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Novel N-Arylmethyl-aniline/chalcone hybrids as potential VEGFR inhibitors: synthesis, biological evaluations, and
Hesham Haffez1,2, Nosaiba A Elsayed3, Marwa F Ahmed3
1Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Cairo, Ain Helwan, Egypt.
Abstract:
Significant advancements have been made in the domain of targeted anticancer therapy for the management of malignancies in recent times. VEGFR-2 is characterised by its pivotal involvement in angiogenesis and subsequent mechanisms that promote tumour cells survival. Herein, novel N-arylmethyl-aniline/chalcone hybrids 5a-5n were designed and synthesised as potential anticancer and VEGFR-2 inhibitors. The anticancer activity was evaluated at the NCI-USA, resulting in the identification of 10 remarkably potent molecules 5a-5j that were further subjected to the five-dose assays. Thereafter, they were explored for their VEGFR-2 inhibitory activity where 5e and 5h emerged as the most potent inhibitors. 5e and 5h induced apoptosis with cell cycle arrest at the SubG0-G1 phase within HCT-116 cells. Moreover, their impact on some key apoptotic genes was assessed, suggesting caspase-dependent apoptosis. Furthermore, molecular docking and molecular dynamics simulations were conducted to explore the binding modes and stability of the protein-ligand complexes.
Insights
Novel hybrid molecules were synthesized and tested for anticancer properties and their ability to inhibit VEGFR-2, a key factor in tumor growth. Compounds 5e and 5h showed significant potential, inducing apoptosis and cell cycle arrest in cancer cells.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Pharmacology
Background:
- Targeted anticancer therapies represent significant advancements in cancer management.
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) plays a critical role in tumor angiogenesis and survival.
- Inhibiting VEGFR-2 is a promising strategy for anticancer drug development.
Purpose of the Study:
- To design and synthesize novel N-arylmethyl-aniline/chalcone hybrids as potential anticancer agents and VEGFR-2 inhibitors.
- To evaluate the anticancer activity and VEGFR-2 inhibitory potential of the synthesized compounds.
- To elucidate the mechanism of action of the most potent compounds.
Main Methods:
- Synthesis of N-arylmethyl-aniline/chalcone hybrids (compounds 5a-5n).
- In vitro anticancer activity screening at NCI-USA and subsequent five-dose assays.
- In vitro VEGFR-2 inhibitory activity evaluation.
- Apoptosis induction and cell cycle analysis in HCT-116 cells.
- Assessment of apoptotic gene expression.
- Molecular docking and molecular dynamics simulations.
Main Results:
- Ten compounds (5a-5j) exhibited potent anticancer activity.
- Compounds 5e and 5h were identified as the most potent VEGFR-2 inhibitors.
- Compounds 5e and 5h induced apoptosis and cell cycle arrest at the SubG0-G1 phase in HCT-116 cells.
- Evidence suggests caspase-dependent apoptosis.
- Molecular simulations provided insights into binding modes and complex stability.
Conclusions:
- Novel N-arylmethyl-aniline/chalcone hybrids demonstrate significant anticancer potential.
- Compounds 5e and 5h are potent inhibitors of VEGFR-2, offering a promising avenue for targeted cancer therapy.
- The mechanism involves the induction of caspase-dependent apoptosis and cell cycle arrest.
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