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

• Published in: Journal of medicinal chemistry 1993-01, Vol.36 (2), p.181-195
• Main Authors: Jeong, Lak S, Schinazi, Raymond F, Beach, J. Warren, Kim, Hea O, Nampalli, Satyanarayana, Shanmuganathan, Kirupathevy, Alves, Antonio J, McMillan, Angela, Chu, Chung K, Mathis, Rodney
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemical synthesis; Blood - drug effects; Blood - microbiology; Carbohydrates. Nucleosides and nucleotides; Cells, Cultured; Chemistry; Exact sciences and technology; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - chemistry; Heterocyclic Compounds - pharmacology; HIV-1 - drug effects; human immunodeficiency virus 1; Humans; Magnetic Resonance Spectroscopy; Nucleosides, nucleotides and oligonucleotides; Organic chemistry; Preparations and properties; Purine Nucleosides - chemical synthesis; Purine Nucleosides - chemistry; Purine Nucleosides - pharmacology; Pyrimidine Nucleosides - chemical synthesis; Pyrimidine Nucleosides - chemistry; Pyrimidine Nucleosides - pharmacology; Structure-Activity Relationship; Thiophenes
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00054a001

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.