Synthesis and Anti-hiv Activity of D- and L-thietanose Nucleosides.
From: College of Pharmacy, The University of Georgia, Athens, Georgia 30602, USA.
Journal of medicinal chemistry
- Publish Date: Mar 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 5
- Pages: 1635-47
- Medium: Print
- Language: English
- Citation (JAMA): Choo Hyunah, Chen Xin, Yadav Vikas, et al. Synthesis and Anti-hiv Activity of D- and L-thietanose Nucleosides.. J. Med. Chem. Mar 2006;49:1635-47
Abstract
Various D- and L-thietanose nucleosides were synthesized from D- and L-xylose. The four-membered thietane ring was efficiently synthesized by the cyclization of 1-thioacetyl-3-mesylate (4/38) under basic conditions. Condensation with various heterocyclic bases was conducted via Pummerer-type rearrangement to afford various nucleoside derivatives. Among the synthesized nucleosides, D-uridine (23), D-cytidine (24), D-5-fluorocytidine (25), and L-cytidine (52) analogues showed moderate anti-HIV activity, with EC50 = 6.9, 1.3, 5.8, and 14.1 microM, respectively. However, these four nucleoside analogues are cytotoxic in peripheral blood mononuclear and CEM cells. The other nucleosides are neither active nor cytotoxic. Interestingly, the oxetanocin A analogue 33 was not active. Comparison of the minimized reverse transcriptases (RTs) complexed with the corresponding triphosphates of the cytidine analogue 24 and the adenosine analogue 33 by molecular modeling studies showed that there is no difference in the binding mode of the triphosphate of the cytidine analogue 24 to the active site of HIV-1 RT from that of the triphosphate of the adenosine analogue 33. Modeling studies on the initial monophosphorylation step by deoxycytidine kinase showed that the catalytic efficiency of phosphorylation through a nucleophilic attack of the 4’-hydroxyl group of thietanose on the gamma-phosphate of ATP is diminished in the case of L-cytidine analogue (52) due to the increased distance between the 4’-hydroxyl group and the gamma-phosphate.
Mesh Headings (Keywords): Adenine, Anti-HIV Agents, Binding Sites, Catalysis, Cell Line, Deoxycytidine Kinase, HIV Reverse Transcriptase, HIV-1, Humans, Models, Molecular, Molecular Conformation, Phosphorylation, Pyrimidine Nucleosides, Stereoisomerism, Structure-Activity Relationship, Sulfides, Xylose
Check for Full Text / PubMed Unique Identifier (PMID): 16509580
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