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- Title
Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors.
- Authors
Alkahtani, Hamad M.; Zen, Amer Alhaj; Obaidullah, Ahmad J.; Alanazi, Mohammed M.; Almehizia, Abdulrahman A.; Ansari, Siddique Akber; Aleanizy, Fadilah Sfouq; Alqahtani, Fulwah Yahya; Aldossari, Rana M.; Algamdi, Raghad Abdullah; Al-Rasheed, Lamees S.; Abdel-Hamided, Sami G.; Abdel-Aziz, Alaa A.-M.; El-Azab, Adel S.
- Abstract
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 IC50 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.
- Subjects
CYCLIN-dependent kinase inhibitors; QUINAZOLINONES; STRUCTURE-activity relationships; ADENOSINE triphosphate; MOLECULAR docking
- Publication
Molecules, 2023, Vol 28, Issue 1, p120
- ISSN
1420-3049
- Publication type
Article
- DOI
10.3390/molecules28010120