Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors.
Hamad M Al KahtaniAmer Alhaj ZenAhmad J ObaidullahA F M Motiur RahmanAbdulrahman A Al-MehiziaSiddique Akber AnsariFadilah Sfouq AleanizyFulwah Yahya AlqahtaniRana M AldossariRaghad Abdullah AlgamdiLamees S Al-RasheedSami G Abdel-HamidedAlaa A-M Abdel-AzizAdel S El-AzabPublished in: Molecules (Basel, Switzerland) (2022)
Cyclin-dependent kinase 9 (CDK9) plays a critical role in transcriptional elongation, through which short-lived antiapoptotic proteins are overexpressed and make cancer cells resistant to apoptosis. Therefore, CDK9 inhibition depletes antiapoptotic proteins, which in turn leads to the reinstatement of apoptosis in cancer cells. Twenty-seven compounds were synthesized, and their CDK9 inhibitory and cytotoxic activities were evaluated. Compounds 7 , 9 , and 25 were the most potent CDK9 inhibitors, with IC 50 values of 0.115, 0.131, and 0.142 μM, respectively. The binding modes of these molecules were studied via molecular docking, which shows that they occupy the adenosine triphosphate binding site of CDK9. Of these three molecules, compound 25 shows good drug-like properties, as it does not violate Lipinski's rule of five. In addition, this molecule shows promising ligand and lipophilic efficiency values and is an ideal candidate for further optimization.
Keyphrases
- cell cycle
- molecular docking
- cell cycle arrest
- cell proliferation
- oxidative stress
- endoplasmic reticulum stress
- cell death
- structure activity relationship
- molecular dynamics simulations
- gene expression
- protein kinase
- pi k akt
- transcription factor
- sensitive detection
- tyrosine kinase
- electronic health record
- drug induced