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Synthesis and Biological Evaluation of Dimeric Furanoid Macroheterocycles: Discovery of New Anticancer Agents

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posted on 15.04.2015, 00:00 by K. C. Nicolaou, Christian Nilewski, Christopher R. H. Hale, Christopher F. Ahles, Chiao An Chiu, Christian Ebner, Abdelatif ElMarrouni, Lifeng Yang, Katherine Stiles, Deepak Nagrath
A recently developed dimerization/macrocyclization was employed to synthesize a series of macroheterocycles which were biologically evaluated, leading to the discovery of a number of potent cytotoxic agents (e.g., 27: GI50 = 51 nM against leukemia CCRF-CEM cell line; 29: GI50 = 99 nM against melanoma MDA-MB-435 cell line). Further biological studies support an apoptosis mechanism of action for these compounds involving deregulation of the tricarboxylic acid cycle activity and suppression of mitochondrial function in cancer cells.