Ara-tiazofurin: conservation of structural features in an unusual thiazole nucleoside.
Tiazofurin (2-beta-D-ribofuranosylthiazole-4-carboxamide, NSC 286193) is a C-glycosyl thiazole nucleoside with antitumor activity. Crystal structures of tiazofurin and its alpha,2'-deoxy and xylo analogues all show close contacts between the thiazole sulfur (S) and the furanose ring oxygen (O1'). These contacts have been interpreted in terms of an attractive intramolecular S-O interaction in the thiazole nucleosides. Ara-tiazofurin (2-beta-D-arabinofuranosylthiazole-4-carboxamide, ara-T) is the inactive arabinose analogue of tiazofurin. The crystal structure of ara-T is reported. This structure provides evidence for an attractive S-O interaction not seen in the other thiazole nucleosides. The conformation about the C-glycosyl bond in ara-T is such that close contacts are formed between the thiazole sulfur and both O1' and the 2'-hydroxyl oxygen O2'. This conformation is interpreted in terms of an additional attractive interaction between S and O2'. This interpretation is supported by comparison of the conformation of ara-T with those of other ara-nucleosides. These findings provide further evidence for an attractive S-O interaction in the thiazole nucleosides. Ara-T also demonstrates a second conformational feature found in these compounds: the carboxamide nitrogen remains cis to the thiazole nitrogen. Implications of these potentially constrained conformational features are discussed in terms of the mechanism of activity of tiazofurin.
Goldstein
B M
BM
Department of Biophysics, University of Rochester Medical Center, New York 14642.
Mao
D T
DT
Marquez
V E
VE
D055598:Chemical Phenomena; D002621:Chemistry; D008968:Molecular Conformation; D012254:Ribavirin / Q000031:analogs & derivatives; D012263:Ribonucleosides; D013329:Structure-Activity Relationship; D013844:Thiazoles; D014961:X-Ray Diffraction
D012263:Ribonucleosides; D013844:Thiazoles; D012254:Ribavirin; C033706:tiazofurin