Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 96, Issue -, Pages 173-186Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.04.018
Keywords
Synthesis; Benzothiazole; Indole-based moiety; 3D-QSAR; Antitumor activity
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Funding
- Program for Liaoning Excellent Talents in University [LR2014030]
- National Natural Science Foundation of China [81102470]
- National High Technology Research and Development Program of China (863 Program) [2012AA020305]
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Through a structure-based molecular hybridization approach, a series of novel benzothiazole derivatives bearing indole-based moiety were designed, synthesized and screened for in vitro antitumor activity against four cancer cell lines (HT29, H460, A549 and MDA-MB-231). Most of them showed moderate to excellent activity against all the tested cell lines. Among them, compounds 20a-w with substituted benzyl-1H-indole moiety showed better selectivity against HT29 cancer cell line than other compounds. Compound 20d exhibited excellent antitumor activity with IC50 values of 0.024, 0.29, 0.84 and 0.88 mu M against HT29, H460, A549 and MDA-MB-231, respectively. Further mechanism studies indicated that the marked pharmacological activity of compound 20d might be ascribed to activation of procaspase-3 (apoptosis-inducing) and cell cycle arrest, which had emerged as a lead for further structural modifications. Furthermore, 3D-QSAR model (training set: q(2) = 0.850, r(2) = 0.987, test set: r(2) = 0.811) was built to provide a comprehensive guide for further structural modification and optimization. (C) 2015 Published by Elsevier Masson SAS.
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