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Design, synthesis, and in silico study of VEGFR-2 and HDAC dual acting quinazoline based molecules for anticancer
Abdallah E Abdallah1, Esmail M El-Fakharany2, Yousra A El-Maradny3
1Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt.
Abstract:
Cancer remains a formidable disease with significantly high mortality rates worldwide. Herein, we attempted to design and evaluate a new class of VEGFR-2 and HDAC dual acting anticancer agents. The rationale was based on the defined pharmacophores of VEGFR-2 inhibitors and HDAC inhibitors, as we synthesized new quinazolinone based-benzamides that bring together both features. The new candidates showed considerable in vitro activity against MDA-MB-231 and HCT-116 cancer cell lines, in particular 4-hydroxyphenylbenzamide derivative of 3-ethylquinazolinone 7d, which revealed IC50 of 5.39 ± 0.08 μM and 4.11 ± 0.13 μM, in comparison with IC50 of 29.13 ± 2.28 μM and 33.50 ± 2.43 μM, obtained for the reference drug, sorafenib, respectively. So, 7d was approximately 5.4-fold and 8.2-fold more potent than sorafenib against the aforementioned cell lines, respectively. Additionally, 7d had far better selectivity to cancer cells, showing selectivity indices of 5.11 and 6.68, compared to 1.73 and 1.51 recorded for sorafenib against the two cancer cell lines, respectively. Furthermore, it also showed a significant dual inhibition of VEGFR-2 and HDAC-2. It showed IC50 of 0.407 ± 0.015 μM against VEGFR-2, revealing approximately half the potency of sorafenib. Whereas, It was approximately 1.26 times more potent than vorinostat against HDAC-2, demonstrating an IC50 of 0.363 ± 0.013 μM. Furthermore, 7a was proven to be an apoptotic inducer to HCT-116 cells, increasing the apoptosis rate by 10-folds and causing cell cycle arrest at the G1 phase. Meanwhile, the expression level of caspase-3 and the BAX/BCL-2 ratio were markedly elevated in HCT-116 cells treated with 7d. Finally, the presented data are reliable for developing dual VEGFR-2 and HDAC inhibitors as anticancer drugs and reveal lead molecules for such purpose.
Insights
Researchers developed novel dual-acting anticancer agents targeting VEGFR-2 and HDAC. Compound 7d demonstrated superior potency and selectivity against cancer cells compared to sorafenib, offering a promising new therapeutic strategy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Cancer poses a significant global health challenge with high mortality rates.
- Targeting key pathways like VEGFR-2 and HDAC is a crucial strategy in cancer therapy.
- Developing dual-acting agents offers a promising approach to overcome resistance and improve efficacy.
Purpose of the Study:
- To design and synthesize novel quinazolinone-based benzamides with dual inhibitory activity against VEGFR-2 and HDAC.
- To evaluate the in vitro anticancer potential of these new compounds against human cancer cell lines.
- To assess the mechanism of action, including apoptosis induction and cell cycle arrest.
Main Methods:
- Synthesis of a new series of quinazolinone-based benzamides incorporating VEGFR-2 and HDAC pharmacophores.
- In vitro evaluation of cytotoxicity against MDA-MB-231 and HCT-116 cancer cell lines.
- Enzyme inhibition assays for VEGFR-2 and HDAC-2.
- Apoptosis assays and cell cycle analysis using flow cytometry.
- Western blot analysis to assess apoptosis-related protein expression.
Main Results:
- The synthesized compounds exhibited significant in vitro anticancer activity.
- Compound 7d showed superior potency and selectivity against MDA-MB-231 and HCT-116 cells compared to sorafenib.
- Compound 7d demonstrated potent dual inhibition of VEGFR-2 and HDAC-2, outperforming reference drugs.
- 7d induced apoptosis and G1 cell cycle arrest in HCT-116 cells, evidenced by elevated caspase-3 and BAX/BCL-2 ratio.
Conclusions:
- The novel quinazolinone-based benzamides are effective dual VEGFR-2 and HDAC inhibitors.
- Compound 7d represents a promising lead molecule for developing new anticancer therapeutics.
- Dual-targeting agents offer a viable strategy for enhanced cancer treatment outcomes.
