title: Structure-activity relationships of beta-D-(2S,5R)- and alpha-D-(2S,5S)-1,3-oxathiolanyl nucleosides as potential anti-HIV agents.
abstract: The beta-D-(2S,5R)- and alpha-D-(2S,5S)-1,3-oxathiolanylpyrimidine and -purine nucleosides with natural nucleoside configuration were synthesized and evaluated against HIV-1 in human peripheral blood mononuclear (PBM) cells. The key intermediate 14, which was utilized for the synthesis of various nucleosides, was synthesized from D-mannose or D-galactose. Condensation of the acetate 14 with thymine, uracil, cytosine, and 5-substituted uracils and cytosines gave various pyrimidine nucleosides. The acetate 14 was also condensed with 6-chloropurine and 6-chloro-2-fluoropurine which were converted to various purine nucleosides. In the case of thymine, uracil, and 5-substituted uracil derivatives, most of the compounds did not exhibit any significant anti-HIV activity except 5-fluorouracil (alpha-isomer) derivative 55. Among 5-substituted cytosine analogues, 5-bromocytosine derivative (beta-isomer) 68 was found to be the most potent anti-HIV agent. In the case of purine derivatives, inosine analogue (beta-isomer) 78 was found to be the most potent anti-HIV agent in the 6-substituted purines and 2-amino-6-chloropurine derivative (beta-isomer) 90 showed the most potent activity in the 2,6-disubstituted purine series. The beta-isomers of 6-chloropurine (74), adenine (76), and N6-methyladenine (77) derivatives showed similar potencies against HIV-1, and the corresponding alpha-isomers also exhibited significant anti-HIV activity, although they were generally less potent than the beta-isomers.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Georgia, Athens 30602.
authors.forename: L S
authors.initials: LS
authors.lastname: Jeong
authors.forename: R F
authors.initials: RF
authors.lastname: Schinazi
authors.forename: J W
authors.initials: JW
authors.lastname: Beach
authors.forename: H O
authors.initials: HO
authors.lastname: Kim
authors.forename: K
authors.initials: K
authors.lastname: Shanmuganathan
authors.forename: S
authors.initials: S
authors.lastname: Nampalli
authors.forename: M W
authors.initials: MW
authors.lastname: Chun
authors.forename: W K
authors.initials: WK
authors.lastname: Chung
authors.forename: B G
authors.initials: BG
authors.lastname: Choi
authors.forename: C K
authors.initials: CK
authors.lastname: Chu
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003596:Cytosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007042:Hypoxanthines / Q000138:chemical synthesis* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000382:microbiology; D008968:Molecular Conformation; D015394:Molecular Structure; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014498:Uracil / Q000031:analogs & derivatives
chemical_list: D000998:Antiviral Agents; D007042:Hypoxanthines; D011687:Purines; C083415:5-bromo-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)cytosine; C083416:9-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)hypoxanthine; C083417:2-amino-6-chloro-9-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)purine; D014498:Uracil; D003596:Cytosine