Syntheses and Antitumor Evaluation of C(6)‐Isobutyl‐ and C(6)‐Isobutenyl‐Substituted Pyrimidines, and Dihydropyrrolo[1,2‐c]pyrimidine‐1,3‐diones

Abstract

AbstractA growing body of evidence supports that pyrimidine derivatives, in which the sugar residues have been replaced by acyclic side chains, might be developed as promising anticancer agents that interfere with tumor cell proliferation, survival, and metastatic formation. In this work, we prepared novel pyrimidines bearing i‐Bu (i.e., 3, 4, and 7–9) and isobutenyl (i.e., 5 and 10) side chains at C(6) and examined their in vitro effects on tumor cell lines. The dihydropyrrolo[1,2‐c]pyrimidine‐1,3‐diones 6 and 11 were obtained as products of intramolecular cyclization, which occurred during the removal of Bn in 5 or MeO protecting groups in 10. Fluorination of 3 with diethylaminosulfur trifluoride (DAST) and then dehydrohalogenation of the resulting fluorinated derivative 4 afforded 6‐isobut‐2′‐enyl pyrimidine derivative 5 with a C(2′)C(3′) bond. For the preparation of 6‐isobut‐1′‐en‐1‐yl pyrimidine 10, a synthetic strategy involving acetylation of the 1,3‐diols was applied. Antitumor evaluation of compounds 3–11 showed that 2,4‐dimethoxypyrimidine containing 6‐[(1,3‐dibenzyloxy)‐2‐hydroxy]methyl side chain, 3, exerted a strong antiproliferative effect on the studied tumor cell lines. Additionally, it was shown that the mechanism of antiproliferative effect of 3 in HeLa cells include early G2/M arrest and apoptosis, as well as a p53‐independent S‐phase arrest upon prolonged treatment.