Biomedical subjects
Publications and source records attributed to Y Thebtaranonth.
Bioassay-guided fractionation of an extract from the fungus Myrothecium verrucaria BCC 112 resulted in the first isolation of roridin E acetate (5) from nature together with four common macrocyclic trichothecene isomers (1-4). Trichothecenes 1-5, while known as mycotoxins, were evaluated for their high antimalarial activity.
Research on natural products provides not only knowledge and understanding of living organisms but chemical entities obtained from bioresources can also be used as structural models for further development in the various fields, notably in the agricultural and pharmaceutical sciences. Selected examples on the scientific aspects of traditional usage of bioresources are described.
Activity-guided investigation of Artemisia indica Willd. has led to isolation of exiguaflavone A, exiguaflavone B, maackiain, and 2-(2, 4-dihydroxyphenyl)-5,6-methylenedioxybenzofuran. Exiguaflavones A and B exhibit in vitro antimalarial activities of 4.60 x 10(-6) and 7.05 x 10(-6) g/mL, respectively, against Plasmodium falciparum.
The antimalarial activity of a number of artemisinin derivatives, both newly synthesized and currently used as drugs, against Plasmodium falciparum in culture shows a correlation with their affinity of binding with ferroprotoporphyrin IX, as measured from the spectral change of the latter. The new C-16-functionalized artemisinin derivatives were obtained through a novel one-pot synthesis of artemisitene (2) from naturally abundant artemisinin (1), followed by Michael addition with nucleophiles. The correlation points to the biological significance of the interaction of these derivatives with ferroprotoporphyrin IX and may provide a basis for primary screening of peroxidic antimalarials of similar structures.
Various derivatives of artemisinin covalently linked to iron chelators were synthesized, and their antimalarial activities were evaluated. Although results show no indication that the presence of an iron chelator in the vicinity of artemisinin potentiates its action, the linked compounds prepared still retain comparable activities to that of artemisinin.
Activity-guided investigation of Cyperus rotundus tubers led to the isolation of patchoulenone, caryophyllene alpha-oxide, 10,12-peroxycalamenene and 4,7-dimethyl-1-tetralone. The antimalarial activities of these compounds are in the range of EC50 10(-4)-10(-6) M, with the novel endoperoxide sesquiterpene, 10,12-peroxycalamenene, exhibiting the strongest effect at EC50 2.33 x 10(-6) M.
The glycosidic antibiotics of the glykenin (GK) family produced by Basidiomycetes sp. were separated into nine components (GK-I-VII and DG) by normal-phase chromatography. It was found that these components differ in the number and location of the acetyl groups in the sugar moiety. Each component (GK-I-VII and DG) was further separated into three isomers (A, B and C), which possess different aglycones, by reversed-phase chromatography on an ODS column with methanol-acetonitrile as eluent. The best composition of the eluent was found to be methanol-acetonitrile-1% trifluoroacetic acid (4:3.5:2.5). The profile analysis of GK-III-VII and DG was also carried out using a modified mobile phase. The combination of normal- and reversed-phase chromatography separated all components of the GK mixture except GK-I and II. The relationship between structure and separation behaviour of GK is discussed.
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No mutagenicity of five diterpenes isolated from the roots of Jatropha curcas was detected by Ame's test using both TA98 and TA100 tester strains with or without S-9 fraction from livers of rats treated with polychlorinated biphenyl.
Nimbolide and nimbic acid are toxic to mice only when given i.p. and i.v. but they are less toxic to rats and hamsters. The LD50 values of a single i.p. administration of nimbolide to adult male, female and weanling mice were 225, 280 and 240 mg/kg body wt, respectively, and its i.v. LD50 value was decreased to 24 mg/kg body wt in adult male mice. No fatality was observed when nimbolide was given i.g., i.m. and s.c. to adult male mice. Estimated LD50 values of nimbolide in rats and hamsters were somewhat higher than 600 and 500 mg/kg body wt. After 12-23 h i.p. administration of a lethal dose, most animals died of possible dysfunctions in kidney (tubular necrosis), small intestine (hemorrhagic necrosis), pancreas (acinar cell necrosis) and liver (mild fatty infiltration and focal necrosis). In contrast, mice and rats given a lethal dose of nimbolide (i.v.) died of a marked and sudden drop in arterial blood pressure and respiratory paralysis within about 1-18 min. Nimbic acid was less toxic to mice with an i.v. LD50 value of 265 mg/kg body wt and i.p. and i.g. LD50 values of higher than 600 mg/kg body wt. The possible cause of death induced by nimbic acid may be similar to that of nimbolide given i.v. and this is a sudden hypotensive shock.
The terpenoid lactone nimbolide, the structure of which has been unambiguously established, was found to inhibit Plasmodium falciparum in culture with a moderate potency. The EC50 against the parasite line K1 from Thailand was approximately 2.0 microM (0.95 microgram/ml). The EC50 of crude aqueous extract of Azadirachta indica var. siamensis (Sadao tree), was 115 micrograms/ml, and of crude ethanol extract was 5.0 micrograms/ml. Since nimbolide is a major constituent in these extracts, it could account substantially for their inhibitory activity. However, neither the crude extracts nor nimbolide showed any activity in vivo against Plasmodium berghei in the mouse either through ingestion (746 mg aqueous extract, 62.5 mg ethanol extract or 12.5 mg nimbolide/kg/day), or subcutaneous injection (93 mg aqueous extract, 31 mg ethanol extract or 12.5 mg nimbolide/kg/day).
A fusiform yeast producing limited pseudomycelium and limited true mycelium on malt extract agar has been isolated. This non-fermentative yeast has hyaline cell walls but produces a thick, black oily exudate which is water insoluble and gives the colony a smooth black lacquered appearance. On the basis of morphology and physiology, this organism is distinctive enough to warrant the designation of a new genus. During stationary phase of cultures on chemically defined medium, a deep red substance is produced which has strong antibiotic activity against Staphylococcus aureus in vitro. The substance has been identified as a new natural naphthaquinone of the empirical formula C16H16O7 .
The reisolation of nimbolide [1] from Azadirachta indica of Tanzanian origin and the isolation and structure elucidation of a new limonoid, 28-deoxonimbolide [2], from the same plant source are reported. For the first time, unambiguous 1H- and 13C-nmr assignments of compounds 1 and 2 are presented, as well as their in vitro cytotoxic activity against human tumor cell lines.