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Research Articles: Therapeutics, Targets, and Development

Synthesis and biological analysis of new curcumin analogues bearing an enhanced potential for the medicinal treatment of cancer

¹ Department of Clinical Oncology, Institute of Development, Aging and Cancer, ² Tohoku University Hospital, and ³ Department of Organic Chemistry, Graduate School of Pharmaceutical Science, Tohoku University; and ⁴ Department of Clinical Oncology, Sendai Medical Center, National Hospital Organization, Sendai, Japan

Requests for reprints: Hiroyuki Shibata, Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan. Phone: 81-22-717-8547; Fax: 81-22-717-8548. E-mail: hiroyuki{at}idac.tohoku.ac.jp

Abstract

Curcumin (diferuloylmethane) is a dietary phytochemical with low toxicity that exhibits growth-suppressive activity against a variety of cancer cells and possesses certain chemopreventive properties. Curcumin has already been the subject of several clinical trials for use as a treatment in human cancers. Synthetic chemical modifications of curcumin have been studied intensively in an attempt to find a molecule with similar but enhanced properties of curcumin. In this study, a series of novel curcumin analogues were synthesized and screened for anticancer activity. New analogues that exhibit growth-suppressive activity 30 times that of curcumin and other commonly used anticancer drugs were identified. Structurally, the new analogues are symmetrical 1,5-diarylpentadienone whose aromatic rings possess an alkoxy substitution at each of the positions 3 and 5. Analysis of the effects of the analogues on the expression of cancer-related genes usually affected by curcumin indicated that some induced the down-regulation of ß-catenin, Ki-ras, cyclin D1, c-Myc, and ErbB-2 at as low as one eighth the concentration at which curcumin normally has an effect. The analogues, however, exhibited neither harmful nor growth-suppressive effects on normal hepatocytes where oncogene products are not activated. They also exhibited no toxicities in vivo that they may provide effective alternative therapies for the prevention and treatment of some human cancers. [Mol Cancer Ther 2006;5(10):2563–71]

Grant support: Grant-in-Aid for Scientific Research (Category C, 16590571) from the Japanese Society for the Promotion of Science (S. Kato, Y. Iwabuchi, and H. Shibata) and Miyagi Health Service Association grant (C. Ishioka).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Y. Iwabuchi and H. Shibata contributed equally to this work.

⁵ Supplementary material for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 3/29/06; revised 6/28/06; accepted 8/16/06.

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