Jay Brownell

Synthesis and activity of γ-(L-γ-azaglutamyl)-S-(p-bromobenzyl)-L-cysteinylglycine: A metabolically stable inhibitor of glyoxalase I

Abstract The inhibition of glyoxalase I enzyme to increase cellular levels of methylglyoxal has been developed as a rationale for the production of anticancer agents. Synthesis of a peptidomimetic analog of the previously prepared potent glyoxalase inhibitor, S-( p -bromobenzyl)glutathione (PBBG), was accomplished by inserting a urea linkage, NHCONH, to replace the γ-glutamyl peptide bond. Thus, the target compound, γ -(L-γ-azaglutamyl)-S-( p -bromobenzyl)-L-cysteinylglycine 6 , was a potent inhibitor of glyoxalase I with almost no loss of activity when compared to PBBG. However, unlike PBBG, 6 was completely resistant to enzymatic degradation by kidney homogenate or by purified γ-glutamyltranspeptidase enzyme.

6-Deoxycarbovir: A Xanthine Oxidase Activated Prodrug of Carbovir

Abstract (-)-(cis)-4-(2-Amino-9H-purin-9-yl)-2-cyclopentenyl carbinol (6-deoxycarbovir) was prepared in order to evaluate prodrug approaches to increased bioavailability of the anti-HIV agent, (-)-carbovir. Incubation experiments demonstrated that 6-deoxycarbovir was rapidly converted to (-)-carbovir by the enzyme, xanthine oxidase. Since xanthine oxidase activity is present in both the intestine and liver, a high first pass conversion to carbovir would be expected in vivo.

Carbovir: A Carbocyclic Nucleoside with Potent and Selective Activity Against Human Immunodeficiency Virus (HIV) in Vitro

Abstract Carbocyclic 2′, 3′-didehydro-2′,3′-dideoxyquanosine (carbovir), a novel nucleoside analog, emerged as a potent and selective anti-HIV agent from a primary screen of a large number of carbocyclic nucleosides.1 Carbovir inhibited the infectivity and replication of HIV in T-cells at concentrations 200 to 400-fold below toxicity to host cells. Carbovir was also evaluated for its Inhibitory effects on the expression of viral antigen in HIV-infected CEM cells. Production of p 24 core antigen at optimal inhibitory concentrations of the antiviral agents indicated comparable results for AZT, ddA and carbovir.

Inhibition of protein biosynthesis: The first active sparsomycin analog

Abstract A (dl) S -deoxo- S -propyl sparsomycin analog has been prepared and examined as an inhibitor of the peptidyl transferase reaction with bacterial ribosomes. A double reciprocal plot and Dixon analysis indicate that the sparsomycin analogy is a competitive inhibitor of phenylalanyl-puromycin formation. The inactivity of the L-isomer has established that the chiral carbon of sparsomycin analogs must be identical with the chirality of D-cysteinol for ribosomal binding.