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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Design and Synthesis of Novel Quinazolinone-Based Oxobutanenitrile Derivatives as Antiproliferative Agents Targeting Human Breast Cancer

Author(s): Omaima Mohamed AboulWafa, Hoda Mohamed Gamal El-Din Daabees and Eman Salah Ezz-ElDien*

Volume 22, Issue 12, 2022

Published on: 17 March, 2022

Page: [2310 - 2326] Pages: 17

DOI: 10.2174/1871520621666211214104144

Price: $65

Abstract

Background: Breast cancer (BC) is among the leading causes of death in women worldwide. Medical interest has focused on quinazolinone derivatives approved and utilized in antitumor medications.

Objective: Novel quinazolinone-based oxobutanenitrile derivatives were designed, synthesized, and screened for in vitro anti-breast cancer activity.

Methods: The antiproliferative activities were determined using MTT assay against MCF-7 and MDA-MB-231 cell lines. EGFR, ARO, and caspase-9 enzymes were selected to explore the mechanism of action of the most potent compounds.

Results: Tested compounds showed better EGFRIs than ARIs. In addition, significant overexpression of caspase-9 level in treated MCF-7 breast cell line samples was observed with the most active compounds. The thienyl derivative 5 induced the greatest activation in caspase-9 level in treated MCF-7 breast cancer samples. The o-tolylhydrazone 3b, exhibiting promising ARO inhibition and weak EGFR inhibition, produced a noticeable high overexpression of caspase- 9 and showed pre-G1 apoptosis and cell cycle arrest at G2/M phase for MCF-7 cells and at S-phase for MDA-MB- 231 cells. Docking results revealed that 3b elicited binding affinities to ARO comparable to those of letrozole.

Conclusion: The obtained results support the therapeutic importance of some of these compounds as anti-breast cancer agents in light of the simple methodology used for their synthesis. Their design offered a way for the optimization and development of apoptotic quinazolinone-based ARO and EGFR inhibitors.

Keywords: Quinazolinone-based oxobutanenitriles, MTT assay, EGFR, ARO, caspase-9 activation, apoptosis, docking.

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