Design, Synthesis, and Cytotoxicity Evaluation of Novel Indolin-2-One Based Molecules on Hepatocellular Carcinoma HepG2 Cells as Protein Kinase Inhibitors
A series of indolinone-based derivatives were designed and synthesized using the hybrid pharmacophoric design approach as cytotoxic kinase inhibitors. The cytotoxic effects of the designed molecules were tested against MCF-7 and HepG-2 cell lines. Compounds <b>9</b> and <b>20</b...
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MDPI AG
2025-02-01
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| author | Manal M. Kandeel Mohamed Kamal AbdElhameid Mohamed Adel Muhammad Y. Al-Shorbagy Ahmed T. Negmeldin |
| author_facet | Manal M. Kandeel Mohamed Kamal AbdElhameid Mohamed Adel Muhammad Y. Al-Shorbagy Ahmed T. Negmeldin |
| author_sort | Manal M. Kandeel |
| collection | DOAJ |
| description | A series of indolinone-based derivatives were designed and synthesized using the hybrid pharmacophoric design approach as cytotoxic kinase inhibitors. The cytotoxic effects of the designed molecules were tested against MCF-7 and HepG-2 cell lines. Compounds <b>9</b> and <b>20</b> were the most cytotoxic, with IC<sub>50</sub> values against HepG-2 and MCF-7 cells ranging from 2.53 to 7.54 µM. Additionally, compounds <b>9</b> and <b>20</b> were also found to be slightly more cytotoxic than indirubin with 2.2–2.7-fold higher cytotoxicity with HepG-2 cells. CDK-2 and CDK-4 kinase enzyme inhibition assay showed that compound <b>9</b> had a higher inhibitory effect (4.8-fold) than indirubin against CDK-2 and comparable inhibition against CDK-4. Moreover, compound <b>20</b> displayed nanomolar inhibitory action against both EGFR kinase and VFGFR-2 enzyme, which were around 8.8- and 5.4-fold higher than the IC<sub>50</sub> values of indirubin. Compounds <b>9</b> and <b>20</b> induced cell cycle arrest at the G<sub>1</sub> phase on HepG2 cells. The levels of the key apoptotic proteins assessed revealed elevated levels of the Bax/Bcl-2 ratio, which in turn initiated the caspase3/7 cascade that led to the activation of both intrinsic and extrinsic apoptotic pathways. The cell cycle inhibitory proteins p53 and p21 were significantly upregulated upon treatment with compounds <b>9</b> and <b>20</b>. The docking results revealed that compound <b>9</b> exhibits stronger binding affinity to CDK-2 than indirubin, and compound <b>20</b> showed a similar binding mode to sorafenib with VEGFR-2. |
| format | Article |
| id | doaj-art-74413a523f5c4e24b01ec44d837861a1 |
| institution | OA Journals |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-74413a523f5c4e24b01ec44d837861a12025-08-20T02:06:12ZengMDPI AGMolecules1420-30492025-02-01305110510.3390/molecules30051105Design, Synthesis, and Cytotoxicity Evaluation of Novel Indolin-2-One Based Molecules on Hepatocellular Carcinoma HepG2 Cells as Protein Kinase InhibitorsManal M. Kandeel0Mohamed Kamal AbdElhameid1Mohamed Adel2Muhammad Y. Al-Shorbagy3Ahmed T. Negmeldin4Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, EgyptDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, EgyptDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Egyptian Russian University, Cairo 11829, EgyptDepartment of Pharmaceutical Sciences, College of Pharmacy, Gulf Medical University, Ajman 4184, United Arab EmiratesDepartment of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo University, Cairo 11562, EgyptA series of indolinone-based derivatives were designed and synthesized using the hybrid pharmacophoric design approach as cytotoxic kinase inhibitors. The cytotoxic effects of the designed molecules were tested against MCF-7 and HepG-2 cell lines. Compounds <b>9</b> and <b>20</b> were the most cytotoxic, with IC<sub>50</sub> values against HepG-2 and MCF-7 cells ranging from 2.53 to 7.54 µM. Additionally, compounds <b>9</b> and <b>20</b> were also found to be slightly more cytotoxic than indirubin with 2.2–2.7-fold higher cytotoxicity with HepG-2 cells. CDK-2 and CDK-4 kinase enzyme inhibition assay showed that compound <b>9</b> had a higher inhibitory effect (4.8-fold) than indirubin against CDK-2 and comparable inhibition against CDK-4. Moreover, compound <b>20</b> displayed nanomolar inhibitory action against both EGFR kinase and VFGFR-2 enzyme, which were around 8.8- and 5.4-fold higher than the IC<sub>50</sub> values of indirubin. Compounds <b>9</b> and <b>20</b> induced cell cycle arrest at the G<sub>1</sub> phase on HepG2 cells. The levels of the key apoptotic proteins assessed revealed elevated levels of the Bax/Bcl-2 ratio, which in turn initiated the caspase3/7 cascade that led to the activation of both intrinsic and extrinsic apoptotic pathways. The cell cycle inhibitory proteins p53 and p21 were significantly upregulated upon treatment with compounds <b>9</b> and <b>20</b>. The docking results revealed that compound <b>9</b> exhibits stronger binding affinity to CDK-2 than indirubin, and compound <b>20</b> showed a similar binding mode to sorafenib with VEGFR-2.https://www.mdpi.com/1420-3049/30/5/1105HepG-2 cellsMCF-7isatinquinazolinesprotein kinasestyrosine kinase |
| spellingShingle | Manal M. Kandeel Mohamed Kamal AbdElhameid Mohamed Adel Muhammad Y. Al-Shorbagy Ahmed T. Negmeldin Design, Synthesis, and Cytotoxicity Evaluation of Novel Indolin-2-One Based Molecules on Hepatocellular Carcinoma HepG2 Cells as Protein Kinase Inhibitors Molecules HepG-2 cells MCF-7 isatin quinazolines protein kinases tyrosine kinase |
| title | Design, Synthesis, and Cytotoxicity Evaluation of Novel Indolin-2-One Based Molecules on Hepatocellular Carcinoma HepG2 Cells as Protein Kinase Inhibitors |
| title_full | Design, Synthesis, and Cytotoxicity Evaluation of Novel Indolin-2-One Based Molecules on Hepatocellular Carcinoma HepG2 Cells as Protein Kinase Inhibitors |
| title_fullStr | Design, Synthesis, and Cytotoxicity Evaluation of Novel Indolin-2-One Based Molecules on Hepatocellular Carcinoma HepG2 Cells as Protein Kinase Inhibitors |
| title_full_unstemmed | Design, Synthesis, and Cytotoxicity Evaluation of Novel Indolin-2-One Based Molecules on Hepatocellular Carcinoma HepG2 Cells as Protein Kinase Inhibitors |
| title_short | Design, Synthesis, and Cytotoxicity Evaluation of Novel Indolin-2-One Based Molecules on Hepatocellular Carcinoma HepG2 Cells as Protein Kinase Inhibitors |
| title_sort | design synthesis and cytotoxicity evaluation of novel indolin 2 one based molecules on hepatocellular carcinoma hepg2 cells as protein kinase inhibitors |
| topic | HepG-2 cells MCF-7 isatin quinazolines protein kinases tyrosine kinase |
| url | https://www.mdpi.com/1420-3049/30/5/1105 |
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