Synthesis andin vitro cytotoxicity of a homologous series of 5-halosubstituted 1,3-bis(ω-cyanoalkyl)uracil analogues

Abstract

A homologous series of twenty, hitherto unreported, analogues of 5-halosubstituted 1,3-bis(ω-cyanoalkyl)uracil acyclic nucleosides were synthesized by the series of alkylation reactions of 5-halouracils with the corresponding chloroacetonitrile, chloropropionitrile, chlorobutyronitrile and 5-chlorovaleronitrile (Cl-(CH2)n-CN: n=1, 2, 3, 4) in anhydrous DMSO (or DMF)/K2CO3 (or NaH) under 75°C temperature. Antitumor activities for the synthesized compounds were determined against three cell lines (FM-3A cell, P-388 cell and U-938 cell lines). The compounds that exhibited moderate activity to significant activity, included1a-b, 2a-b, 3a-c, and4a, whose compounds were active against P-388, FM-3A and U-937 cell lines with the compounds1a, 1b, and2a, showing significant antitumor activity (inhibitory concentrations (IC50) ranged from 2.2 to 7.0 μg/ml). Their structure-activity relationship did not show any activity differences in their effective chain length (methyl, ethyl, propyl, butyl) in 1,3-bis(ω-cyanoalkyl) uracils.