ABSTRACT
On the basis of the observed biological activity of coumarin and acrylamide derivatives, a new set of coumarin-acrylamide-CA-4 hybrids was designed and synthesized. These compounds were investigated for their cytotoxic activity against cancerous human liver cell line HepG2 cells using 5-fluorouracil (5-FU) as a reference drug. Compound 6e had promising antiproliferative activity with an IC50 value of 1.88 µM against HepG2 cells compared to 5-FU (IC50 = 7.18 µM). The results of ß-tubulin polymerization inhibition indicated that coumarin-acrylamide derivative 6e was the most active, with a percentage inhibition value of 84.34% compared to podophyllotoxin (88.19% ß-tubulin inhibition). Moreover, the active coumarin-acrylamide molecule 6e exerted cell cycle cession at the G2/M phase stage of HepG2 cells. In addition, this compound produced a 15.24-fold increase in apoptotic cell induction compared to no-treatment control. These observations were supported by histopathological studies of liver sections. The conducted docking studies illustrated that 6e is perfectly positioned within the tubulin colchicine binding site, indicating a significant interaction that may underlie its potent tubulin inhibitory activity. The main objective of the study was to develop new potent anticancer compounds that might be further optimized to prevent the progression of cancer disease.
ABSTRACT
Overexpression of HDAC 2 promotes cell proliferation in ovarian cancer. HDAC 2 is involved in chromatin remodeling, transcriptional repression, and the formation of condensed chromatin structures. Targeting HDAC 2 presents a promising therapeutic approach for correcting cancer-associated epigenetic abnormalities. Consequently, HDAC 2 inhibitors have evolved as an attractive class of anti-cancer agents. This work intended to investigate the anti-cancer abilities and underlying molecular mechanisms of Rhamnetin in human epithelial ovarian carcinoma cells (SKOV3), which remain largely unexplored. We employed various in vitro methods, including MTT, apoptosis study, cell cycle analysis, fluorescence microscopy imaging, and in vitro enzymatic HDAC 2 protein inhibition, to examine the chemotherapeutic sensitivity of Rhamnetin in SKOV3 cells. Additionally, we conducted in silico studies using molecular docking, MD simulation, MM-GBSA, DFT, and pharmacokinetic analysis to investigate the binding interaction mechanism within Rhamnetin and HDAC 2, alongside the compound's prospective as a lead candidate. The in vitro assay confirmed the cytotoxic effects of Rhamnetin on SKOV3 cells, through its inhibition of HDAC 2 activity. Rhamnetin, a nutraceutical flavonoid, halted at the G1 phase of the cell cycle and triggered apoptosis in SKOV3 cells. Furthermore, computational studies provided additional evidence of its stable binding to the HDAC 2 protein's binding site cavity. Based on our findings, we conclude that Rhamnetin effectively promotes apoptosis and mitigates the proliferation of SKOV3 cells through HDAC 2 inhibition. These results highlight Rhamnetin as a potential lead compound, opening a new therapeutic strategy for human epithelial ovarian cancer.Communicated by Ramaswamy H. Sarma.
