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

• Published in: Bioorganic & medicinal chemistry letters 2017-02, Vol.27 (4), p.764-775
• Main Authors: DeBord, Michael A, Southerland, Marie R, Wagers, Patrick O, Tiemann, Kristin M, Robishaw, Nikki K, Whiddon, Kyle T, Konopka, Michael C, Tessier, Claire A, Shriver, Leah P, Paruchuri, Sailaja, Hunstad, David A, Panzner, Matthew J, Youngs, Wiley J
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - toxicity; Benzimidazoles - chemistry; Benzimidazoles - metabolism; Benzimidazoles - toxicity; Carbocyanines - chemistry; Carbocyanines - metabolism; Carbocyanines - toxicity; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - mortality; Carcinoma, Non-Small-Cell Lung - pathology; Cell Line, Tumor; Cell Survival - drug effects; Drug Screening Assays, Antitumor; Humans; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - toxicity; Kaplan-Meier Estimate; Lung Neoplasms - drug therapy; Lung Neoplasms - mortality; Lung Neoplasms - pathology; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred C57BL; Microscopy, Fluorescence; Mitochondria - drug effects; Mitochondria - metabolism; Molecular Conformation; Naphthols - chemistry; Salts - chemistry; Structure-Activity Relationship; Transplantation, Heterologous
• ISSN: 1464-3405
• DOI: 10.1016/j.bmcl.2017.01.035

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 IC values 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 4.4mg/mL using 2-hydroxypropyl-β-cyclodextrin as a chemical excipient, thereby providing sufficient solubility for systemic administration.