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Novel quinoxaline-3-propanamides as VGFR-2 inhibitors and apoptosis inducers
Magda M F Ismail1, Taghreed Z Shawer1, Rabab S Ibrahim1
1Department of Pharmaceutical Medicinal Chemistry and Drug Design, Faculty of Pharmacy (Girls), Al-Azhar University Cairo 11754 Egypt m.elalfy101@gmail.com magdaismail@azhar.edu.eg.
Abstract:
Vascular endothelial growth factor receptor-2 is a vital target for therapeutic mediation in various types of cancer. This study was aimed at exploring the cytotoxic activity of seventeen novel quinoxaline-3-propanamides against colon cancer (HCT-116) and breast cancer (MCF-7) using MTT assay. Results revealed that compounds 8, 9, and 14 elicited higher cytotoxicity than the reference drugs, doxorubicin (DOX) and sorafenib. Interestingly, they are more selective for HCT-116 (SI 11.98-19.97) and MCF-7 (SI 12.44-23.87) compared to DOX (SI HCT-116 0.72 and MCF-7 0.9). These compounds effectively reduced vascular endothelial growth factor receptor-2; among them, compound 14 displayed similar VEGFR-2 inhibitory activity to sorafenib (IC50 0.076 M). The ability of 14 to inhibit angiogenesis was demonstrated by a reduction in VEGF-A level compared to control. Furthermore, it induced a significant increase in the percentage of cells at pre-G1 phase by almost 1.38 folds (which could be indicative of apoptosis) and an increase in G2/M by 3.59 folds compared to the control experiment. A flow cytometry assay revealed that compound 14 triggered apoptosis via the programmed cell death and necrotic pathways. Besides, it caused a remarkable increase in apoptotic markers, i.e., caspase-3 p53 and BAX. When compared to the control, significant increase in the expression levels of caspase-3 from 47.88 to 423.10 and p53 from 22.19 to 345.83 pg per ml in MCF-7 cells. As well, it increased the proapoptotic protein BAX by 4.3 times while lowering the antiapoptotic marker BCL2 by 0.45 fold. Docking studies further supported the mechanism, where compound 14 showed good binding to the essential amino acids in the active site of VEGFR-2. Pharmacokinetic properties showed the privilege of these hits over sunitinib: they are not substrates of P-gp protein; this suggests that they have less chance to efflux out of the cell, committing maximum effect; and in addition, they do not allow permeation to the BBB.
Insights
Novel quinoxaline-3-propanamides show potent anti-cancer activity, with compounds 8, 9, and 14 exhibiting significant cytotoxicity against colon and breast cancer cells. Compound 14 effectively inhibits vascular endothelial growth factor receptor-2 (VEGFR-2) and induces apoptosis.
Area of Science:
- Medicinal Chemistry
- Cancer Biology
- Pharmacology
Background:
- Vascular endothelial growth factor receptor-2 (VEGFR-2) is a key target in cancer therapy.
- Developing novel therapeutics with improved efficacy and selectivity is crucial for cancer treatment.
Purpose of the Study:
- To synthesize and evaluate the cytotoxic activity of novel quinoxaline-3-propanamides against colon cancer (HCT-116) and breast cancer (MCF-7) cell lines.
- To investigate the mechanism of action, including VEGFR-2 inhibition, angiogenesis, apoptosis induction, and pharmacokinetic properties of promising compounds.
Main Methods:
- Synthesis of seventeen novel quinoxaline-3-propanamide derivatives.
- Cytotoxicity assessment using MTT assay against HCT-116 and MCF-7 cell lines.
- VEGFR-2 inhibition assay, VEGF-A level analysis, cell cycle analysis, flow cytometry for apoptosis, Western blotting for apoptotic markers, molecular docking, and pharmacokinetic profiling.
Main Results:
- Compounds 8, 9, and 14 demonstrated significant cytotoxicity against HCT-116 and MCF-7 cells, outperforming doxorubicin and sorafenib.
- Compound 14 exhibited potent VEGFR-2 inhibitory activity, comparable to sorafenib, and effectively reduced VEGF-A levels, indicating anti-angiogenic potential.
- Compound 14 induced apoptosis via programmed cell death and necrosis, significantly increasing apoptotic markers (caspase-3, p53, BAX) and decreasing anti-apoptotic marker BCL2.
- Molecular docking studies confirmed favorable binding of compound 14 to VEGFR-2 active site.
- Pharmacokinetic studies indicated favorable properties, with no P-gp substrate activity and limited blood-brain barrier penetration.
Conclusions:
- Novel quinoxaline-3-propanamides, particularly compounds 8, 9, and 14, represent promising candidates for anti-cancer drug development.
- Compound 14's potent VEGFR-2 inhibition, anti-angiogenic effects, and apoptosis-inducing capabilities warrant further investigation.
- The favorable pharmacokinetic profile suggests enhanced cellular uptake and therapeutic potential for these compounds.
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