Synthesis and anti-HIV activity of D- and L-thietanose nucleosides.
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.
Choo
Hyunah
H
College of Pharmacy, The University of Georgia, Athens, Georgia 30602, USA.
Chen
Xin
X
Yadav
Vikas
V
Wang
Jianing
J
Schinazi
Raymond F
RF
Chu
Chung K
CK
D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002384:Catalysis; D002460:Cell Line; D003842:Deoxycytidine Kinase / Q000737:chemistry; D054303:HIV Reverse Transcriptase / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D010766:Phosphorylation; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014994:Xylose / Q000737:chemistry
D019380:Anti-HIV Agents; D011741:Pyrimidine Nucleosides; D013440:Sulfides; C051061:oxetanocin; D014994:Xylose; D003842:Deoxycytidine Kinase; D054303:HIV Reverse Transcriptase; D000225:Adenine