title: Synthesis, characterization, in vitro SAR and in vivo evaluation of N,N'bisnaphthylmethyl 2-alkyl substituted imidazolium salts against NSCLC.
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 4.4mg/mL using 2-hydroxypropyl-β-cyclodextrin as a chemical excipient, thereby providing sufficient solubility for systemic administration.
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: DeBord
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States.
authors.forename: Marie R
authors.initials: MR
authors.lastname: Southerland
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States.
authors.forename: Patrick O
authors.initials: PO
authors.lastname: Wagers
authors.affiliation: Departments of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, United States.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Tiemann
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States.
authors.forename: Nikki K
authors.initials: NK
authors.lastname: Robishaw
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States.
authors.forename: Kyle T
authors.initials: KT
authors.lastname: Whiddon
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Konopka
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States.
authors.forename: Claire A
authors.initials: CA
authors.lastname: Tessier
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States; Department of Biology, University of Akron, Akron, OH 44325, United States.
authors.forename: Leah P
authors.initials: LP
authors.lastname: Shriver
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States.
authors.forename: Sailaja
authors.initials: S
authors.lastname: Paruchuri
authors.affiliation: Departments of Pediatrics and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, United States.
authors.forename: David A
authors.initials: DA
authors.lastname: Hunstad
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Panzner
authors.affiliation: Department of Chemistry, University of Akron, Akron, OH 44325, United States. Electronic address: youngs@uakron.edu.
authors.forename: Wiley J
authors.initials: WJ
authors.lastname: Youngs
mesh_terms: D000072283:A549 Cells; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D002232:Carbocyanines / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008968:Molecular Conformation; D009284:Naphthols / Q000737:chemistry*; D012492:Salts / Q000737:chemistry; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D001562:Benzimidazoles; D002232:Carbocyanines; D007093:Imidazoles; D009284:Naphthols; D012492:Salts; C068624:5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine
keywords: Anti-cancer; Anti-tumor; Cyclodextrin; Imidazolium salt; Lung cancer