Synthesis, characterization, in vitro SAR and in vivo evaluation of N,N′bisnaphthylmethyl 2-alkyl substituted imidazolium salts against NSCLC

Michael A. DeBord, Marie R. Southerland, Patrick O. Wagers, Kristin M. Tiemann, Nikki K. Robishaw, Kyle T. Whiddon, Michael C. Konopka, Claire A. Tessier, Leah P. Shriver, Sailaja Paruchuri, David A. Hunstad, Matthew J. Panzner, Wiley J. Youngs

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3 Scopus citations

Abstract

Alkyl- and N,N′-bisnaphthyl-substituted imidazolium salts were tested in vitro for their anti-cancer activity against four non-small cell lung cancer cell lines (NCI–H460, NCI–H1975, HCC827, A549). All compounds had potent anticancer activity with 2 having IC50values in the nanomolar range for three of the four cell lines, a 17-fold increase in activity against NCI-H1975 cells when compared to cisplatin. Compounds 1–4 also showed high anti-cancer activity against nine NSCLC cell lines in the NCI-60 human tumor cell line screen. In vitro studies performed using the Annexin V and JC-1 assays suggested that NCI-H460 cells treated with 2 undergo an apoptotic cell death pathway and that mitochondria could be the cellular target of 2 with the mechanism of action possibly related to a disruption of the mitochondrial membrane potential. The water solubilities of 1–4 was over 4.4 mg/mL using 2-hydroxypropyl-β-cyclodextrin as a chemical excipient, thereby providing sufficient solubility for systemic administration.

Original languageEnglish
Pages (from-to)764-775
Number of pages12
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number4
DOIs
StatePublished - Jan 1 2017

Keywords

  • Anti-cancer
  • Anti-tumor
  • Cyclodextrin
  • Imidazolium salt
  • Lung cancer

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    DeBord, M. A., Southerland, M. R., Wagers, P. O., Tiemann, K. M., Robishaw, N. K., Whiddon, K. T., Konopka, M. C., Tessier, C. A., Shriver, L. P., Paruchuri, S., Hunstad, D. A., Panzner, M. J., & Youngs, W. J. (2017). Synthesis, characterization, in vitro SAR and in vivo evaluation of N,N′bisnaphthylmethyl 2-alkyl substituted imidazolium salts against NSCLC. Bioorganic and Medicinal Chemistry Letters, 27(4), 764-775. https://doi.org/10.1016/j.bmcl.2017.01.035