Synthesis and biological activity of nucleosides and nucleotides related to the antitumor agent 2-.beta.-D-ribofuranosylthiazole-4-carboxamide

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Abstract
Phosphorylation of 2-.beta.-D-ribofuranosylthiazole-4-carboxamide (1) provided by the 5''-phosphate derivative 2 [2-.beta.-D-ribofuranosylthiazole-4-carboxamide 5''-phosphate], which was converted to the corresponding 5''-triphosphate 4 and the cyclic 3'',5''-phosphate 5 [2-.beta.-D-robofuranosylthiazole-4-carboxamide cyclic 3'',5''-phosphate]. Treatment of 2-(2,3,5-tri-O-acetyl-.beta.-D-ribofuranosyl)thiazole-4-carbonitrile (6) with NH3-NH4Cl provided 2-.beta.-D-robofuranosylthiazole-4-carboxamidine hydrochloride (7), and treatment with H2S-pyridine provided the corresponding 4-thiocarboxamide 9. Compound 9 was treated with ethyl bromopyruvate, followed by treatment with methanolic ammonia, to yield 2''-(2-.beta.-D-ribofuranosylthiazol-4-yl)-thiazole-4''-carboxamide (11). 5''-Phosphate 2 was cytotoxic to L1210 [mouse leukemia] cells in culture and significantly effective against the i.p. implanted murine leukemias in mice. Amidine 7 was slightly toxic to L1210 in culture and inhibitory to purine nucleoside phosphorolysis. The cyclic 3'',5''-phosphate 5 was less effective than the corresponding 5''-phosphate 2 or the parent nucleoside 1 as an antitumor agent.