Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors

• Published in: Molecules (Basel, Switzerland) Vol. 28; no. 1; p. 120
• Main 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
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.12.2022; MDPI
• Subjects: Adenosine triphosphate; Antineoplastic Agents - chemistry; Apoptosis; ATP; Cancer; CDK9; Cell cycle; Cell death; Chemical properties; Chemical synthesis; Cyclin-dependent kinase; Cyclin-Dependent Kinase 9; Cyclin-dependent kinases; cytotoxic agents; Cytotoxicity; Drugs; Elongation; Hematology; Heterocyclic compounds; Inhibitors; Investigations; Iodine; Kinases; Lipophilic; Molecular docking; Molecular Docking Simulation; Optimization; Pharmaceutical research; Physiological aspects; Production processes; Protein Kinase Inhibitors - chemistry; Proteins; quinazolinones; Quinazolinones - pharmacology; Structure-Activity Relationship; Structure-activity relationship (Pharmacology); Structure-activity relationships; Transcription elongation; Saudi Arabia; CDK9; cytotoxic agents; molecular docking; quinazolinones
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules28010120

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 , , and were the most potent CDK9 inhibitors, with 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 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.