New Indole-6-Carboxylic Acid Derivatives as Multi-Target Antiproliferative Agents: Synthesis, in Silico Studies, and
Mustafa M Allawi1, Ammar A Razzak Mahmood2, Lubna H Tahtamouni3,4
1Department of Pharmaceutical Chemistry, College of Pharmacy, Uruk University, Baghdad, Iraq.
Abstract:
Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are commonly overexpressed in cancers making them appealing targets for cancer therapeutics. Two groups of indole-6-carboxylic acid derivatives, hydrazone derivatives targeting EGFR and oxadiazole derivatives targeting VEGFR-2, were synthesized and characterized using FT-IR, 1 H-NMR, 13 CNMR, and HR-MS techniques. Binding patterns to potential molecular targets were studied using molecular docking and compared to standard EGFR and VEGFR-2 inhibitors. The newly synthesized compounds were cytotoxic to the three cancer cell lines tested (HCT-116, HeLa, and HT-29 cell lines) as evaluated by the MTT assay. Compound 3 b (EGFR-targeting) and compound 6 e (VEGFR-2-targeting) possessed the highest antiproliferation activity, were cancer-selective, arrested cancer cells in the G2/M phase, induced the extrinsic apoptosis pathway, and had the highest EGFR/VEGFR-2 enzyme inhibitory activity, respectively. The structure-activity relationships of the new compounds showed that the presence of an aryl or heteroaryl fragment attached to a linker is required for the anti-tumor activity. In conclusion, the findings of the current study suggest that compounds 3 b and 6 e are promising cytotoxic agents that act by inhibiting EGFR and VEGFR-2 tyrosine kinases, respectively.
Insights
New indole derivatives show promise as cancer therapeutics by targeting key growth factor receptors. Compound 3b inhibits epidermal growth factor receptor (EGFR), while compound 6e targets vascular endothelial growth factor receptor 2 (VEGFR-2), demonstrating significant anti-cancer activity.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Cancer Biology
Background:
- Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) are frequently overexpressed in various cancers.
- Targeting EGFR and VEGFR presents a promising strategy for developing novel anti-cancer therapeutics.
Purpose of the Study:
- To synthesize and characterize novel indole-6-carboxylic acid derivatives as potential inhibitors of EGFR and VEGFR-2.
- To evaluate the cytotoxic and antiproliferative activities of these compounds against human cancer cell lines.
- To investigate the mechanism of action and structure-activity relationships of the most potent compounds.
Main Methods:
- Synthesis of indole-6-carboxylic acid derivatives, including hydrazone (EGFR-targeting) and oxadiazole (VEGFR-2-targeting) compounds.
- Characterization using spectroscopic techniques (FT-IR, 1H-NMR, 13C-NMR) and high-resolution mass spectrometry (HR-MS).
- In vitro cytotoxicity assessment using MTT assay on HCT-116, HeLa, and HT-29 cancer cell lines; molecular docking studies; cell cycle analysis; apoptosis assays.
Main Results:
- Two series of indole derivatives were successfully synthesized and characterized.
- Compounds 3b (EGFR-targeting) and 6e (VEGFR-2-targeting) exhibited significant cytotoxic and antiproliferative effects.
- These lead compounds demonstrated cancer selectivity, induced G2/M cell cycle arrest, triggered apoptosis, and showed potent enzyme inhibitory activity against EGFR and VEGFR-2, respectively.
- Structure-activity relationship analysis indicated the importance of aryl/heteroaryl fragments for anti-tumor activity.
Conclusions:
- Compounds 3b and 6e are identified as potent, cancer-selective cytotoxic agents.
- These compounds effectively inhibit EGFR and VEGFR-2 tyrosine kinases, respectively.
- The synthesized indole derivatives represent promising candidates for further development as targeted cancer therapeutics.
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