Synthesis and Anti-HIV Activities of Suramin Conjugates of 3'-Fluoro- 2',3'-dideoxythymidine and 3'-Azido-2',3'-dideoxythymidine

Hitesh K. Agarwal, Gustavo F. Doncel, Keykavous Parang

Abstract

Conjugates between suramin, a polyanionic naphthalene sulfonate derivative, and nucleoside reverse transcriptase inhibitors (NRTIs), 3'-azido-2',3'-dideoxythymidine (AZT) and 3'-fluoro-2',3'-dideoxythymidine (FLT), were designed to create an antiretroviral with multiple mechanisms of action that could be developed as an anti-HIV topical microbicide candidate. The anti-HIV activity of these conjugates was compared with that of suramin and the corresponding physical mixtures of suramin and nucleosides. The conjugates were synthesized as sulfonate esters by reaction of suramin with the nucleoside analogs in the presence of phosphorus pentoxide, and were tested against X4 and R5 labadapted strains of HIV-1. Suramin conjugates of AZT (EC50= 19.4 μg/ml) and FLT (EC50= 23.6 μg/ml) demonstrated improved anti-HIV activity against X4 strain of virus by 2.5 and 2 fold, respectively, when compared with suramin. The physical mixtures of suramin with nucleosides significantly improved anti-HIV activity of suramin against X4 strain by more than 55 fold.

Keywords: Anti-HIV, AZT, FLT, nucleoside, reverse transcriptase, suramin, polyanionic naphthalene sulfonate, polyanionic polymers, virus