COMPUTATIONAL STUDIES OF NONBONDED SULFUR OXYGEN AND SELENIUM OXYGEN INTERACTIONS IN THE THIAZOLE AND SELENAZOLE NUCLEOSIDES

Computational studies have been performed to investigate the origin and magnitude of a biologically important nonbonded interaction: the sulfur-oxygen and selenium-oxygen interaction observed in the thiazole and selenazole nucleosides. Crystallographic studies of the antitumor agents tiazofurin and selenazofurin and their analogues have demonstrated close contacts between the thiazole sulfur or selenazole selenium and the furanose oxygen. Crystallographic evidence that these contacts result from a true intramolecular interaction is reviewed. Computational findings indicate that these contacts are the result of an attractive electrostatic interaction between a positively charged heteroatom and a negatively charged oxygen. This hypothesis is supported by examination of geometry optimizations, population analyses, and molecular electrostatic isopotential maps obtained from ab initio computations (RHF/STO-3G, 3-21G, 3-21G*, and 6-31G* levels) for both isolated thiazole and selenazole rings and for model nucleoside fragments. Semiempirical (MNDO) computations on the thiazole nucleosides estimate that this attractive sulfur-oxygen interaction, in combination with a repulsive nitrogen-oxygen interaction, produces a barrier to rotation about the C-glycosidic bond of approximately 4 kcal/mol.