Synthesis and biological evaluation of 1-phenyl-tetrahydro-ß-carboline-based first dual PRMT5/EGFR inhibitors as potential anticancer agents.

Protein arginine methyltransferase 5 (PRMT5) and epidermal growth factor receptor (EGFR) are both involved in the regulation of various cancer-related processes, and their dysregulation or overexpression has been observed in many types of tumors. In this study, we designed and synthesized a series of 1-phenyl-tetrahydro-ß-carboline (THßC) derivatives as the first class of dual PRMT5/EGFR inhibitors. Among the synthesized compounds, 10p showed the most potent dual PRMT5/EGFR inhibitory activity, with IC50 values of 15.47 ± 1.31 and 19.31 ± 2.14 µM, respectively. Compound 10p also exhibited promising antiproliferative activity against A549, MCF7, HeLa, and MDA-MB-231 cell lines, with IC50 values below 10 µM. Molecular docking studies suggested that 10p could bind to PRMT5 and EGFR through hydrophobic, π-π, and cation-π interactions. Furthermore, 10p displayed favorable pharmacokinetic properties and oral bioavailability (F = 30.6%) in rats, and administrated orally 10p could significantly inhibit the growth of MCF7 orthotopic xenograft tumors. These results indicate that compound 10p is a promising hit compound for the development of novel and effective dual PRMT5/EGFR inhibitors as potential anticancer agents.

An Updated Overview of Synthetic α-glucosidase Inhibitors: Chemistry and Bioactivities.

Diabetes mellitus (DM) is a critical global health issue, affecting nearly half a billion people worldwide, with an increasing incidence rate and mortality. Type 2 diabetes is caused by the body's inability to effectively use insulin, and approximately 95% of patients have type 2 diabetes. α-glucosidase has emerged as an important therapeutic target for the treatment of type 2 diabetes. In the past years, three α-glucosidase inhibitors have been approved for clinical use, namely acarbose, voglibose, and miglitol. However, the undesirable effects associated with these carbohydrate mimic-based α-glucosidase inhibitors have limited their clinical applications. Consequently, researchers have shifted their focus towards the development of non-carbohydrate mimic α-glucosidase inhibitors that can safely and effectively manage postprandial hyperglycemia in type 2 diabetes. Herein, this article provides an overview of the synthetic α-glucosidase inhibitors, particularly those based on heterocycles, which have been reported from 2018 to 2022. This article aims to provide useful information for medicinal chemists in further developing clinically available anti-type 2 diabetes drugs.

Discovery of marine phidianidine-based Nrf2 activators and their potential against oxLDL- and HG-induced injury in HUVECs.

One effective strategy for treating atherosclerosis is to inhibit the injury of vascular endothelial cells (VECs) induced by oxidized low-density lipoprotein (oxLDL) and high glucose (HG). This study synthesized and evaluated a series of novel Nrf2 activators derived from the marine natural product phidianidine for their ability to protect human umbilical VECs against oxLDL- and HG-induced injury. The results of in vitro bioassays demonstrated that compound D-36 was the most promising Nrf2 activator, effectively inhibiting the apoptosis of HUVECs induced by oxLDL and HG. Furthermore, Nrf2 knockdown experiments confirmed that compound D-36 protected against oxLDL- and HG-induced apoptosis in HUVECs by activating the Nrf2 pathway. These findings provide important insights into a new chemotype of marine-derived Nrf2 activators that could potentially be optimized to develop effective anti-atherosclerosis agents.