title: Synthesis and anti-HIV activities of symmetrical dicarboxylate esters of dinucleoside reverse transcriptase inhibitors.
abstract: Three nucleoside analogues, 3'-fluoro-2',3'-dideoxythymidine (FLT), 3'-azido-2',3'-dideoxythymidine (AZT), and 2',3'-dideoxy-3'-thiacytidine (3TC) were conjugated with three different dicarboxylic acids to afford the long chain dicarboxylate esters of nucleosides. In general, dinucleoside ester conjugates of FLT and 3TC with long chain dicarboxylic acids exhibited higher anti-HIV activity than their parent nucleosides. Dodecanoate and tetradecanoate dinucleoside ester derivatives of FLT were found to be the most potent compounds with EC(50) values of 0.8-1.0 nM and 3-4 nM against HIV-1(US/92/727) and HIV-1(IIIB) cells, respectively. The anti-HIV activity of the 3TC conjugates containing long chain dicarboxylate diester (EC(50)=3-60 nM) was improved by 1.5-66 fold when compared to 3TC (EC(50)=90-200 nM). This study reveals that the symmetrical ester conjugation of dicarboxylic acids with a number of nucleosides results in conjugates with improved anti-HIV profile.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA.
authors.forename: Hitesh K
authors.initials: HK
authors.lastname: Agarwal
authors.forename: Karen W
authors.initials: KW
authors.lastname: Buckheit
authors.forename: Robert W
authors.initials: RW
authors.lastname: Buckheit
authors.forename: Keykavous
authors.initials: K
authors.lastname: Parang
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D003998:Dicarboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D003998:Dicarboxylic Acids; D015224:Dideoxynucleosides; D018894:Reverse Transcriptase Inhibitors