Synthesis and biological evaluation of novel pyrimidine-5-carbonitriles featuring morpholine moiety as antitumor agents

Abstract

Aim: Design and synthesis of novel morpholinopyrimidine-5-carbonitriles as antitumor agents. Materials & methods: New series of morpholinopyrimidine-5-carbonitriles have been synthesized. 19 derivatives (3b, 4a, 5-6, 9-12, 13a-e, 14a-c and 15-17) were evaluated for their in vitro antitumor activity by the National Cancer Institute (NCI; MD, USA). Moreover, compound 13e was evaluated against PI3K (α, β and δ) and the mechanism of its cytotoxic activity on leukemia SR was studied. Results: Compound 13e possessed remarkable broad spectrum antitumor activity with GI₅₀ (median growth inhibition) and TGI (total growth inhibition) values of 6.15 and 28.66 μM, respectively, caused cell cycle arrest at G2-M phase and significant increase in the percentage of annexin V-FITC - positive apoptotic cells, also increased the level of active caspase-3. Moreover, 13e revealed good safety profile against transformed human liver epithelial-2 (THLE2).

Keywords: apoptosis; caspase-3; cytotoxicity; morpholinopyrimidine-5-carbonitrile.