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.

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.