Antiproliferative Effect and Autophagy Inhibition of Dihydropyrimidinone‐Cinnamic Acid Hybrids

Abstract

Here we report the design, synthesis and evaluation of dihydropyrimidinones (DHPMs)‐cinnamic acids hybrids as potential anti‐cancer compounds. The synthetic route was successfully performed and the products obtained in good to excellent yields. These compounds were tested against LNCaP and PC‐3 metastatic prostate cancer cells and RWPE‐1 prostate cells. The results indicate that hybridization was effective, since the hybrids were much more cytotoxic than DHPMs and cinnamic acids evaluated separately. Compound 3 a was the most potent hybrid against PC‐3 cells (IC50 of 15.7 μM) and LNCaP cells (IC50 of 11.5 μM) and was further optimized by bioisosterism and molecular simplification strategies leading to three new analogues (5, 7 and 8). Compounds 3 a, 7 and 8 showed an antiproliferative effect against PC‐3 cells without inducing cell death nor cell cycle arrest. The mechanism of action of compound 8 was further investigated. The results indicated that compound 8 inhibits autophagic flux, and this effect could be linked to the antiproliferative activity. Moreover, in silico prediction of some molecular properties related to pharmacokinetics showed that all the hybrids meet the criteria for a drug prototype to have a good absorption and permeation for oral administration. These results highlight the potential use of DHPMs‐cinnamic acids hybrids as antiproliferative agents for further evaluation of the antitumor activity in vivo.

Design, synthesis and antiproliferative screening of newly synthesized acrylate derivatives as potential anticancer agents

“…26 The two most frequently utilized methods in medicinal chemistry in the design of novel molecules are bioisosterism and molecular hybridization. 27 The isosteric modication method is an efficient and oen used technique that many drug candidates employ to enhance their pharmacodynamic behavior. 28 It was of interest to further exploit the lead antimitotic agent, CA-4, with the possibility of producing effective drugs active against breast carcinoma cells.…”