Ronald G. Micetich

Synthesis and antifungal activity of coumarins and angular furanocoumarins

Angelicin, a naturally occurring furanocoumarin, that showed antifungal activity, was considered as a lead structure for a group of synthetic coumarins. Antifungal activities of the synthesized coumarins and angelicin derivatives were reported against Candida albicans, Cryptococcus neoformans, Saccharomyces cerevisiae and Aspergillus niger. Human cell line cytotoxicity of several coumarins was evaluated against KB cells. Angelicin and several potent antifungals showed to be non-toxic in this assay.

Facile conversion of azides to amines

Les azides sont reduits en amines primaires par reaction avec le chlorure stanneux dans le methanol

High‐throughput Caco‐2 cell permeability screening by cassette dosing and sample pooling approaches using direct injection/on‐line guard cartridge extraction/tandem mass spectrometry

A method for high-throughput Caco-2 permeability screening of drug candidates has been developed using thirteen generic drugs as test compounds. The high throughput was achieved by either a sample pooling or a cassette dosing approach, along with the use of a rapid, simple and sensitive direct injection/on-line guard cartridge extraction/tandem mass spectrometric assay that was also developed in this study. It was of concern that possible drug-drug interactions (e.g., inhibition of P-glycoprotein-mediated transport of a drug by another, and/or competition of the drugs for transport pathways), when the cassette dosing regimen was implemented, may give rise to inconsistent results compared with those attained by a traditional single-drug dosing approach. However, the apparent permeability coefficients of the test drugs across Caco-2 monolayers measured by the sample pooling or cassette dosing (up to five drugs co-administered in this study) strategy were in good conformity with the data obtained by single-drug dosing followed by discrete sample analysis.

3-Acylamino-azetidin-2-one as a novel class of cysteine proteases inhibitors

A new class of inhibitors for cysteine proteases cathepsin B, L, K and S is described. These inhibitors are based on the beta-lactam ring designed to interact with the nucleophilic thiol of the cysteine in the active site of cysteine proteases. Some 3-acylamino-azetidin-2-one derivatives showed very potent inhibition activities for cathepsins L, K and S at the nanomolar or subnanomolar IC(50) values.

Reductive Cleavage of Symmetrical Disulfides with Hydrazines

Abstract An efficient method for the reductive cleavage of symmetrical disulfides with hydrazines is described.

Detection and quantitation of a ring-hydroxylated metabolite of the antidepressant drug tranylcypromine

The formation ofp-hydroxytranylcypromine from intraperitoneally injected tranylcypromine was confirmed using two types of experiments. In the first, tranylcypromine levels were shown to be increased in brains of rats pretreated with agents known to be inhibitors of ring hydroxylation compared to rats pretreated with physiological saline. For the second set of experiments,p-nydroxytranylcypromine was identified in brain and urine (following intraperitoneal injection) by derivatizing with perfluoroacylating reagents and analyzing by electron-capture gas chromatography and by combined gas chromatography-mass spectrometry. In experimentsin vitro, p-hydroxytranylcypromine was demonstrated to inhibit monoamine oxidase, although it was weaker than TCP in this regard and was a much stronger inhibitor of MAO-A than of MAO-B.

Potentiation of ricin A immunotoxin by monoclonal antibody targeted monensin containing small unilamellar vesicles

The carboxylic ionophore monensin could be successfully entrapped in small unilamellar vesicles made by the extruder method. Monensin liposomes of size range 100-150 nm were more potent in potentiating ricin A immunotoxin activity in vitro as compared to monensin liposomes of diameter 500 nm or more. These liposomes were further successfully linked to tumor specific monoclonal antibodies with full retention of immunoreactivity. Monoclonal antibody targeted monensin liposomes were 100 times more potent than monensin liposomes in potentiating the activity of ricin A immunotoxins against various tumor cell lines in vitro.

Neurochemical and neuropharmacological properties of 4-Fluorotranylcypromine

Summary1.The 4-fluoro analogue of the monoamine oxidase-inhibiting antidepressant tranylcypromine was compared to the parent drug with regard to the following: inhibition of monoamine oxidases A and Bin vitro andex vivo; levels of both drugs in brain, liver, and blood after injection of equimolar doses; and effects on brain levels of the amines 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine.2.4-Fluorotranylcypromine was found to be 10 times more potent than tranylcypromine at inhibiting monoamine oxidases A and Bin vitro in rat brain homogenates.3.After administration (0.1 mmol/kg, ip), 4-fluorotranylcypromine attained higher brain and liver levels and provided greater availability than did tranylcypromine after the injection of an equimolar amount.4.At the dose employed, theex vivo monoamine oxidases A and B inhibitory profiles in brain and liver over a 24-hr period following tranylcypromine and 4-fluorotranylcypromine treatment were not different from each other.5.Although the drugs had similar effects on inhibition of brain MAOex vivo, they differed from one another at several time intervals in the increases in concentrations of 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine produced in brain.6.In conclusion, fluorination of tranylcypromine in the 4 position of the phenyl ring produced a drug which was more potent than the parent drug at inhibiting MAOin vitro and attained higher levels in brain than did tranylcypromine itself after intraperitoneal injection of equimolar amounts of the drugs. 4-Fluorotranylcypromine increased the concentrations of trace amines, catecholamines, and 5-hydroxytryptamine in brain at most time intervals following intraperitoneal injection, and at some time intervals there were differences from tranylcypromine with regard to the amine concentrations produced.

Sensitive high-performance liquid chromatographic assay for norfloxacin utilizing fluorescence detection.

A rapid, sensitive and reproducible reversed-phase high-performance liquid chromatographic assay was developed for the determination of norfloxacin. Following protein precipitation with 10% trichloroacetic acid, norfloxacin and the internal standard enoxacin were extracted from plasma with chloroform, dried and reconstituted in the mobile phase. The chromatographic separation of norfloxacin and the internal standard enoxacin was achieved on a C8 column with fluorescence detection set at 280 and 418 nm for excitation and emission, respectively. The peaks with a resolution factor greater than 1.5 were free from interferences. Excellent linearity (r2 > or = 0.998) was observed over the concentration range 0.025-5.0 micrograms/ml in plasma. The inter-assay variability was 13.6% or less at all concentrations examined. The suitability of the assay for pharmacokinetic studies was determined by measuring norfloxacin concentration in rat plasma after administration of a single intravenous 10 mg/kg dose.

SYNTHETIC STUDIES TOWARDS TAXOL ANALOGS : CHEMOSELECTIVE CLEAVAGE OF C-5 CINNAMOYL GROUP IN TAXANE GROUP OF DITERPENOIDS WITH HYDROXYLAMINE

Abstract Taxane group of diterpenoids 2 and 3 which possess cinnamoyl moiety at C-5 position underwent selective cleavage to C-5 hydroxy compounds 4 and 5 on treatment with hydroxylamine. The resulting compounds were characterised based on their spectral data.