In-vitro, in-silico studies on the proposed penasulfate A and its derivatives as dual inhibitors of α-glucosidases and human cancer cells

Abstract

α-Glucosidase inhibitors have been receiving significant attention from the scientific community in recent years due to their potential in treating a variety of diseases, including diabetes, cancer, and obesity. The synthetic penasulfate A, a novel α-glucosidase inhibitor, displayed outstanding inhibitory activity against α-glucosidases G0660 and G5003 with IC50 values of 11.00 and 9.62 µM, respectively. Two derivatives of the synthetic penasulfate A, namely compound 2 and 3, also inhibited α-glucosidase G0660 with IC50 values of 1101.00 and 111.00 µM separately. Enzyme kinetic experiments showed penasulfate A acted as a mixed inhibitor against α-glucosidase. In addition, MTT cytotoxicity assay revealed that all three synthetic compounds exhibited potent anti-proliferative activity against eight human cancer cell lines, hepatocellular carcinoma cell line (HepG2), breast cancer cell line (MCF-7), colon cancer cell line (HCT116), colorectal cancer cell line (HT29), prostate cancer cell line (DU145), lung cancer cell line (A549), ovarian cancer cell line (SKOV-3) and cervical cancer cell line (HeLa), with IC50 values ranging from 0.04 to 6.77 µM after treatment with compounds for 48 h. Cell morphology observations indicated that anti-proliferative effect of the compounds was induced by apoptosis, which was mostly associated with the late apoptosis state (Q2), confirmed by flow cytometry. Subsequent mechanistic investigation indicated that the synthetic compounds triggered Hela cell apoptosis by reducing its mitochondrial membrane potential, thus leading to an increase in intracellular levels of reactive oxygen species (ROS). Additionally, analysis of apoptosis-related factors verified that the synthetic compounds induced Hela cell apoptosis by upregulating the activity of the protein caspase-3. Furthermore, the binding affinity between compounds and relevant proteins was expressed in total scores and the pose of ligand from the docked complex was visualized using Surflex-Dock in SYBYL-X software. Molecular dynamic simulations were also applied to assess the stability of the targeting enzyme-compound 1 complex. These findings suggest that these compounds could offer promising new lead derivatives for further potential hypoglycemic and anticancer drug discovery.