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

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) analogues. 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).

SUBMITTER: Pemmaraju B

PROVIDER: S-EPMC4001930 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Synthesis and Biological Evaluation of 5'-<i>O</i>-Dicarboxylic Fatty Acyl Monoester Derivatives of Anti-HIV Nucleoside Reverse Transcriptase Inhibitors.

Pemmaraju Bhanu B Agarwal Hitesh K HK Oh Donghoon D Buckheit Karen W KW Buckheit Robert W RW Tiwari Rakesh R Parang Keykavous K

Tetrahedron letters 20140301 12

A number of 5'-<i>O</i>-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) analogues. The compounds were evaluated for their anti-HIV activity. Three different fatty acids with varying chain length of suberic acid (octa ...[more]

PMID: 24791029

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Project description:BackgroundDolutegravir (DTG) is a once-daily unboosted second-generation integrase-inhibitor that along with two nucleoside reverse transcriptase inhibitors is one of several regimens recommended by the United States, United Kingdom and European Union for first-line antiretroviral treatment of people with HIV infection. Our objective was to review the evidence for the efficacy and safety of DTG-based first-line regimens compared to efavirenz (EFV)-based regimens.MethodsWe conducted a systematic review. We comprehensively searched a range of databases as well as conference abstracts and a trials registry. We used Cochrane methods in screening and data collection and assessed each study's risk of bias with the Cochrane tool. We meta-analyzed data using a fixed-effects model. We used GRADE to assess evidence quality.ResultsFrom 492 search results, we identified two randomized controlled trials, reported in five peer-reviewed articles and one conference abstract. One trial tested two DTG-based regimens (DTG + abacavir (ABC) + lamivudine (3TC) or DTG + tenofovir + emtricitabine) against an EFV-based regimen (EFV+ ABC+3TC). The other trial tested DTG+ABC+3TC against EFV+ABC+3TC. In meta-analysis, DTG-containing regimens were superior to EFV-containing regimens at 48 weeks and at 96 weeks (RR = 1.10, 95% CI 1.04-1.16; and RR = 1.12, 95% CI 1.04-1.21, respectively). In one trial, the DTG-containing regimen was superior at 144 weeks (RR = 1.13, 95% CI 1.02-1.24). DTG-containing regimens were superior in reducing treatment discontinuation compared to those containing EFV at 96 weeks and at 144 weeks (RR = 0.27, 95% CI 0.15-0.50; and RR = 0.28, 95% CI 0.16-0.48, respectively). Risk of serious adverse events was similar in each regimen at 96 weeks (RR = 1.15, 95% CI 0.80-1.63) and 144 weeks (RR = 0.93, 95% CI 0.68-1.29). Risk of bias was moderate overall, as was GRADE evidence quality.ConclusionsDTG-based regimens should be considered in future World Health Organization guidelines for initial HIV treatment.

Dataset Information

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

Publications

Synthesis and Biological Evaluation of 5'-<i>O</i>-Dicarboxylic Fatty Acyl Monoester Derivatives of Anti-HIV Nucleoside Reverse Transcriptase Inhibitors.

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

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Synthesis and Biological Evaluation of 5'-&lt;i&gt;O&lt;/i&gt;-Dicarboxylic Fatty Acyl Monoester Derivatives of Anti-HIV Nucleoside Reverse Transcriptase Inhibitors.

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OmicsDI is part of the ELIXIR infrastructure

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Synthesis and Biological Evaluation of 5'-<i>O</i>-Dicarboxylic Fatty Acyl Monoester Derivatives of Anti-HIV Nucleoside Reverse Transcriptase Inhibitors.