Targeting mitochondrial ATP production of glioblastoma using sulfonamide and amide analogs of amantadine and memantine as metabolic inhibitors

Abstract

A library of 67 analogs of amantadine and memantine has been synthesized and screened for activity against 4 mammalian cell lines, including U-87 (glioblastoma). The library was screened using both a traditional cytotoxicity assay and a rapid assay to detect activity as metabolic inhibitors of ATP production. Two protocols were employed to identify activity targeting mitochondrial ATP (TCA cell cycle) production. In Protocol A (DMEM media + 2-DG), 16 compounds were identified as strong hits against U-87 cells at 50 μM. Using Protocol B (L-15 media), 10 compounds were identified as strong hits at 12.5 μM against U-87 cells. Several compounds were identified as hits toward U-87 cells using the rapid assay that were not identified using the traditional cytotoxicity assay. The IC₅₀ values of the hits against U-87 cells were determined against U-87 and non-cancerous HDF cells. The investigation has resulted in the identification of several compounds with the predicted ability to cross the blood-brain barrier that display high potency (0.82 μM for compound 20) and selectivity (selectivity index value ≥7 for compound 24) toward U-87 cells.

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