Journal
CHEMISTRYSELECT
Volume 7, Issue 27, Pages -Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/slct.202200274
Keywords
antiproliferative activity; autophagy; cinnamic acids; dihydropyrimidinones; molecular hybridization
Categories
Funding
- CAPES (CoordenacAo de Aperfeicoamento de Pessoal de Nivel Superior)
- CERSusChem GSK/FAPESP [2014/50249-8]
- INCT-Catalise
- CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico) Brazil
- FAPESC-Pronex
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In this study, design, synthesis, and evaluation of DHPMs-cinnamic acids hybrids as potential anti-cancer compounds were reported. The results indicated that the hybridization was effective, leading to compounds with much more cytotoxicity than DHPMs and cinnamic acids evaluated separately. Compound 3a was the most potent hybrid and further optimization led to the discovery of three new analogues. Moreover, compound 8 was found to inhibit autophagic flux, which could be linked to its antiproliferative activity.
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 mu M) and LNCaP cells (IC50 of 11.5 mu M) 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.
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