Novel synthetic chalcones induce apoptosis in the A549 non-small cell lung cancer cells harboring a KRAS mutation

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Wang, Yiqiang^1,4  Hedblom, Andreas^2,3,4  Koerner, Steffi K.^1,4  Li, Mailin^2,3,4  Jernigan, Finith E.^1,4  Wegiel, Barbara^2,3,4  Sun, Lijun^1,4 

[1] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Ctr Drug Discovery & Translat Res, Boston, MA 02215 USA

[2] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Transplant Inst, Boston, MA 02215 USA

[3] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Canc Res Inst, Boston, MA 02215 USA

[4] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Surg, Boston, MA 02215 USA

关键词: Chalcone;    Cell cycle;    Apoptosis;    KRAS;    Non-small cell lung cancer;   

DOI  :  10.1016/j.bmcl.2016.10.063

来源: Elsevier

【 摘 要 】

A series of novel chalcones were synthesized by the Claisen-Schmidt condensation reaction of tetralones and 5-/6-indolecarboxaldehydes. Treatment of human lung cancer cell line harboring KRAS mutation (A549) with the chalcones induced dose-dependent apoptosis. Cell cycle analyses and Western blotting suggested the critical role of the chalcones in interrupting G2/M transition of cell cycle. SAR study demonstrated that substituent on the indole N atom significantly affects the anticancer activity of the chalcones, with methyl and ethyl providing the more active compounds (EC50: 110-200 nM), Compound 1g was found to be > 4-fold more active in the A549 cells (EC50: 110 nM) than in prostate (PC3) or pancreatic cancer (CLR2119, PAN02) cells. Furthermore, compound 1l selectively induced apoptosis of lung cancer cells A549 (EC50: 0.55 mu M) but did not show measurable toxicity in the normal lung bronchial epithelial cells (hBEC) at doses as high as 10 mu M, indicating specificity towards cancer cells. (C) 2016 Elsevier Ltd. All rights reserved.

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