Solid-state and solution conformations of isotiazofurin: crystallographic, computational and 1H NMR studies.
Isotiazofurin (C9H12N2O5S, NSC363223) is a thiazole nucleoside analogue of the antitumour agent tiazofurin. The conformation of this analogue has been studied using a variety of experimental and computational techniques. The crystal and molecular structure of isotiazofurin has been determined using single-crystal X-ray diffraction techniques and refined to a conventional R value of 0.030 for all data. Conformational features conserved in other thiazole nucleoside structures are also observed in the solid-state structure of isotiazofurin. The C-glycosidic torsion angle remains in the anti conformation and the carboxamide amino group remains cis-planar to the ring nitrogen. Ab initio calculations at the RHF/321G*@321G* level and natural bond orbital analysis of the results suggest that the carboxamide cis-planar conformation observed in the solid state is maintained in solution. However, semiempirical calculations suggest that a syn conformation about the C-glycosidic bond is energetically favored. This is supported by 1H nuclear Overhauser enhancement (NOE) studies. Analyses of NOE results using both slow- and rapid-exchange models indicate a preference for the syn conformation in solution. Thus, the anti conformation observed in the crystal structures of isotiazofurin is not maintained by isotiazofurin in solution.
Department of Biophysics, University of Rochester Medical Center, New York 14642.
H
H
Li
S D
SD
Kennedy
B M
BM
Goldstein
D000970:Antineoplastic Agents / Q000737:chemistry*; D006860:Hydrogen Bonding; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D015394:Molecular Structure; D012254:Ribavirin / Q000031:analogs & derivatives / Q000737:chemistry; D012263:Ribonucleosides / Q000737:chemistry*; D012996:Solutions; D013844:Thiazoles / Q000737:chemistry*; D014961:X-Ray Diffraction
D000970:Antineoplastic Agents; D012263:Ribonucleosides; D012996:Solutions; D013844:Thiazoles; D012254:Ribavirin; C083363:isotiazofurin; C033706:tiazofurin