Synthesis and Biological Evaluation of 5′-O-Dicarboxylic Fatty Acyl Monoester Derivatives of Anti-HIV Nucleoside Reverse Transcriptase Inhibitors

Authors

Bhanu Pemmaraju, University of Rhode Island
Hitesh K. Agarwal, University of Rhode Island
Donghoon Oh, University of Rhode Island
Karen W. Buckheit
Robert W. Buckheit Jr.
Rakesh Tiwari, University of Rhode Island
Keykavous Parang, University of Rhode IslandFollow

Document Type

Article

Date of Original Version

2014

Department

Biomedical and Pharmaceutical Sciences

Abstract

A number of 5′-O-dicarboxylic fatty acyl monoester derivatives of 3′-azido-3′-deoxythymidine (zidovudine, AZT), 2′,3′-didehydro-2′,3′-dideoxythymidine (stavudine, d4T), and 3′-fluoro-3′-deoxythymidine (alovudine, FLT) were synthesized to improve the lipophilicity and potentially the cellular delivery of parent polar 2′,3′-dideoxynucleoside (ddN) analogs. The compounds were evaluated for their anti-HIV activity. Three different fatty acids with varying chain length of suberic acid (octanedioic acid), sebacic acid (decanedioic acid), and dodecanedioic acid were used for the conjugation with the nucleosides. The compounds were evaluated for anti-HIV activity and cytotoxicity. All dicarboxylic ester conjugates of nucleosides exhibited significantly higher anti-HIV activity than that of the corresponding parent nucleoside analogs. Among all the tested conjugates, 5′-O-suberate derivative of AZT (EC₅₀ = 0.10 nM) was found to be the most potent compound and showed 80-fold higher anti-HIV activity than AZT without any significant toxicity (TC₅₀ >500 nM).

Citation/Publisher Attribution

Pemmaraju, B., Agarwal, H. K., Oh, D., Buckhei, K. W., Buckheit, R. W., Jr.,
Tiwari, R., & Parang, K. (2014, February 10). Synthesis and biological evaluation of 5′-O-dicarboxylic fatty acyl monoester derivatives of anti-HIV nucleoside reverse transcriptase inhibitors. Tetrahedron Letters. http://dx.doi.org/10.1016/j.tetlet.2014.02.001

Available at: http://dx.doi.org/10.1016/j.tetlet.2014.02.001