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).

Design, Synthesis, Antiviral Activity, and Pre-Formulation Development of Poly-L-Arginine-Fatty Acyl Derivatives of Nucleoside Reverse Transcriptase Inhibitors

“…6–14 These ester conjugates and other reported by others 15,16 were expected to act as bifunctional agents through intracellular hydrolysis by esterases to release nucleoside reverse transcriptase inhibitors, and the fatty acids.…”

“…The development of theses polyarginine transporter molecules was inspired by the lead HIV-1 transcription transactivator protein (Tat) made up of repeated arginine and lysine residues. 14 This transporter is highly polar, readily soluble in water, and unlike other polar drugs travels across the lipid bilayer membrane. 17 Studies have shown that peptides with 6–20 arginine residues pass through the membrane showing rapid uptake across the membrane and into the nucleus without any signs of acute toxicity.…”

Zidovudine: Structural Modifications and Their Impact on Biological Activities and Pharmacokinetic Properties

“…The 5'-O-suberate derivative of AZT (compound 5) was found to be most potent (EC50 = 0.10 nM) in this series as evaluated in human peripheral blood mononuclear cells (PBMC). Compound 5 demonstrated prominent activity as compared to AZT and was also found to be less toxic (TC50 > 500 nM) [22]. Al Masoudi et al synthesized 5'-alkyl sulfonate derivatives of AZT.…”

Nucleosides and Nucleotides for the Treatment of Viral Diseases

“…[10][11][12] The second mechanism of action would result from the fatty acid inhibition of n-myristoyl transferase, which is involved in the myristoylation of several proteins in the HIV life cycle. [10][11][12] The second mechanism of action would result from the fatty acid inhibition of n-myristoyl transferase, which is involved in the myristoylation of several proteins in the HIV life cycle.…”