Curcumin analog cytotoxicity against breast cancer cells: Exploitation of a redox-dependent mechanism

• Type of Material: Article
• Authors: Aiming Sun, Emory University; Yang J. Lu, Emory University; Haipeng Hu, Emory University; Mamoru Shoji, Emory University; Dennis C Liotta, Emory University; James P Snyder, Emory University
• Language: English
• Date: 2009-12-01
• Publisher: Elsevier
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2009 Elsevier Ltd. All rights reserved.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bmcl.2009.10.023
• Title of Journal or Parent Work: Bioorganic and Medicinal Chemistry Letters
• ISSN: 0960-894X
• Volume: 19
• Issue: 23
• Start Page: 6627
• End Page: 6631
• Grant/Funding Information: This work was financially supported by the National Institutes of Health (NIH) grants R21 CA82995-01A1 and U.S. Department of Defense, the Division of U.S. Army DAMD17-00-1-0241 (to M. Shoji) and 1 U54 HG003918 (to J.P. Snyder).
• Research Categories: Chemistry, General; Health Sciences, Oncology

Abstract

A series of novel curcumin analogs, symmetrical dienones, were previously shown to possess cytotoxic, anti-angiogenic and anti-tumor activities. Analogs 1 (EF24) and 2 (EF31) share the dienone scaffold and serve as Michael acceptors. We propose that the anticancer effects of 1 and 2 are mediated in part by redox-mediated induction of apoptosis. In order to support this concept, 1 and 2 were treated with L-glutathione (GSH) and cysteine containing dipeptides under mild conditions to form colorless water-soluble adducts, which were identified by LC/MS. Comparison of the cytotoxic action of 1, 2 and the corresponding conjugates, 1-(GSH)2 and 2-(GSH)2, illustrated that the two classes of compounds exhibit essentially identical cell killing capabilities. Compared with the yellow, somewhat light sensitive and nearly water insoluble compounds 1 and 2, the glutathione conjugates represent a promising new series of stable and soluble anti-tumor pro-drugs.