Synthesis and Biological Evaluation of N-(1H-Indol-6-ylmethyl)benzenesulfonamide Analogs as Metabolic Inhibitors of Mitochondrial ATP Production in Pancreatic Cancer Cells

Abstract

A library of 26 indolyl sulfonamides and 12 amide and ester analogs based upon the 6-indolyl framework has been synthesized in an effort to target pancreatic cancer. The cytotoxicity of the indolyl sulfonamide compounds has been determined using a traditional (48-h compound exposure) assay against 7 pancreatic cancer cell lines and 1 non-cancerous cell line. The potential role of the compounds as metabolic inhibitors of ATP production was evaluated using a rapid screening (2-h compound exposure) assay developed within our laboratories. The IC₅₀ values of the active compounds were determined using the rapid assay and six compounds displayed an IC₅₀ value <5 μM against one or more pancreatic cancer cell lines. The ester analogs also display activity as potential metabolic inhibitors of ATP production with four of the six compounds displaying an IC₅₀ value <5 μM against one or more pancreatic cancer cell lines.

Keywords: Chemotherapy resistance; Indole; Pancreatic cancer; Sulfonamide; Targeted cancer therapy.