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 IC50 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.
Keywords:
Anti-cancer; Anti-tumor; Cyclodextrin; Imidazolium salt; Lung cancer.
Copyright © 2017 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, Non-U.S. Gov't
MeSH terms
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A549 Cells
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Animals
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / toxicity
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Benzimidazoles / chemistry
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Benzimidazoles / metabolism
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Benzimidazoles / toxicity
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Carbocyanines / chemistry
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Carbocyanines / metabolism
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Carbocyanines / toxicity
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / mortality
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Cell Survival / drug effects
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Drug Screening Assays, Antitumor
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry*
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Imidazoles / toxicity
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Kaplan-Meier Estimate
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Lung Neoplasms / drug therapy
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Lung Neoplasms / mortality
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Lung Neoplasms / pathology
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Membrane Potential, Mitochondrial / drug effects
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Mice
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Mice, Inbred C57BL
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Microscopy, Fluorescence
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Mitochondria / drug effects
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Mitochondria / metabolism
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Molecular Conformation
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Naphthols / chemistry*
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Salts / chemistry
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Structure-Activity Relationship
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Transplantation, Heterologous
Substances
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Antineoplastic Agents
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Benzimidazoles
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Carbocyanines
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Imidazoles
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Naphthols
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Salts
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5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine