Synthesis and Biological Evaluation of 5′-O-Fatty Acyl Ester Derivatives of 3′-Fluoro-2′,3′-dideoxythymidine as Potential Anti-HIV Microbicides

Authors

Hitesh Agarwal, South University
Bhupender S. Chhikara, University of Rhode Island
Guofeng Ye, University of Rhode Island
Sitaram Bhavaraju, University of Rhode Island
Ajay Dixit, University of Rhode Island
Anil Kumar, University of Rhode Island
Gustavo F. Doncel, Eastern Virginia Medical School
Keykavous Parang, Chapman UniversityFollow

Document Type

Article

Publication Date

5-23-2022

Abstract

A number of 5′-O-fatty acyl derivatives of 3′-fluoro-2′,3′-dideoxythymidine (FLT, 1) were synthesized. These conjugates were evaluated for their potential as topical microbicides with anti-HIV activity against cell-free (X4 and R5), cell-associated, and multidrug-resistant viruses. Compared to FLT and 3′-azido-2′,3′-dideoxythymidine (AZT), 5′-O-(12-azidododecanoyl) (5), 5′-O-myristoyl (6), and 5′-O-(12-thioethyldodecanoyl) (8) derivatives of FLT were found to be more active against both cell-free viruses (lymphocytotropic and monocytotropic strains) with EC₅₀ values of 0.4 μM, 1.1 μM, and <0.2 μM, respectively, as well as cell-associated virus with EC₅₀ values of 12.6, 6.4, and 2.3 μM, respectively. Conjugates 5, 6, and 8 exhibited >4 and >30 times better antiviral index than FLT and AZT, respectively. Conjugates 5 and 8 were significantly more potent than FLT against many multidrug-resistant strains. A comparison of the anti-HIV activity with the corresponding non-hydrolyzable ether conjugates suggested that ester hydrolysis to FLT and fatty acids is critical to enable anti-HIV activity. Cellular uptake studies were conducted using fluorescent derivatives of FLT attached with 5(6)-carboxyfluorescein through either β-alanine (23) or 12-aminododecanoic acid (24) spacers. The lipophilic fluorescent analog with a long chain (24) showed more than 12 times higher cellular uptake profile than the fluorescent analog with a short chain (23). These studies further confirmed that the attachment of fatty acids improved the cellular uptake of nucleoside conjugates. In addition, 5, 6, and 8 were the least cytotoxic and did not alter vaginal cell and sperm viability compared to the positive control, a commercial topical spermicide (N-9), which significantly decreased sperm and vaginal cell viability inducing the generation of proinflammatory cytokines.

Comments

This article was originally published in Molecules, volume 27, in 2022. https://doi.org/10.3390/molecules27103352

Recommended Citation

Agarwal, H.K.; Chhikara, B.S.; Ye, G.; Bhavaraju, S.; Dixit, A.; Kumar, A.; Doncel, G.F.; Parang, K. Synthesis and Biological Evaluation of 5′ -O-Fatty Acyl Ester Derivatives of 3′ -Fluoro-2′ ,3′ -Dideoxythymidine as Potential Anti-HIV Microbicides. Molecules 2022, 27, 3352. https://doi.org/10.3390/molecules27103352

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