Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors
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...
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MDPI AG
2022-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/1/120 |
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| author | Hamad M. Alkahtani Amer Alhaj Zen Ahmad J. Obaidullah Mohammed M. Alanazi Abdulrahman A. Almehizia Siddique Akber Ansari Fadilah Sfouq Aleanizy Fulwah Yahya Alqahtani Rana M. Aldossari Raghad Abdullah Algamdi Lamees S. Al-Rasheed Sami G. Abdel-Hamided Alaa A.-M. Abdel-Aziz Adel S. El-Azab |
| author_facet | Hamad M. Alkahtani Amer Alhaj Zen Ahmad J. Obaidullah Mohammed M. Alanazi Abdulrahman A. Almehizia Siddique Akber Ansari Fadilah Sfouq Aleanizy Fulwah Yahya Alqahtani Rana M. Aldossari Raghad Abdullah Algamdi Lamees S. Al-Rasheed Sami G. Abdel-Hamided Alaa A.-M. Abdel-Aziz Adel S. El-Azab |
| author_sort | Hamad M. Alkahtani |
| collection | DOAJ |
| description | 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 <b>7</b>, <b>9</b>, and <b>25</b> were the most potent CDK9 inhibitors, with <i>IC</i><sub>50</sub> 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 <b>25</b> 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. |
| first_indexed | 2024-03-09T12:06:53Z |
| format | Article |
| id | doaj.art-a4269de574344339b3085a3d027ffb36 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-09T12:06:53Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-a4269de574344339b3085a3d027ffb362023-11-30T22:56:43ZengMDPI AGMolecules1420-30492022-12-0128112010.3390/molecules28010120Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 InhibitorsHamad M. Alkahtani0Amer Alhaj Zen1Ahmad J. Obaidullah2Mohammed M. Alanazi3Abdulrahman A. Almehizia4Siddique Akber Ansari5Fadilah Sfouq Aleanizy6Fulwah Yahya Alqahtani7Rana M. Aldossari8Raghad Abdullah Algamdi9Lamees S. Al-Rasheed10Sami G. Abdel-Hamided11Alaa A.-M. Abdel-Aziz12Adel S. El-Azab13Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaChemistry & Forensics Department, Clifton Campus, Nottingham Trent University, Nottingham Ng11 8NS, UKDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi ArabiaDepartment of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi ArabiaDepartment of Pharmacology & Toxicology, College of Pharmacy, 11 Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj 11942, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, EgyptDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi ArabiaCyclin-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 <b>7</b>, <b>9</b>, and <b>25</b> were the most potent CDK9 inhibitors, with <i>IC</i><sub>50</sub> 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 <b>25</b> 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.https://www.mdpi.com/1420-3049/28/1/120quinazolinonescytotoxic agentsCDK9molecular docking |
| spellingShingle | Hamad M. Alkahtani Amer Alhaj Zen Ahmad J. Obaidullah Mohammed M. Alanazi Abdulrahman A. Almehizia Siddique Akber Ansari Fadilah Sfouq Aleanizy Fulwah Yahya Alqahtani Rana M. Aldossari Raghad Abdullah Algamdi Lamees S. Al-Rasheed Sami G. Abdel-Hamided Alaa A.-M. Abdel-Aziz Adel S. El-Azab Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors Molecules quinazolinones cytotoxic agents CDK9 molecular docking |
| title | Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors |
| title_full | Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors |
| title_fullStr | Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors |
| title_full_unstemmed | Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors |
| title_short | Synthesis, Cytotoxic Evaluation, and Structure-Activity Relationship of Substituted Quinazolinones as Cyclin-Dependent Kinase 9 Inhibitors |
| title_sort | synthesis cytotoxic evaluation and structure activity relationship of substituted quinazolinones as cyclin dependent kinase 9 inhibitors |
| topic | quinazolinones cytotoxic agents CDK9 molecular docking |
| url | https://www.mdpi.com/1420-3049/28/1/120 |
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