Synthesis and in vitro antitumor evaluation of novel 3,4-dihydropyrimidinone-vorinostat hybrids against gastric and breast cancer cell lines

Abstract

Novel 5-substituted dihydropyrimidinones (DHPMs) bearing a methoxy terminal group, together with DHPM–SAHA molecular hybrids inspired by the clinically approved antitumour agent Vorinostat (SAHA), were synthesised via the Biginelli multicomponent reaction and evaluated for their in vitro antitumour activity against AGS (gastric) and MCF-7 (breast) cancer cell lines. All compounds exhibited low cytotoxicity towards human fibroblasts (SW872), maintaining cell viabilities ≥70%. The derivatives displayed pronounced antiproliferative activity, particularly against MCF-7 cells, consistently showing higher potency than when against AGS cells and, in several cases, superior activity compared to Monastrol. Within the ester DHPM series, three compounds exhibited IC₅₀ values below 5 µM, with derivative 6a emerging as the most active ester analogue (IC₅₀ = 1.33 ± 0.09 µM). Notably, substitution of the terminal ester by a hydroxamic acid moiety—responsible for Zn²⁺ chelation in HDAC inhibition and central to Vorinostat's antitumour mechanism—resulted in a marked enhancement of antiproliferative activity, yielding highly potent DHPM–SAHA hybrids. Several hybrids displayed submicromolar IC₅₀ values against MCF-7 cells, irrespective of the aromatic substituent, with four compounds exhibiting IC₅₀ values below 1 µM and a further four below 5 µM. Among them, DHPM–SAHA hybrid 7i, derived from 4-methoxybenzaldehyde, emerged as the most potent compound (IC₅₀ = 0.02 ± 0.00 µM). Collectively, these results underscore the successful integration of DHPM and HDAC-inhibitory pharmacophores and highlight DHPM–SAHA hybrids as promising multitarget scaffolds for the development of new breast cancer therapeutics.