title: Novel 4'-substituted stavudine analog with improved anti-human immunodeficiency virus activity and decreased cytotoxicity.
abstract: The antiviral drug 2',3'-didehydro-3'-deoxythymidine (D4T; also know as stavudine and Zerit), which is used against human immunodeficiency virus (HIV), causes delayed toxicity (peripheral neuropathy) in long-term use. After examining a series of 2',3'-didehydro-3'-deoxy-4'-substituted thymidine (4'-substituted D4T) analogs, 4'-ethynyl D4T was found to have a fivefold-better antiviral effect and to cause less cellular and mitochondrial toxicity than D4T. The antiviral activity of this compound can be reversed by dThd but not by dCyd. The compound acted synergistically with beta-L-2',3'-deoxy-3'-thiacytidine (also known as lamivudine) and beta-L-2',3'-dideoxy-2',3'-didehydro-5-fluorocytidine (also known as elvucitabine) and additively with 2',3'-dideoxyinosine (also known as didanosine and Videx) and 3'-azido-3'-deoxythymidine (also known as Retovir and zidovudine) against HIV. 4'-Ethynyl D4T is phosphorylated by purified human thymidine kinase 1 (TK-1) from CEM cells with a faster relative V(max) and a lower K(m) value than D4T. The efficiency of TK-1 in the phosphorylation of 4'-ethynyl D4T is fourfold better than that of D4T. While D4T is broken down by the catabolic enzyme thymidine phosphorylase, the level of breakdown of 4'-ethynyl D4T was below detection. Since 4'-ethynyl D4T has increased anti-HIV activity and decreased toxicity and interacts favorably with other currently used anti-HIV drugs, it should be considered for further development as an anti-HIV drug.
authors.affiliation: Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA.
authors.forename: Ginger E
authors.initials: GE
authors.lastname: Dutschman
authors.forename: Susan P
authors.initials: SP
authors.lastname: Grill
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Gullen
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Haraguchi
authors.forename: Shingo
authors.initials: S
authors.lastname: Takeda
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Tanaka
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
authors.forename: Yung-Chi
authors.initials: YC
authors.lastname: Cheng
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004272:DNA, Mitochondrial / Q000235:genetics; D004357:Drug Synergism; D006801:Humans; D007700:Kinetics; D010766:Phosphorylation; D018119:Stavudine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D018119:Stavudine; D013939:Thymidine Phosphorylase; D013937:Thymidine Kinase