Quinazoline‐chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in‐silico studies of potential anticancer activity against multiple myeloma
Mostafa A. Mansour, Asmaa M. AboulMagd, Samar H. Abbas, Mohamed Abdel‐Aziz, Hamdy M. Abdel‐Rahman
Abstract
Abstract Two new series of quinazoline‐chalcone hybrids were designed, synthesized as histone deacetylase (HDAC)/epidermal growth factor receptor (EGFR) dual inhibitors, and screened in vitro against the NCI 60 human cancer cell line panel. The most potent derivative, compound 5e bearing a 3,4,5‐trimethoxyphenyl chalcone moiety, showed the most effective growth inhibition value against the panel of NCI 60 human cancer cell lines. Thus, it was selected for further investigation for NCI 5 log doses. Interestingly, this trimethoxy‐substituted analog inhibited the proliferation of Roswell Park Memorial Institute (RPMI)‐8226 cells by 96%, at 10 µM with IC 50 = 9.09 ± 0.34 µM and selectivity index = 7.19 against normal blood cells. To confirm the selectivity of this compound, it was evaluated against a panel of tyrosine kinase enzymes. Mechanistically, it successfully and selectively inhibited HDAC6, HDAC8, and EGFR with IC 50 = 0.41 ± 0.015, 0.61 ± 0.027, and 0.09 ± 0.004 µM, respectively. Furthermore, the selected derivative induced apoptosis via the mitochondrial apoptotic pathway by raising the Bax/Bcl‐2 ratio and activating caspases 3, 7, and 9. Also, the flow cytometry analysis of RPMI‐8226 cells showed that the trimethoxy‐substituted analog produced cell cycle arrest in the G1 and S phases at 55.82%. Finally, an in silico study was performed to explore the binding interaction of the most active compound within the zinc‐containing binding site of HDAC6 and HDAC8.