title: Phosphoramidate and phosphate prodrugs of (-)-beta-D-(2R,4R)-dioxolane-thymine: synthesis, anti-HIV activity and stability studies.
abstract: A series of phosphoramidate and phosphate prodrugs of DOT were synthesized via dichlorophosphate or H-phosphonate chemistry and evaluated for their anti-HIV activity against LAI M184V mutants in PBM cells as well as for their cytotoxicity. The antiviral and cytotoxic profiles of the prodrugs were compared with that of the parent compound (DOT), and it was found that four aryl phosphoramidates 5, 18, 20, and 26 showed a significant enhancement (8- to 12-fold) in anti-HIV activity without cytotoxicity. Chemical stability of these prodrugs was evaluated in phosphate buffer at pH values of biological relevance (i.e., pH 2.0 and 7.4). Enzymatic hydrolysis was also studied in esterase or lipase in buffer solution. Chemical stability studies indicate that the phosphoramidates have good chemical stability at pH 2.0 and at pH 7.4 phosphate buffer. Phosphoramidate prodrugs were hydrolyzed in vitro by esterase or lipase and found to be better substrates for lipases than for esterases. 1,3-Diol cyclic phosphates showed potent anti-HIV activity without increasing the cytotoxicity compared with that of DOT and have good chemical and enzymatic stability. Long-chain lipid phosphates, although showed potent anti-HIV activity, exhibited increased cytotoxicity.
authors.affiliation: The University of Georgia, College of Pharmacy, Athens, GA 30602, USA.
authors.forename: Yuzeng
authors.initials: Y
authors.lastname: Liang
authors.forename: Janarthanan
authors.initials: J
authors.lastname: Narayanasamy
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: Chung K
authors.initials: CK
authors.lastname: Chu
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002522:Chlorocebus aethiops; D004148:Dioxolanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D006678:HIV / Q000187:drug effects*; D006801:Humans; D006868:Hydrolysis; D007700:Kinetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D010710:Phosphates / Q000737:chemistry*; D010756:Phosphoric Acids / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014709:Vero Cells / Q000187:drug effects
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D004148:Dioxolanes; D010710:Phosphates; D010756:Phosphoric Acids; D011355:Prodrugs; C511146:dioxolane-thymine; C011067:phosphoramidic acid; D013941:Thymine