This paper examines the functional mechanism of thioxolone, a compound recently identified as a weak inhibitor of human carbonic anhydrase II by Iyer et al. (2006) J. Biomol. Screening 11, 782-791 . Thioxolone lacks sulfonamide, sulfamate, or hydroxamate functional groups that are typically found in therapeutic carbonic anhydrase (CA) inhibitors, such as acetazolamide. Analytical chemistry and biochemical methods were used to investigate the fate of thioxolone upon binding to CA II, including Michaelis-Menten kinetics of 4-nitrophenyl acetate esterase cleavage, liquid chromatography-mass spectrometry (LC-MS), oxygen-18 isotope exchange studies, and X-ray crystallography. Thioxolone is proposed to be a prodrug inhibitor that is cleaved via a CA II zinc-hydroxide mechanism known to catalyze the hydrolysis of esters. When thioxolone binds in the active site of CA II, it is cleaved and forms 4-mercaptobenzene-1,3-diol via the intermediate S-(2,4-thiophenyl)hydrogen thiocarbonate. The esterase cleavage product binds to the zinc active site via the thiol group and is therefore the active CA inhibitor, while the intermediate is located at the rim of the active-site cavity. The time-dependence of this inhibition reaction was investigated in detail. Because this type of prodrug inhibitor mechanism depends on cleavage of ester bonds, this class of inhibitors may have advantages over sulfonamides in determining isozyme specificity. A preliminary structure-activity relationship study with a series of structural analogues of thioxolone yielded similar estimates of inhibition constants for most compounds, although two compounds with bromine groups at the C1 carbon of thioxolone were not inhibitory, suggesting a possible steric effect. 相似文献
This study reports critical changes in the behaviour patterns of lion-tailed macaques (Macaca silenus) inhabiting a continuously changing and deteriorating rain forest fragment in the Western Ghats, India. The study area, a privately owned rain forest patch in a tea/coffee garden called Puthuthotam, has suffered two massive selective logging episodes. Over the years, the native rain forest trees have been largely replaced by non-native/pioneer species resulting in loss of canopy contiguity and significant changes in other vegetation parameters. The almost wholly arboreal lion-tailed macaque now spends a considerable amount of time on the ground in this area. The species has also experienced a major shift in its diet, ranging patterns and other activities. 相似文献
A novel series of bisthiourea derivatives of four dipeptides consisting of Lys-Asp, lys-Asp, Lys-Trp and lys-Trp conjugated to 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole were synthesized and characterized by physical method and spectroscopic data. The molecules 1–24 were evaluated for their in vitro antioxidant activity and compared with commercial antioxidants ascorbic acid (AA) and gallic acid (GA), employing 1,1-diphenyl-2-picryl-hydrazyl (DPPH), N,N-dimethyl-p-phenylenediamine dihydrochloride (DMPD) and 2,2-azinobis-(3-ethylbenzothiazoline-6-sufonic acid) (ABTS) assays. The results revealed that IC50 of 8, 11, 20 and 23 with electron donating OCH3 group were lower than the IC50 of commercial standards AA and GA in all the three performed antioxidant assays indicating the good activities of these compounds. The analogues with Trp (13–24) showed better activity than the corresponding analogues with Asp (1–12). Further, the dipeptide derivatives with d-configuration (lys) were found to be more potent than the dipeptide derivatives with l-configuration (Lys). 相似文献
We assessed the distribution and conservation status of bonnet macaques (Macaca radiata), rhesus macaques (Macaca mulatta) and Hanuman langurs (Semnopithecus entellus) in the state of Karnataka, India. Karnataka is situated in southwest India with an area of 191,791 km2. A total of 9697 km of vehicular survey was made from November 2001 to July 2004. We also visited 107 temples/tourist spots
to determine the presence of primates. Bonnet macaques and Hanuman langurs were widely distributed, whereas rhesus macaques
were not found in the state. However, bonnet macaques were absent in a few districts in the northern plains and Hanuman langurs
were absent in some districts of the southern plains. A total of 205 groups of bonnet macaques and 139 groups of Hanuman langurs
were sighted. The relative encounter rate of both species differed across biogeographic zones. Bonnet macaques were largely
encountered in the Western Ghats and the Southern Plateau whereas Hanuman langurs were abundant in the Western Ghats and Northern
Plains. We found that bonnet macaques have been eliminated from about 48% temples/tourist spots where they occurred in the
recent past. The Hanuman langur population of Dharwar–Haliyal Road was assessed during April 2003, and we found that the present
population size was about 38% of a previous survey in 1961. Habitat change, hunting/trapping and translocation were the major
factors causing a decline in the langur population. 相似文献
Rohitukine is a chromane alkaloid possessing anti-inflammatory, anti-cancer and immuno-modulatory properties. The compound
was first reported from Amoora rohituka (Meliaceae) and later from Dysoxylum binectariferum (Meliaceae) and Schumanniophyton problematicum (Rubiaceae). Flavopiridol, a semi-synthetic derivative of rohitukine is a potent CDK inhibitor and is currently in Phase
III clinical trials. In this study, the isolation of an endophytic fungus, Fusarium proliferatum (MTCC 9690) from the inner bark tissue of Dysoxylum binectariferum Hook.f (Meliaceae) is reported. The endophytic fungus produces rohitukine when cultured in shake flasks containing potato
dextrose broth. The yield of rohitukine was 186 μg/100 g dry mycelial weight, substantially lower than that produced by the
host tissue. The compound from the fungus was authenticated by comparing the LC–HRMS and LC–HRMS/MS spectra with those of
the reference standard and that produced by the host plant. Methanolic extract of the fungus was cytotoxic against HCT-116
and MCF-7 human cancer cell lines (IC50 = 10 μg/ml for both cancer cell lines). 相似文献
Diversity and phylogenetic relationship between four closely related Salacia species, i.e., Salacia chinensis, Salacia macrosperma, Salacia fruticosa and Salacia oblonga, collected from the Western Ghats of Karnataka, India, was assessed. Ten each of RAPD and ISSR primers generated a total of 76 and 68 loci, generating polymorphisms of 92.21 and 89.71%, respectively. Maximum likelihood analysis of the ITS sequences revealed three clades. Dendrogram analyses of RAPD and ISSR revealed two and four clusters, respectively. Overall polymorphism revealed by RAPD was 41.45?±?10%, ISSR was 33.58?±?6.52%, and ITS was 25.50?±?17.25%. Molecular variance revealed significant variance within and among the Salacia species. Tajima’s D neutrality test and Fu’s Fs were negative for all four species, implying presences of rare alleles and population expansion. Comparative study of RAPD, ISSR and ITS for Salacia species has given an insight into the efficiency of each technique in detecting diversity within and among the population sampled in the Western Ghats of Karnataka.