2-(3-Bromophenyl)-8-fluoroquinazoline-4-carboxylic Acid as a Novel and Selective Aurora A Kinase Inhibitory Lead with Apoptosis Properties: Design, Synthesis, In Vitro and In Silico Biological Evaluation

Life

Ahmed Elkamhawy¹  Wessam Mady²  Eun Joo Roh³  Mohamed H. Elsherbeny³  Magda H. Abdellattif⁴  Samah F. Ibrahim⁵  Doaa Abdelrahaman⁵  Ahmed Abdeen⁶  Mohammed A. S. Abourehab⁷  Usama M. Ammar⁸ 

[1] BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Korea;Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, Saudi Arabia;Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea;Department of Chemistry, College of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;Department of Clinical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia;Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Benha University, Toukh 13736, Egypt;Department of Pharmaceutics, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia;Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral Street, Glasgow G4 0NR, UK;

关键词: quinazoline;    Aurora A;    kinases;    anticancer;    molecular docking;    cell cycle;   

DOI  :  10.3390/life12060876

来源: DOAJ

【 摘 要 】

New quinazoline derivatives were designed based on the structural modification of the reported inhibitors to enhance their selectivity toward Aurora A. The synthesized compounds were tested over Aurora A, and a cytotoxicity assay was performed over NCI cell lines to select the best candidate for further evaluation. Compound 6e (2-(3-bromophenyl)-8-fluoroquinazoline-4-carboxylic acid) was the most potent compound among the tested derivatives. A Kinase panel assay was conducted for compound 6e over 14 kinases to evaluate its selectivity profile. Further cell cycle and apoptosis analysis were evaluated for compound 6e over the MCF-7 cell line at its IC₅₀ of 168.78 µM. It arrested the cell cycle at the G1 phase and induced apoptosis. Molecular docking was performed to explore the possible binding mode of compound 6e into the active site. It showed significant binding into the main pocket in addition to potential binding interactions with the key amino acid residues. Accordingly, compound 6e can be considered a potential lead for further structural and molecular optimization of the quinazoline-based carboxylic acid scaffold for Aurora A kinase selective inhibition with apoptosis properties.

【 授权许可】

Unknown