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

Heba S A ElZahabi; Mohamed S Nafie; Dina Osman; Nehal H Elghazawy; Dalia H Soliman; Abdelghany Ali H El-Helby; Reem K Arafa

doi:10.1016/j.ejmech.2021.113609

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

Eur J Med Chem. 2021 Oct 15:222:113609. doi: 10.1016/j.ejmech.2021.113609. Epub 2021 Jun 5.

Authors

Heba S A ElZahabi¹, Mohamed S Nafie², Dina Osman³, Nehal H Elghazawy⁴, Dalia H Soliman¹, Abdelghany Ali H El-Helby⁵, Reem K Arafa⁶

Affiliations

¹ Department of Medicinal and Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Girls Branch, Cairo, Egypt.
² Chemistry Department, Faculty of Science, Suez Canal University, Ismailia, 41522, Egypt.
³ Pharmaceutical Chemistry Department, Faculty of Pharmacy, MSA University, Egypt.
⁴ Drug Design and Discovery Lab, Zewail City of Science and Technology, Giza, 12578, Egypt.
⁵ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Boys Branch, Cairo, Egypt.
⁶ Drug Design and Discovery Lab, Zewail City of Science and Technology, Giza, 12578, Egypt; Biomedical Sciences Program, University of Science and Technology, Zewail City of Science and Technology, Giza, 12578, Egypt. Electronic address: rkhidr@zewailcity.edu.eg.

PMID: 34119830
DOI: 10.1016/j.ejmech.2021.113609

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 (IC_{50 =} 0.06 μM) and better than 5-fluorouracil (IC_{50 =} 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.

Keywords: Apoptosis; Autophagy; Breast cancer; Cell cycle analysis; EGFR; Quinazolin-4-ones.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Autophagy / drug effects*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Humans
MCF-7 Cells
Molecular Structure
Quinazolinones / chemical synthesis
Quinazolinones / chemistry
Quinazolinones / pharmacology*
Structure-Activity Relationship

Substances

Antineoplastic Agents
Quinazolinones
4-hydroxyquinazoline