Hydroxamates of para-aminobenzoic acid as selective inhibitors of HDAC8.

A series of hydroxamates (4a-4l) were prepared from p-aminobenzoic acid to inhibit HDAC8. The idea is to substitute rigid aromatic ring in place of less rigid piperazine ring of hydroxamates reported earlier by our group. It is expected to increase potency retaining the selectivity. Result obtained suggested that the modifications carried out retained the selectivity towards HDAC8 isoform and increasing the potency in very few cases. Increase in potency is also associated with variation in cap aryl region. Two compounds (4f &4l) were found to inhibit HDAC8 at concentrations (IC50) less than 20µM.

Synthesis, antineoplastic and cytotoxic activities of some mononuclear Ru(II) complexes.

A series of mononuclear Ru(II) complexes of the type [Ru(S)(2)(K)](2+), where S = 1,10-phenanthroline/2,2'-bipyridine and K = 4-OH-btsz, 4-CH(3)-btsz, 3,4-di-OCH(3)-btsz, 4-OH-binh, 4-CH(3)-binh, 3,4-di-OCH(3)-binh, were prepared and characterized by elemental analysis, FTIR, (1)H-NMR, and mass spectroscopy. The complexes displayed metal-ligand charge transfer (MLCT) transitions in the visible region. These ligands formed bidentate octahedral ruthenium complexes. The title complexes were evaluated for their in vivo anticancer activity against a transplantable murine tumor cell line, Ehrlisch's ascites carcinoma (EAC), and in vitro cytotoxic activity against human cancer cell lines Molt 4/C(8) and CEM and murine tumor cell line L1210. The ruthenium complexes showed promising biological activity especially in decreasing tumor volume and viable ascites cell counts. Treatment with these complexes prolonged the life span of mice bearing EAC tumors by 10-52%. In vitro evaluation of these ruthenium complexes revealed cytotoxic activity from 0.21 to 24 muM against Molt 4/C(8), 0.16 to 19 microM against CEM, and 0.75 to 32 microM against L1210.

Development and validation of high-throughput liquid chromatography-tandem mass spectrometric method for simultaneous quantification of clopidogrel and its metabolite in human plasma.

A simple, sensitive and reliable method is described for simultaneous quantification of Clopidogrel and its metabolite in human plasma by using HTLC-MS/MS. The analytical procedure involves on-line coupling of extraction with Cyclone P (50 mm x 0.5 mm 50 microm) HTLC column by injecting 15 microL sample and chromatographic separation is performed with Cohesive Propel C18 (5 microm, 3.0 mm x 50 mm), followed by quantification with mass detector in SRM mode using ESI as an interface. The calibration curves were linear over a concentration range of 0.1-8 ng/mL of Clopidogrel and 70 ng/mL to 6 microg/mL of its metabolite using 20 mL human plasma per batch. The total run time of analysis was 7.5 min and the lower limits of quantification were 0.1 ng/mL for Clopidogrel and 70 ng/mL for its metabolite. The method validation was carried out in terms of specificity, sensitivity, linearity, precision, accuracy and stability. The validated method was applied in bioavailability and bioequivalence study.

Determination of the quaternary ammonium compound trospium in human plasma by LC-MS/MS: application to a pharmacokinetic study.

A highly sensitive, specific and evaporation free SPE extraction, LC-MS/MS method has been developed for the estimation of trospium in human plasma using trospium-d8 as an internal standard (IS). The analyte was separated using isocratic mobile phase on reverse phase column and analyzed by MS/MS in the multiple reaction monitoring mode using the respective [M(+)] cations, m/z 392-164 for trospium and m/z 400-172 for the IS. The total run time was 3.50 min and the elution of trospium and trospium-d8 (IS) occurred at 2.8 min. The developed method was validated in human plasma with a lower limit of quantification of 0.05 ng/mL. A linear response function was established for the range of concentrations 0.05-10 ng/mL (r>0.998) for trospium in human plasma. The intra- and inter-day precision values for trospium met the acceptance as per FDA guidelines. Trospium was stable in the battery of stability studies viz., bench-top, auto-sampler, dry extracts and freeze/thaw cycles. The developed assay method was applied to an oral pharmacokinetic study in humans.

Evaluation of toxicological and antioxidant potential of Nardostachys jatamansi in reversing haloperidol-induced catalepsy in rats.

An aqueous root extract from Nardostachys jatamansi was investigated for its antioxidant and anticataleptic effects in the haloperidol-induced catalepsy rat model of the disease by measuring various behavioral and biochemical parameters. Catalepsy was induced by administration of haloperidol (1 mg/kg, ip) in male albino rats. A significant (P < 0.01) reduction in the cataleptic scores were observed in all the drug-treated groups as compared to the haloperidol-treated group; with maximum reduction observed in the Nardostachys jatamansi (250 and 500 mg/kg body weight) administered group. To estimate biochemical parameters: the generation of thiobarbituric acid reactive substances (TBARS); reduced glutathione (GSH) content and glutathione-dependent enzymes; catalase; and superoxide dismutase (SOD), in the brain were assessed. Haloperidol administration increased generation of TBARS and significantly reduced GSH, which were restored to near normal level with the Nardostachys jatamansi treatment. Catalase and SOD levels were also increased to normal levels, having been reduced significantly by haloperidol administration. Our findings of behavioral studies and biochemical estimations show that Nardostachys jatamansi reversed the haloperidol-induced catalepsy in rats. We conclude that the antioxidant potential has contributed to the reduction in the oxidative stress and catalepsy induced by haloperidol administration.

Removal of toxic Cr(VI) by the adsorption of activated carbons prepared from Simarouba shells.

Removal of toxic Cr(VI) in aqueous medium was investigated using activated carbon adsorbents prepared from Simarouba glauca seed shells. The pH effect, Cr(VI) concentration, adsorbent dosage and contact time period were studied in batch experiment. The removal of Cr(VI) was in general most effective at pH range 2.0-4.0 and high Cr(VI) concentrations. Activated carbons are prepared at 80050 degrees C temperature. One is non-impregnated and the remaining three are impregnated with zinc chloride in 1:1,1:2,1:3 ratio. Important characteristics of activated carbons are also investigated. The data for all the adsorbents fit well to the Freundlich adsorption isotherm. The removal of Cr(VI) is around 97% was observed with 1:2 impregnated activated carbon at pH 3.0 where as other adsorbents showed much lower activities.