Inhibition of Adenosine Triphosphate Production in Pancreatic Cancer Cells by a Library of N-(1H-Indol-4-ylmethyl)benzenesulfonamide and N-(1H-Indol-5-ylmethyl)benzenesulfonamide Analogs

Abstract

A library of 50 indolyl sulfonamides and 9 amide analogs based upon the 4-indolyl and 5-indolyl frameworks has been synthesized to target the metabolic processes of pancreatic cancer. Thirteen of the 50 compounds are identified as cytotoxic at 50 μM using a traditional (48-h compound exposure) assay against 7 pancreatic cancer cell lines and 1 noncancerous cell line. The potential role of the compounds as metabolic inhibitors of adenosine triphosphate (ATP) production is then evaluated using a rapid screening (1-2 h compound exposure) assay developed within our laboratories. The rapid assay identifies ten compounds as strong or moderate hits at 3 μM against the panel of pancreatic and noncancerous cell lines. The IC₅₀ values of the active compounds are determined using the rapid assay in the absence of glucose and four of the compounds display an IC₅₀ value <1 μM against one or more pancreatic cancer cell lines. A comparison of IC₅₀ values of the active compounds in the presence of glucose implicates the potential role of the compounds as oxidative phosphorylation inhibitors of ATP production. Finally, a series of amide analogs are synthesized and screened for activity to determine the structural importance of the sulfonamide functionality.

Keywords: chemotherapy resistances; indoles; oxidative phosphorylation inhibitors; pancreatic cancers.