New 3‘-Azido-3‘-deoxythymidin-5‘-yl O-(ω-Hydroxyalkyl) Carbonate Prodrugs:  Synthesis and Anti-HIV Evaluation

• Published in: Journal of medicinal chemistry Vol. 44; no. 5; pp. 777 - 786
• Main Authors: Vlieghe, Patrick, Bihel, Frédéric, Clerc, Thierry, Pannecouque, Christophe, Witvrouw, Myriam, De Clercq, Erik, Salles, Jean-Pierre, Chermann, Jean-Claude, Kraus, Jean-Louis
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-03-2001
• Subjects: Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Carbamates - chemical synthesis; Carbamates - chemistry; Carbamates - metabolism; Carbamates - pharmacology; Cell Line; Chemical Sciences; Drug Stability; HIV-1 - drug effects; Humans; Hydrolysis; Magnetic Resonance Spectroscopy; Medical sciences; Medicinal Chemistry; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacology; Structure-Activity Relationship; Zidovudine - analogs & derivatives; Zidovudine - chemical synthesis; Zidovudine - chemistry; Zidovudine - metabolism; Zidovudine - pharmacology; Organic carbonate; HIV-1 virus; Organic azide; Retroviridae; Lipophily; Prodrug; Lentivirus; Organic carbamate; In vitro; Virus; Hydrolysis resistance; Structure activity relation; Dideoxynucleoside; Antiviral; Human immunodeficiency virus; Chemical synthesis; Acylate; Pyrimidine nucleoside; Zidovudine
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm001033s

Prodrugs of zidovudine (AZT) have been synthesized in an effort to enhance its uptake by HIV-1 infected cells and its anti-HIV activity. The 5‘-OH function of AZT was functionalized with various enzymatically labile alkyl groups using specific procedures. The prodrug moieties included 5‘-O-carbonate, 5‘-O-carbamate, and 5‘-O-ester. Analogues of the 3‘-azido-3‘-deoxythymidin-5‘-yl O-(ω-hydroxyalkyl) carbonate series were particularly interesting since they were rearranged through an intramolecular cyclic process during their enzymatic hydrolysis. Evidence of this prodrug rearrangement was confirmed by comparison of the serum half-lives of 5‘-O-carbonate prodrugs with their corresponding 5‘-O-ester- and 5‘-O-carbamate-AZT prodrugs. Interestingly, the anti-HIV-1 activities (EC50) of 3‘-azido-3‘-deoxythymidin-5‘-yl O-(4-hydroxybutyl) carbonate 10 in acutely infected MT-4 cells and in peripheral blood mononuclear cells (PBMCs) were 0.5 nM and 0.78 nM, respectively. Compound 10 was 30 to 50 times more potent than its parent drug AZT. Our results suggest that the specific intramolecular rearrangement associated with the 3‘-azido-3‘-deoxythymidin-5‘-yl O-(ω-hydroxyalkyl) carbonate prodrugs could explain the remarkable anti-HIV-1 activity of this series of AZT prodrugs. Prodrug 10 may therefore have better clinical potential than AZT for the treatment of AIDS.