SYNTHESIS AND CYTOTOXICITY OF DEOXYADENOSINE ANALOGS - ISOMER DISTRIBUTION IN THE SODIUM-SALT GLYCOSYLATION OF 2,6-DISUBSTITUTED PURINES

Several 2-substituted deoxyadenosine derivatives were synthesized and screened for cytotoxicity toward hematopoietic cells in culture. To prepare intermediates for these syntheses, the sodium salts of 2,6-dibromopurine and 2,6-bis(methylthio)purine were reacted with l-chloro-3,5-di-p-toluyl-α-D-erythro-pentofuranose in acetonitrile. Similar reactions using 6-chloropurines have been reported to give only 9–β and 7-β nucleosides as major and minor products, respectively. 2,6-Dibromopurine, however, gave 9-β and 9-α isomers as major and minor products, along with a lesser amount of the 7-β isomer. 2,6-Bis(methylthio) purine, in contrast, produced 9–β and 7-β isomers as major and minor products. These results are discussed in terms of sugar anomerization and possible steric and kinetic effects of base substituents in the sodium salt glycosylation reaction. Reactions of the 9–0 nucleoside isomers with ammonia and alkylamines produced several 2-bromo, 2-methylthio, and 2-amino deoxyadenosines. All of the compounds showed weaker cytotoxic activity than 2-bromodeoxyadenosine against hematopoietic cells in culture, when [14C]leucine incorporation into cellular proteins was measured. © 1990, American Chemical Society. All rights reserved.