Synthesis and cytotoxicity of deoxyadenosine analogues: 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 1-chloro-3,5-di-p-toluyl-alpha-D-erythro-pentofuranose in acetonitrile. Similar reactions using 6-chloropurines have been reported to give only 9-beta and 7-beta nucleosides as major and minor products, respectively. 2,6-Dibromopurine, however, gave 9-beta and 9-alpha isomers as major and minor products, along with a lesser amount of the 7-beta isomer. 2,6-Bis(methylthio)purine, in contrast, produced 9-beta and 7-beta 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-beta 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.
Kazimierczuk
Z
Z
Department of Biophysics, University of Warsaw, Poland.
Vilpo
J
J
Hildebrand
C
C
Wright
G
G
D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D003839:Deoxyadenosines / Q000138:chemical synthesis* / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D006801:Humans; D007536:Isomerism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003839:Deoxyadenosines