New sulfonamide derivatives as HDAC inhibitors and apoptosis inducers: design, synthesis, in silico study and anticancer evaluation
TL;DR
The design and synthesis of new sulfonamide derivatives for potential histone deacetylase (HDAC) inhibition showed antiproliferative activity against three cancer cell lines, and this study suggests that compound 10 may serve as a lead molecule for further optimization toward new anticancer drugs.
Abstract
Cancer statistics indicate that more research is required to combat such a global fatal disease. In an attempt to develop an effective anticancer scaffold, we designed and synthesized new sulfonamide derivatives for potential histone deacetylase (HDAC) inhibition. The new derivatives showed antiproliferative activity against three cancer cell lines: HepG-2 (hepatoma), A549 (lung carcinoma), and MCF-7 (breast carcinoma). The most sensitive cancer cell line to the new derivatives was MCF-7, followed by A549 then HepG-2. Compound 10 emerged as the most effective candidate, especially against MCF-7, where it showed an IC50 of 13.56 ± 1.36 µM. Meanwhile, it had an IC50 of 20.03 ± 2.17 and 34.71 ± 4.62 µM against A549 and HepG-2 cells, respectively. Interestingly, molecule 10 exhibited a markedly higher in vitro selectivity toward the tested cancer cell lines than the reference drug 5-fluorouracil (5-FU), with selectivity indices of 8.74 ± 0.88, 5.92 ± 0.74, and 3.41 ± 0.39 against MCF-7, A549, and HepG-2 cells, respectively, compared with 1.59 ± 0.13, 1.16 ± 0.09, and 1.67 ± 0.14 for 5-FU, respectively. These findings indicate greater in vitro selectivity of compound 10 toward the tested cancer cells relative to the normal WI-38 cell line; however, they should not be interpreted as evidence of superior overall safety compared with 5-FU. Furthermore, 10 caused inhibition to HDAC especially HDAC-2, showing an IC50 of 2.27 ± 0.07 µM, in comparison to the reference molecule entinostat (IC50 of 1.21 ± 0.04 µM). The Annexin V-FITC/PI assay indicated that apoptosis was the predominant mode of cell death caused by compound 10. Compound 10 caused an approximately 15-fold increase in the total number of apoptotic MCF-7 cells relative to untreated control cells. Meanwhile, compound 10 increased the expression levels of apoptotic markers p53, and the protein levels of caspase-9 in MCF-7 cells. Whereas it decreased the expression levels of Bcl-2 and VEGF. The docking data that revealed insights into the binding pattern of compound 10 to HDAC-2, were consistent with the biological data. Finally, this study suggests that compound 10 may serve as a lead molecule for further optimization toward new anticancer drugs.
