Donna Lee Romero

The benzylthio-pyrimidine U-31,355, a potent inhibitor of HIV-1 reverse transcriptase

U-31,355, or 4-amino-2-(benzylthio)-6-chloropyrimidine is an inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and possesses anti-HIV activity in HIV-1-infected lymphocytes grown in tissue culture. The compound acts as a specific inhibitor of the RNA-directed DNA polymerase function of HIV-1RT and does not impair the functions of the DNA-catalyzed DNA polymerase or the Rnase H of the enzyme. Kinetic studies were carried out to elucidate the mechanism of RT inhibition by U-31,355. The data were analyzed using Briggs-Haldane kinetics, assuming that the reaction is ordered in that the template:primer binds to the enzyme first, followed by the addition of dNTP, and that the polymerase is a processive enzyme. Based on these assumptions, a velocity equation was derived that allows the calculation of all the essential forward and backward rate constants for the reactions occurring between the enzyme, its substrates, and the inhibitor. The results obtained indicate that U-31,355 acts as a mixed inhibitor with respect to the template:primer and dNTP binding sites associated with the RNA-directed DNA polymerase domain of the enzyme. The inhibitor possessed a significantly higher binding affinity for the enzyme-substrate complexes, than for the free enzyme and consequently did not directly affect the functions of the substrate binding sites. Therefore, U-31,355 appears to impair an event occurring after the formation of the enzyme-substrate complexes, which involves either inhibition of the phosphoester bond formation or translocation of the enzyme relative to its template:primer following the formation of the ester bond. Moreover, the potency of U-31,355 depends on the base composition of the template:primer in that the inhibitor showed a much higher binding affinity for the enzyme-poly (rC):(dG)10 complexes than for the poly (rA):(dT)10 complexes.

The palladium catalyzed allylic alkylation of bis(trimethylsilyl) substituted propenyl acetates or carbonates in the presence of chiral ligands

Abstract Palladium catalyzed asymmetric allylic alkylations of a bis(trimethylsilyl) substituted propenyl acetate and carbonate were investigated using various chiral ligands and reaction conditions. The best enantioselectivity (86% e.e.) was obtained with the substrate 1-phenyl-3,3-bis(trimethylsilyl)propenyl carbonate 13 and the chiral oxazoline ligand 4c.

Synthesis of N-substituted 1,2,5-thiadiazolidine and 1,2,6-thiadiazinane 1,1-dioxides from primary amines

Abstract Alkyl and aryl N -substituted 1,2,5-thiadiazolidine and 1,2,6-thiadiazinane 1,1-dioxides 6 were synthesized in good yields from the reaction of sulfuryl chloride with 2-chloroethylamine or 3-chloropropylamine hydrochlorides, respectively, followed by treatment with a primary amine and triethylamine, and ring closure with K 2 CO 3 in DMSO.

Bacterial translation inhibitors, 1-acylindazol-3-ols as anthranilic acid mimics.

The discovery and initial optimization of a novel anthranilic acid derived class of antibacterial agents has been described in a recent series of papers. This paper describes the discovery of 1-acylindazol-3-ols as a novel bioisostere of an anthranilic acid. The synthesis and structure-activity relationships of the indazol bioisosteres are described herein.

Design and synthesis of a conformationally constrained analog of the bis(heteroaryl)piperazine (BHAP) HIV-1 reverse transcriptase inhibitor atevirdine

Abstract The design and synthesis of a novel conformationally constrained spiro analog of the BHAP class of HIV-1 reverse transcriptase inhibitors, based on the molecular modeling and the X-ray crystal structure of the clinical candidate atevirdine, is described.

Discovery and Development of the BHAP Nonnucleoside Reverse Transcriptase Inhibitor Delavirdine Mesylate

A program directed toward the discovery and development of novel and efficacious nonnucleoside HIV RT inhibitors involved a close collaboration between medicinal chemists and biologists and their colleagues in drug delivery, drug metabolism, and drug safety. An initial clinical candidate, PNU-87201E (atevirdine mesylate), helped pave the way for a far more potent and effective second-generation BHAP candidate, delavirdine mesylate (PNU-90152T). Emerging results from clinical trials suggest that delavirdine mesylate is a promising new agent for the treatment of AIDS.

A novel method for the t-butylation of aromatic amines

Abstract A new method for the synthesis of t -butylamines from amines in two steps via α-aminonitriles, and its application to various arylamines is discussed.