Design, synthesis and antiproliferative evaluation of lipidated 1,3-diaryl propenones and their cyclized pyrimidine derivatives as tubulin polymerization inhibitors

Abstract

Malignant transformations are dependent on an aberrant increase in tubulin and microtubule activities for cancer cell growth, migration, invasion and metastasis. The present work includes design and synthesis of a new series of lipidated 1,3-diaryl propenones and their cyclized pyrimidine derivatives as tubulin polymerization inhibitors. These derivatives harness lipophilicity, ease of synthesis and antiproliferative activity of lipidated 1,3-diaryl propenones and their cyclized derivatives. New compounds were synthesized from 4′-hydroxyacetophenone via O-alkylation, condensation with different aromatic aldehydes followed by cyclization with urea, thiourea or guanidine. Cyclization of 1,3-diaryl propenones into 4,6-diaryl pyrimidines increased their antiproliferative activity with the most potent derivative 19 achieving IC50 values at low micro molar concentration against two human cancer cell lines; MCF-7 (breast) and HepG-2 (liver). Compound 19 induced S-phase cell cycle arrest and apoptosis in MCF-7 with tubulin IC50 = 9.7 μM. It is well accommodated at the colchicine binding site of the tubulin protein as demonstrated by molecular docking.