Investigating the Effect of Replacing the Difuran Platform with Benzofurans on the Cytotoxicity of Proximicins Against U-87 MG

Abstract

Grade IV glioma, also known as glioblastoma multiforme (GBM) is an aggressive form of cancer that affects the central nervous system (CNS). Without treatment, the expected median survival is only 3-4 months and with treatment this only increases up to 15 months. Natural products and their analogues have long served as powerful tools for the treatment of various human diseases, including cancer. Many of the anticancer drugs that are currently in clinical use are either natural products, derivatives of natural products, or their analogues. Proximicins A, B and C are a class of newly discovered aminofuran-antibiotics isolated from the MG-37 strains of Verrucosispora found in aquatic environments. These antibiotics were found to possess cytotoxic effects in many cell lines that include U-87 MG, a cell line frequently used to model glioblastoma. Twenty-seven structural analogues were synthesized by replacing the two furan rings in proximicins with benzofuran rings linked to various aromatic and/or heteroaromatic rings via a peptide bond. The aim of this study was to use a cell viability assay, specifically, the MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) to test the cytotoxic effects of these analogues against one human cancerous cell line (U-87 MG) and one human healthy cell line (WI-38), and compare them to those of temozolomide, the chemotherapeutic agent of choice for the treatment of glioblastoma. Two proximicin analogues were found to be more effective than temozolomide in U-87 MG, however, more cytotoxic to WI-38 cells.