title: Synthesis and biological evaluation of dimeric furanoid macroheterocycles: discovery of new anticancer agents.
abstract: 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.
authors.forename: K C
authors.initials: KC
authors.lastname: Nicolaou
authors.forename: Christian
authors.initials: C
authors.lastname: Nilewski
authors.forename: Christopher R H
authors.initials: CR
authors.lastname: Hale
authors.affiliation: ‡Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Ahles
authors.affiliation: ‡Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Chiao An
authors.initials: CA
authors.lastname: Chiu
authors.affiliation: ‡Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
authors.forename: Christian
authors.initials: C
authors.lastname: Ebner
authors.forename: Abdelatif
authors.initials: A
authors.lastname: ElMarrouni
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yang
authors.forename: Katherine
authors.initials: K
authors.lastname: Stiles
authors.forename: Deepak
authors.initials: D
authors.lastname: Nagrath
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D019281:Dimerization; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005663:Furans / Q000737:chemistry*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D006571:Heterocyclic Compounds; C039281:furan