Ara-tiazofurin: conservation of structural features in an unusual thiazole nucleoside

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Abstract
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.-.DELTA.-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 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.

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