title: In vitro antitumor SAR of threo/cis/threo/cis/erythro bis-THF acetogenins: correlations with their inhibition of mitochondrial Complex I.
abstract: Annonaceous acetogenins (ACG) are a large family of natural products that have been described as the most potent in vitro inhibitors of the mitochondrial respiratory chain Complex I. During the last two decades a large number of related structures have been discovered, increasing the number of members of this family. The large diversity of structural moieties and the general trends observed for inhibiting both growth of tumor cell lines and mitochondrial respiratory chain activity have resulted in the classification of these compounds into several structural groups according to their potency. Among them, the adjacent bis-tetrahydrofuranic acetogenins (bis-THF ACG) with a threo/cis/threo/cis/erythro relative configuration, have been described as the most potent subgroup, the prototypical member of which, rolliniastatin-1, was originally isolated from Rollinia membaranacea seeds. In this report we describe the different structure-activity relationships (SAR) observed for some natural ACG and semisynthetic derivatives as growth inhibitors of human tumor breast, lung, liver, and colon cell lines. All the compounds assayed showed potencies in the micromolar range. Trends observed in the cytotoxicity assay have been compared with previous data reported for these compounds as inhibitors of mitochondrial respiratory chain.
authors.affiliation: CIBE-Merck Research Laboratories, MERCK, SHARP & DOHME de ESPANIA S.A., C/ Josefa Valcárcel, 38 Madrid 28027, Spain. immaculada_royo@merck.com
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Royo
authors.forename: Nuria
authors.initials: N
authors.lastname: DePedro
authors.forename: Ernesto
authors.initials: E
authors.lastname: Estornell
authors.forename: Diego
authors.initials: D
authors.lastname: Cortes
authors.forename: Fernando
authors.initials: F
authors.lastname: Peláez
authors.forename: José R
authors.initials: JR
authors.lastname: Tormo
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy; D015195:Drug Design; D004579:Electron Transport / Q000187:drug effects; D005260:Female; D005663:Furans / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D008175:Lung Neoplasms / Q000188:drug therapy; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013810:Therapeutic Equivalency
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005663:Furans; C061022:bullatacin