Antiproliferative activity of purine nucleoside dialdehydes against leukemia L1210 in vitro

Sixteen purine nucleoside dialdehydes were assayed for antiproliferative activity against murine leukemia L1210 grown in vitro. These compounds either lacked the terminal hydroxymethyl group that is necessary in most cases for phosphorylation, and/or had stereochemically different configurations at one or two positions, or had some alteration in the purine ring structure. Among the latter were two lipophilic N6-benzyladenine containing dialdehydes, and two nucleoside dialdehydes with a bromine atom at C-8 of the purine. These nucleoside dialdehydes, unlike most clinically useful anticancer nucleosides, did not require enzymatic phosphorylation to become activated. The most interesting agent in this group of compounds was the lipophilic nucleoside dialdehyde obtained from N6-benzyladenosine after periodate oxidation. It had an IC50 of 1.0 +/- 0.2 microM, and appears to function by limiting the formation of deoxyguanosine diphosphate (dGDP) by inhibition of ribonucleoside diphosphate reductase, the rate limiting step in the biosynthesis of deoxyribonucleotides.