title: Asymmetric synthesis and biological evaluation of beta-L-(2R,5S)- and alpha-L-(2R,5R)-1,3-oxathiolane-pyrimidine and -purine nucleosides as potential anti-HIV agents.
abstract: In order to study the structure-activity relationships of L-oxathiolanyl nucleosides as potential anti-HIV agents, a series of enantiomerically pure L-oxathiolanyl pyrimidine and purine nucleosides were synthesized and evaluated for anti-HIV-1 activity in human peripheral blood mononuclear (PBM) cells. The key intermediate 8 was synthesized starting from L-gulose via 1,6-thioanhydro-L-gulopyranose. The acetate 8 was condensed with thymine, 5-substituted uracils and cytosines, 6-chloropurine, and 6-chloro-2-fluoropurine to give pyrimidine and purine nucleosides. Upon evaluation of these final nucleosides, the 5-fluorocytosine derivative 51 was found to be the most potent compound among those tested. In the case of 5-substituted cytosine analogues, the antiviral potency was found to be in the following decreasing order: cytosine (beta-isomer) > 5-iodocytosine (beta-isomer) > 5-fluorocytosine (alpha-isomer) > 5-methylcytosine (alpha-isomer) > 5-methylcytosine (beta-isomer) > 5-bromocytosine (beta-isomer) > 5-chlorocytosine (beta-isomer). Among the thymine, uracil, and 5-substituted uracil derivatives, thymine (alpha-isomer) and uracil (beta-isomer) derivatives exhibited moderate anti-HIV activity. In the purine series, the antiviral potency is found to be in the following decreasing order: adenine (beta-isomer) > 6-chloropurine (beta-isomer) > 6-chloropurine (alpha-isomer) > 2-NH2-6-Cl-purine (beta-isomer) > guanine (beta-isomer) > N6-methyladenine (alpha-isomer) > N6-methyladenine (beta-isomer). The cytotoxicity was also determined in human PBM cells as well as Vero cells. None of the synthesized nucleosides was toxic up to 100 microM in PBM cells.
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: S
authors.initials: S
authors.lastname: Nampalli
authors.forename: K
authors.initials: K
authors.lastname: Shanmuganathan
authors.forename: A J
authors.initials: AJ
authors.lastname: Alves
authors.forename: A
authors.initials: A
authors.lastname: McMillan
authors.forename: C K
authors.initials: CK
authors.lastname: Chu
authors.forename: R
authors.initials: R
authors.lastname: Mathis
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis*; D001769:Blood / Q000187:drug effects / Q000382:microbiology; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes
chemical_list: D000998:Antiviral Agents; D006571:Heterocyclic Compounds; D011684:Purine Nucleosides; D011741:Pyrimidine Nucleosides; D013876:Thiophenes; C013177:1,3-oxathiolane