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

Abstract

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 (EC 50 : 110-200 nM), Compound 1g was found to be >4-fold more active in the A549 cells (EC 50 : 110 nM) than in prostate (PC3) or pancreatic cancer (CLR2119, PAN02) cells. Furthermore, compound 1l selectively induced apoptosis of lung cancer cells A549 (EC 50 : 0.55 μM) but did not show measurable toxicity in the normal lung bronchial epithelial cells (hBEC) at doses as high as 10 μM, indicating specificity towards cancer cells. Graphical Abstract KeywordsChalcone; Cell cycle; Apoptosis; KRAS; Non-small cell lung cancer * Corresponding authors: LS: Tel.: +1-617-667-1902; lsun1@bidmc.harvard.edu. Or BW: Tel: 617-735-2846; bwegiel@bidmc.harvard.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Chalcone is a key structural moiety occurring in a number of natural products known to have broad biological activities, including curcumin 3 and xanthohumol. [4][5] It has gained considerable interests in the synthesis of novel anticancer agents with diverse of mechanisms of action. 6-14 HHS Public AccessWe had previously described indole and indazoline series of anticancer agents capable of overcoming multi-drug resistance [15][16][17][18] . Herein we report the identification and preliminary structure-activity relationship (SAR) findings of novel indolyl-tetralone chalcones in the A549 NSCLC cell line, a widely used in vitro model system for investigating KRAS mutation. Our survey of published literature indicated that there were no known chalcones that contain the same key moieties of tetralone and 5-/6-indolyl group. [19][20][21][22][23][24][25][26][27][28] We report that a number of the novel chalcones were highly potent in inducing apoptosis of A549 cells, with sub-μM EC 50 , which are not commonly observed in reported synthetic chalcones. Among them, compound 1l demonstrated preferential cytotoxicity in A549 cells (EC 50 : 0.55 μM) and did not show any toxicity in the normal lung epithelial cells at concentrations ranging from 0.01 to 10 μM.The indolyl-tetralone chalcones (1 and 2) were synthesized...

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