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...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-02-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/5/1105 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| Summary: | 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. |
|---|---|
| ISSN: | 1420-3049 |