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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

DeBord, Michael A.¹  Southerland, Marie R.¹  Wagers, Patrick O.¹  Tiemann, Kristin M.^2,3  Robishaw, Nikki K.¹  Whiddon, Kyle T.¹  Konopka, Michael C.¹  Tessier, Claire A.¹  Shriver, Leah P.^1,4  Paruchuri, Sailaja¹  Hunstad, David A.^2,3  Panzner, Matthew J.¹  Youngs, Wiley J.¹ 

[1] Univ Akron, Dept Chem, Akron, OH 44325 USA

[2] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA

[3] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA

[4] Univ Akron, Dept Biol, Akron, OH 44325 USA

关键词: Imidazolium salt;    Anti-cancer;    Anti-tumor;    Lung cancer;    Cyclodextrin;   

DOI  :  10.1016/j.bmcl.2017.01.035

来源: Elsevier

【 摘 要 】

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 4.4 mg/mL using 2-hydroxypropyl-beta-cyclodextrin as a chemical excipient, thereby providing sufficient solubility for systemic administration. (C) 2017 Elsevier Ltd. All rights reserved.

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