Design, synthesis and evaluation of new quinazolin-4-one derivatives as apoptotic enhancers and autophagy inhibitors with potent antitumor activity

Abstract

European Journal of Medicinal Chemistry Volume 222, 15 October 2021, 113609 Design, synthesis and evaluation of new quinazolin-4-one derivatives as apoptotic enhancers and autophagy inhibitors with potent antitumor activity Author links open overlay panelHeba S.A.ElZahabiaMohamed S.Nafieb1DinaOsmanc1Nehal H.ElghazawydDalia H.SolimanaAbdelghany Ali H.EL-HelbyeReem K.Arafadf a Department of Medicinal and Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Girls Branch, Cairo, Egypt b Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, 41522, Egypt c Pharmaceutical Chemistry Department, Faculty of Pharmacy, MSA University, Egypt d Drug Design and Discovery Lab, Zewail City of Science and Technology, Giza, 12578, Egypt e Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Boys Branch, Cairo, Egypt f Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt Received 6 February 2021, Revised 29 May 2021, Accepted 30 May 2021, Available online 5 June 2021.

crossmark-logo https://doi.org/10.1016/j.ejmech.2021.113609 Get rights and content Highlights • Discovery of new 2,3-substituted-6,8-dibromoquinazolin-4-ones antiproliferative agents.

• 3-Amino-2-methyl analogue 17 shows in vitro (IC50 = 0.06 μM) and in vivo breast cancer cytotoxicity.

• 17 induces apoptosis, increases proapoptotic markers and cause G1 cell cycle arrest.

• 17 inhibits autophagic pathway by inhibiting EGFR, downregulating EGFR, PI3K, AKT and mTOR.

Abstract This work presents the design and synthesis of a series of new quinazolin-4-one derivatives, based on the established effectiveness of quinazoline-based small molecules as anticancer agents. Synthesized compounds were more potent against MCF-7 than A-549 with low to submicromolar IC50s. Compound 17 exhibited the best IC50 being equipotent with the positive control doxorubicin (IC50 = 0.06 μM) and better than 5-fluorouracil (IC50 = 2.13 μM). Compound 17 was further tested against MDA-MB-231 and MCF-10A and was found to be > 2 folds more cytotoxic on MCF-7. Significant apoptotic activity was elicited by 17 on MCF-7 where it increased apoptotic cell death along with induction of pre-G1 and G1-phase cell cycle arrest. Similarly, 17 was able to induce apoptosis in MD-MB-231 treated cells associated with a disruption of the cell cycle causing arrest at the pre-G1 and S phases. Investigation of gene expression in MCF-7 demonstrated an increased expression of the proapoptotic genes P53, PUMA, Bax, caspases 3, 8 and 9 and a decrease of the anti-apoptotic gene Bcl2. Also, 17 reduced autophagy giving way for apoptosis to induce cancer cells death. This latter observation was associated with downregulation of EGFR and its downstream effectors PI3K, AKT and mTor. As its biomolecular target, 17 also inhibited EGFR similar to erlotinib (IC50 = 0.072 and 0.087 μM, respectively). Additionally, in vivo testing in a mouse model of breast cancer affirmed the anti-tumor efficacy of 17. Finally, docking of 17 against EGFR ATP binding site demonstrated its ability to bind with EGFR resembling erlotinib.