Synthesis and biological activity of certain 3,4-disubstituted pyrazolo[3,4-d]pyrimidine nucleosides

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Abstract
A number of 3,4-disubstituted pyrazolo[3,4-d]pyrimidine ribonucleosides were synthesized and tested for their biological activity. Glycosylation of persilylated as well as nonsilylated 3-bromoallopurinol with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (4) provided the key intermediate 3-bromo-1-(2,3,5-tri-O-benzoyl-.beta.-D-ribofuranosyl)pyrazolo[3,4-d]pyrimidin-4(5H)-one (5a). Similar glycosylations of 3-cyanoallopurinol and 3-(methylthio)allopurinol furnished the corresponding protected N-1 glycosyl derivatives. Debenzoylation of these nucleosides gave the corresponding 3-bromo-, 3-cyano- and 3-(methylthio)allopurinol nucleosides (6a-6c). The site of glycosylation and anomeric configuration of 6a and 6c were assigned on the basis of spectral studies as well as conversion to allopurinol ribonucleoside, whereas the structural assignment of 6b was made by single-crystal X-ray analysis. Conventional functional group transformation of 5a and 5b provided a number of novel 3-substituted allopurinol nucleosides, which included [3-amino-1-.beta.-D-ribofuranosylpyrazolo[3,4-d]pyrimidin-4(5H)-one] and 18a-d [4(5H)-oxo-1-.beta.-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-3-carboxamide; 4(5H)-oxo-1-.beta.-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-3-thiocarboxamide; 4(5H)-oxo-1-.beta.-D-ribofuranosylpyrazolo[3,4-d]pyrimidine-3-carboxamidine hydrochloride; and N-hydroxy-4(5H)-oxo-1-.beta.-D-ribofuranosylpyrazolo[3,4-d] pyrimidine-3-carboxamidine]. Glycosylation of 4-amino-3-bromopyrazolo[3,4-d]pyrimidine (14) with 4 and subsequent debenzoylation gave 3-bromo-4-aminopyrazolo[3,4-d]pyrimidine ribonucleoside (13a), from which 3,4-diamino-1-.beta.-D-ribofuranosylpyrazolo[3,4-d]pyrimidine (13b) was obtained by amination. Thiation of 5b, followed by deblocking, gave 3-cyanothiopurinol ribonucleoside (20). All of these compounds were tested in vitro against certain viruses, tumor cells and the parasite Leishmania tropica. Among the 3-substituted allopurinol nucleosides, 18b and 18c showed significant activity against Para 3 virus and were potent inhibitors of growth of L1210 and P388 leukemia. Compound 20 [1-.beta.-D-ribofuranosyl-4(5H)-thioxopyrazolo[3,4-d]pyrimidine-3-carbonitrile] exhibited the most significant broad-spectrum in vitro antiviral and antitumor activity. 3-Bromoallopurinol ribonucleoside (6a) was more active than allopurinol ribonucleoside against Leishmania tropica within human macrophages in vitro.