Design, synthesis, molecular simulation, and biological activities of novel quinazolinone-pyrimidine hybrid derivatives as dipeptidyl peptidase-4 inhibitors and anticancer agents

• Published in: New journal of chemistry 2020-12, Vol.44 (45), p.19515-19531
• Main Authors: Emami, Leila, Faghih, Zahra, Sakhteman, Amirhossein, Rezaei, Zahra, Faghih, Zeinab, Salehi, Farnaz, Khabnadideh, Soghra
• Format: Article
• Language: English
• Subjects: Anticancer properties; Apoptosis; Biotechnology; Cancer; Cell cycle; Cell death; Chemical synthesis; Colon; Cytotoxicity; Flow cytometry; Inhibitors; Peptidases
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/d0nj03774e

Two novel series of quinazolinone-pyrimidine (series a: 9a-9i ) and benzyl-pyrimidine hybrids (series b: 12a-12c ) were designed, synthesized and characterized by spectroscopic methods. The dipeptidyl peptidase-4 inhibition potencies of these compounds were assessed through a MAK 203 kit. Compound 9e was found to be the most potent agent with an IC 50 value of 34.3 ± 3.3 μM. A kinetic study revealed that it acted as a competitive inhibitor. Molecular modeling of these compounds was in agreement with the in vitro results. Due to the crucial role of dipeptidyl peptidase-4 in cancer therapy, the cytotoxic activities of the compounds were also evaluated against three cancerous cell lines (HT-29, SW1116 and A549). Almost all the compounds displayed better antiproliferative activity on colon cancer cell lines (HT-29 and SW1116) compared to a lung cancer cell line (A549). Compounds 9e and 12c exhibited significant activity toward the HT-29 cell line with an IC 50 of 10.67 ± 0.3 μM and 27.9 ± 6.5 μM in comparison to sitagliptin and cisplatin as a positive control, respectively. Among the different cells, the compounds showed the best inhibitory effects on HT-29, which was compatible with the greater expression of the dipeptidyl peptidase-4 marker detected by flow cytometry in this cell line. Further studies on the hit compounds ( 9e and 12c ) through cell cycle and apoptosis assays also showed that these compounds could induce cell death by apoptosis or arrest cells in the G2/M phase. Accordingly, the results imply that 9e is a potent inhibitor of dipeptidyl peptidase-4 with efficient anti-cancer activity and could play a role as a cytotoxic agent in colorectal cancer. Twelve novel quinazolinone-pyrimidine hybrids were synthesized, of which some of them showed dual functions as DPP-4 inhibitors and anti-cancer agents.