 17, 4, 13, and 19 microg/mL. Halorosellinic acid (5) possessed only weak antimycobacterial activity with the minimum inhibitory concentration of 200 microg/mL.
Bioassay-guided fractionation of the extracts from the insect pathogenic fungus Cordyceps nipponica BCC 1389 led to the isolation of N-hydroxy- and N-methoxy-2-pyridones, cordypyridones A-D (1-4). Structures of these compounds, including absolute configuration, were determined by spectroscopic methods, chemical conversions and single-crystal X-ray diffraction analyses. Codypyridones A and B, atropisomers of each other, exhibited potent in vitro antimalarial activity with IC(50) values of 0.066 and 0.037 microg/mL, respectively, while their cytotoxicity was much weaker.
Stereospecific deprotonation of the epoxy proton at the beta-position of the alpha,beta-epoxy esters 5 and 6 yielded oxiranyl "remote" anions 7 and 8, which could then be used for alkylation. The anions 7 and 8 underwent a consecutive aldol lactonization to give, respectively, epoxy lactones 11 and 13 with high stereoselectivity. Generation of the remote anions as well as their stereoselective reactions served as a new synthetic route to the naturally occurring alpha-methylenebis-gamma-butyrolactones, 1.
Two new 10-membered lactones, namely, multiplolides A (1) and B (2), were isolated from the broth extract of the fungus Xylaria multiplex BCC 1111. Chemical structures of 1 and 2 were elucidated on the basis of their spectral data. Multiplolides A (1) and B (2) exhibited antifungal activity against Candida albicans with IC(50) values of 7 and 2 microg/mL, respectively. Both 1 and 2 were inactive in the screening systems toward the malarial parasite Plasmodium falciparum (at 20 microg/mL) and were not cytotoxic to BC-1 and KB cell lines (at 20 microg/mL).
New furanoid labdane diterpenes, potamogetonyde (3) and potamogetonol (4), together with two known compounds, potamogetonin (1) and 15,16-epoxy-12-oxo-8(17),13(16),14-labdatrien-20,19-olide (2), were isolated from the CH(2)Cl(2) extract of Potamogeton malaianus. The chemical structures of 1-4 were elucidated by the analyses of their spectral data, mainly by 1D and 2D NMR techniques. Potamogetonyde (3) and potamogetonol (4) exhibited potent antiviral (HSV-1) activity with respective IC(50) values of 8 and 3 microg/mL. Compounds 1-4 possessed cytotoxicity toward insect cells (fall armyworm and mosquito larvae, IC(50) of 11-72 microg/mL). Furanoid diterpenes 3 and 4 also exhibited cytotoxicity against the Vero cell line with respective IC(50)'s of 31 and 28 microg/mL, while 1 and 2 were inactive at 50 microg/mL. Compounds 1-4 were inactive (at 20 microg/mL) against KB and BC cell lines and showed only weak antimycobacterial activity against Mycobacterium tuberculosis H37Ra with minimum inhibitory concentrations of 50-100 microg/mL.
Phomoxanthones A (1) and B (2), two novel xanthone dimers, were isolated from the endophytic fungus Phomopsis sp. BCC 1323. Structures of 1 and 2 were elucidated by spectroscopic methods. These compounds exhibited significant in vitro antimalarial and antitubercular activities and cytotoxicity.
Bioassay-guided fractionation of the cell extract of the insect pathogenic fungus Aschersonia tubulata BCC 1785 led to the isolation of dustanin (1), 3 beta,15 alpha,22-trihydroxyhopane (3), 5 alpha,8 alpha-epidioxy-24(R)-methylcholesta-6,22-diene-3 beta-ol (6), together with the new 3 beta-acetoxy-15 alpha,22-dihydroxyhopane (4). Chemical structures of these compounds were elucidated by spectral analyses as well as chemical transformation. Compounds 1 and 4 exhibited antimycobacterial activity with the minimum inhibitory concentration (MIC) of 12.5 micrograms/ml.
Eleven bioxanthracenes and two monomers, six novel in nature, were isolated from the insect pathogenic fungus Cordyceps pseudomilitaris BCC 1620. Growth optimization of the strain led to the improvement of bioxanthracenes production. The bioxanthracenes were evaluated for their antimalarial activity and cytotoxicity.
Structures of eleven bioxanthracenes (1 approximately 11) and two monomers (12 and 13), isolated from the insect pathogenic fungus Cordyceps pseudomilitaris BCC 1620, were elucidated. The structure, including the axial stereochemistry, of one of the major symmetrical dimers (1) was determined by X-ray crystallographic analysis, while the stereochemistries of the other isomers were deduced by chemical conversions and spectroscopic means.
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Antimalarial activity-guided study of the aerial parts of Artocarpus integer led to the isolation of the prenylated stilbene, trans-4-(3-methyl-E-but-1-enyl)-3,5,2',4'-tetrahydroxystilbene with an EC50 of 1.7 micrograms/ml against Plasmodium falciparum in culture. The known stilbenes, trans-4-isopentenyl-3,5,2',4'-tetrahydroxystilbene and 4-methoxy-2,2-dimethyl-6-(2-(2,4-dihydroxy)phenyl-trans-ethenyl)chromene , were also isolated. Structures of these compounds were deduced on the basis of their spectral data.
Racemosol and demethylracemosol, together with their possible biogenetic precursors, preracemosol A and preracemosol B, were isolated from the roots of Bauhinia malabarica Roxb. While only racemosol and demethylracemosol exhibited cytotoxicity against KB and BC cell lines, all four compounds exhibited moderate antimalarial activity.
The nature of the interactions between Plasmodium falciparum dihydrofolate reductase (pfDHFR) and antimalarial antifolates, i.e., pyrimethamine (Pyr), cycloguanil (Cyc) and WR99210 including some of their analogues, was investigated by molecular modeling in conjunction with the determination of the inhibition constants (Ki). A three-dimensional structural model of pfDHFR was constructed using multiple sequence alignment and homology modeling procedures, followed by extensive molecular dynamics calculations. Mutations at amino acid residues 16 and 108 known to be associated with antifolate resistance were introduced into the structure, and the interactions of the inhibitors with the enzymes were assessed by docking and molecular dynamics for both wild-type and mutant DHFRs. The Ki values of a number of analogues tested support the validity of the model. A 'steric constraint' hypothesis is proposed to explain the structural basis of the antifolate resistance.
Activity guided fractionation of extracts from Clausena harmandiana have led to the identification of four known compounds, heptaphylline (1), clausine K (2), dentatin (5), and clausarin (6). All these compounds, except clausine K (2), exhibited antiplasmodial activity against Plasmodium falciparum. While the new dimethylated derivative 4, derived from 2, showed no antiplasmodial activity, the monomethylated product 3 (clausine H) exhibited activity comparable to that observed for compounds 1 and 5.
Bioassay-guided fractionation of the extract from the wood-decayed fungus Xylaria sp. BCC 1067 led to the isolation of five antiplasmodial compounds, (-)-depudecin, (+)-phaseolinone, (+)-phomenone, 19,20-epoxycytochalasin Q, and (E)-methyl 3-(4-methoxyphenoxy)propenoate. These structures were elucidated using spectroscopic methods, especially NMR analysis.
Bioassay-guided fractionation of the crude extract from the insect pathogenic fungus Paecilomyces tenuipes BCC 1614 led to the isolation and identification of two antimycobacterial and antiplasmodial cyclodepsipeptides, beauvericin and beauvericin A.