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Design, Synthesis, Molecular Docking, and Anticancer Activity of Phthalazine Derivatives as VEGFR-2 Inhibitors
Abdel-Ghany A El-Helby1, Rezk R A Ayyad1,2, Helmy Sakr1
1Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt.
Abstract:
Novel series of phthalazine derivatives 6-11 were designed, synthesized, and evaluated for their anticancer activity against two human tumor cell lines, HCT-116 human colon adenocarcinoma and MCF-7 breast cancer cells, targeting the VEGFR-2 enzyme. Compounds 7a,b and 8b,c showed the highest anticancer activities against both HCT116 human colon adenocarcinoma cells with IC50 of 6.04 ± 0.30, 13.22 ± 0.22, 18 ± 0.20, and 35 ± 0.45 μM, respectively, and MCF-7 breast cancer cells with IC50 of 8.8 ± 0.45, 17.9 ± 0.50, 25.2 ± 0.55, and 44.3 ± 0.49 μM, respectively, in comparison to sorafenib as reference drug with IC50 of 5.47 ± 0.3 and 7.26 ± 0.3 μM, respectively. Eleven compounds in this series were further evaluated for their inhibitory activity against VEGFR-2, where compounds 7a, 7b, 8c, and 8b also showed the highest VEGFR-2 inhibition with IC50 of 0.11 ± 0.01, 0.31 ± 0.03, 0.72 ± 0.08, and 0.91 ± 0.08 μM, respectively, in comparison to sorafenib as reference ligand with IC50 of 0.1 ± 0.02. Furthermore, molecular docking studies were performed for all synthesized compounds to predict their binding pattern and affinity towards the VEGFR-2 active site, in order to rationalize their anticancer activity in a qualitative way.
Insights
New phthalazine derivatives show potent anticancer activity by inhibiting the vascular endothelial growth factor receptor 2 (VEGFR-2). Compounds 7a,b and 8b,c demonstrated significant efficacy against colon and breast cancer cells, warranting further investigation.
Area of Science:
- Medicinal Chemistry
- Oncology
- Pharmacology
Background:
- Cancer remains a leading cause of mortality worldwide, necessitating the development of novel therapeutic agents.
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) is a key target in angiogenesis and cancer progression.
- Phthalazine derivatives represent a promising scaffold for anticancer drug discovery.
Purpose of the Study:
- To design, synthesize, and evaluate a novel series of phthalazine derivatives for anticancer activity.
- To investigate the inhibitory potential of these compounds against the VEGFR-2 enzyme.
- To explore the binding interactions of the synthesized compounds with the VEGFR-2 active site through molecular docking.
Main Methods:
- Synthesis of eleven novel phthalazine derivatives (compounds 6-11).
- In vitro anticancer activity evaluation against HCT-116 (colon adenocarcinoma) and MCF-7 (breast cancer) cell lines.
- Enzyme inhibition assays against VEGFR-2.
- Molecular docking studies to predict binding modes and affinities.
Main Results:
- Compounds 7a,b and 8b,c exhibited significant anticancer activity against both HCT-116 and MCF-7 cell lines, with IC50 values comparable to the reference drug sorafenib.
- Compounds 7a, 7b, 8c, and 8b demonstrated potent inhibition of VEGFR-2, with IC50 values in the nanomolar range, similar to sorafenib.
- Molecular docking studies provided insights into the binding patterns and affinities of the active compounds within the VEGFR-2 active site.
Conclusions:
- The synthesized phthalazine derivatives represent a promising class of anticancer agents targeting VEGFR-2.
- Compounds 7a,b and 8b,c show potential for further development as therapeutic candidates for colon and breast cancers.
- The study provides a foundation for the rational design of more potent VEGFR-2 inhibitors based on the phthalazine scaffold.
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