title: Antiviral activities and cellular toxicities of modified 2',3'-dideoxy-2',3'-didehydrocytidine analogues.
abstract: The antiviral efficacies and cytotoxicities of 2',3'- and 4'-substituted 2',3'-didehydro-2',3'-dideoxycytidine analogs were evaluated. All compounds were tested (i) against a wild-type human immunodeficiency virus type 1 (HIV-1) isolate (strain xxBRU) and lamivudine-resistant HIV-1 isolates, (ii) for their abilities to inhibit hepatitis B virus (HBV) production in the inducible HepAD38 cell line, and (iii) for their abilities to inhibit bovine viral diarrhea virus (BVDV) production in acutely infected Madin-Darby bovine kidney cells. Some compounds demonstrated potent antiviral activities against the wild-type HIV-1 strain (range of 90% effective concentrations [EC(90)s], 0.14 to 5.2 micro M), but marked increases in EC(90)s were noted when the compounds were tested against the lamivudine-resistant HIV-1 strain (range of EC(90)s, 53 to >100 micro M). The beta-L-enantiomers of both classes of compounds were more potent than the corresponding beta-D-enantiomers. None of the compounds showed antiviral activity in the assay that determined their abilities to inhibit BVDV, while two compounds inhibited HBV production in HepAD38 cells (EC(90), 0.25 micro M). The compounds were essentially noncytotoxic in human peripheral blood mononuclear cells and HepG2 cells. No effect on mitochondrial DNA levels was observed after a 7-day incubation with the nucleoside analogs at 10 micro M. These studies demonstrate that (i) modification of the sugar ring of cytosine nucleoside analogs with a 4'-thia instead of an oxygen results in compounds with the ability to potently inhibit wild-type HIV-1 but with reduced potency against lamivudine-resistant virus and (ii) the antiviral activity of beta-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine against wild-type HIV-1 (EC(90), 0.08 micro M) and lamivudine-resistant HIV-1 (EC(90) = 0.15 micro M) is markedly reduced by introduction of a 3'-fluorine in the sugar (EC(90)s of compound 2a, 37.5 and 494 micro M, respectively).
authors.affiliation: Veterans Affairs Medical Center and Department of Pediatrics, Emory University School of Medicine, Decatur, Georgia 30033, USA.
authors.forename: Lieven J
authors.initials: LJ
authors.lastname: Stuyver
authors.forename: Stefania
authors.initials: S
authors.lastname: Lostia
authors.forename: Marjorie
authors.initials: M
authors.lastname: Adams
authors.forename: Judy S
authors.initials: JS
authors.lastname: Mathew
authors.forename: Balakrishna S
authors.initials: BS
authors.lastname: Pai
authors.forename: Jason
authors.initials: J
authors.lastname: Grier
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Tharnish
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Choi
authors.forename: Youhoon
authors.initials: Y
authors.lastname: Chong
authors.forename: Hyunah
authors.initials: H
authors.lastname: Choo
authors.forename: Chung K
authors.initials: CK
authors.lastname: Chu
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Otto
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000187:drug effects; D004279:DNA, Viral / Q000187:drug effects; D001908:Diarrhea Viruses, Bovine Viral / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects*; D006515:Hepatitis B virus / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D016047:Zalcitabine / Q000031:analogs & derivatives*
chemical_list: D000998:Antiviral Agents; D004272:DNA, Mitochondrial; D004279:DNA, Viral; D016047:Zalcitabine