5 '-O-Aliphatic and amino acid ester prodrugs of (-)-beta-D-(2R,4R)-dioxolane-thymine (DOT): Synthesis, anti-HIV activity, cytotoxicity and stability studies

• Type of Material: Article
• Authors: Yuzeng Liang, University of Georgia; Ashoke Sharon, University of Georgia; Jason P. Grier, Emory University; Kimberly L. Rapp, Emory University; Raymond Schinazi, Emory University; Chung K. Chu, University of Georgia
• Language: English
• Date: 2009-02-01
• Publisher: PERGAMON-ELSEVIER SCIENCE LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2009
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmc.2008.10.078
• Title of Journal or Parent Work: BIOORGANIC & MEDICINAL CHEMISTRY
• Volume: 17
• Issue: 3
• Start Page: 1404
• End Page: 1409
• Grant/Funding Information: This research was supported by the US Public Health Service Grant 4R37-AI25899 and by the Department of Veterans Affairs.
• Keywords: Pharmacology & Pharmacy; Anti-HIV activity; MECHANISM; Dioxolane thymine (DOT); NUCLEOSIDES; PHARMACOKINETICS; DIOXOLANE; Physical Sciences; IMMUNODEFICIENCY-VIRUS TYPE-1; ASYMMETRIC-SYNTHESIS; Nucleoside prodrugs; Biochemistry & Molecular Biology; RHESUS-MONKEYS; 5 '-O-aliphatic acid esters; Science & Technology; Chemistry, Organic; AGENTS; Chemistry; 5 '-O-amino acid esters; ORAL ABSORPTION; Life Sciences & Biomedicine; LYMPHOCYTES; Chemistry, Medicinal
• Research Categories: Chemistry, Biochemistry; Biology, Virology; Chemistry, General

Abstract

A series of (-)-β-d-(2R,4R)-dioxolane-thymine-5′-O-aliphatic acid esters as well as amino acid esters were synthesized as prodrugs of (-)-β-d-(2R,4R)-dioxolane-thymine (DOT). The compounds were evaluated for anti-HIV activity against HIV-1LAI in human peripheral blood mononuclear (PBM) cells as well as for their cytotoxicity in PBM, CEM and Vero cells. Improved anti-HIV potency in vitro was observed for the compound 2-4 (5′-O-aliphatic acid esters) without increase in cytotoxicity in comparison to the parent drug. Chemical and enzymatic hydrolysis of the prodrugs was also studied, in which the prodrugs exhibited good chemical stability with the half-lives from 3 h to 54 h at pH 2.0 and 7.4 phosphate buffer. However, the prodrugs were relatively labile to porcine esterase with the half-lives from 12.3 to 48.0 min. © 2008 Elsevier Ltd. All rights reserved.