title: In vitro antitumor structure-activity relationships of threo/trans/threo/trans/erythro bis-tetrahydrofuranic acetogenins: correlations with their inhibition of mitochondrial complex I.
abstract: Annonaceous acetogenins are known to be cytotoxic against tumor cell lines by virtue of their inhibition of mitochondrial complex I. We decided to conclude part of our recent revisions of the different structure-activity relationships (SARs) found within these compounds with a detailed description of the cytotoxic activity, and correlations with the inhibition of the target enzyme, of the broadest subclass of this family of natural products, the bis-tetrahydrofuranic acetogenins (bis-THF ACGs) of threo/trans/threo/trans/erythro relative configuration. Five naturally occurring ACGs and more than 10 semisynthetic analogs were tested against the MCF-7 (breast), A-549 (lung), HepG2 (liver), HT-29 (colon), MES-SA (ovary), and a multidrug-resistant (MDR-MES-SA/Dx5) cell lines using the MTr cytotoxicity assay to determine if the mitochondrial complex I inhibition correlated with the in vitro antitumor potency of the most common ACGs. Results indicated that a previously observed trend for other subclasses of ACGs between the ED50 of the cytotoxicity assay and the polarity of compounds was not present in this set and that there were several specific interactions that enhanced the antitumor activity. For example, some of the guanacone derivatives prepared were two orders of magnitude more potent than the parent compound for specific cell lines.
authors.affiliation: CIBE-Merck Research Laboratories, MERCK, SHARP & DOHME de ESPANA S.A., C/Josefa Valcdrcel, 38, Madrid 28027, Spain. jose_tormo@merck.com
authors.forename: José R
authors.initials: JR
authors.lastname: Tormo
authors.forename: Nuria
authors.initials: N
authors.lastname: DePedro
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Royo
authors.forename: Isabel
authors.initials: I
authors.lastname: Barrachina
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Zafra-Polo
authors.forename: Cristina
authors.initials: C
authors.lastname: Cuadrillero
authors.forename: Pilar
authors.initials: P
authors.lastname: Hernández
authors.forename: Diego
authors.initials: D
authors.lastname: Cortes
authors.forename: Fernando
authors.initials: F
authors.lastname: Peláez
mesh_terms: D054378:Acetogenins; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002417:Cattle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D005233:Fatty Alcohols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D054378:Acetogenins; D000972:Antineoplastic Agents, Phytogenic; D005233:Fatty Alcohols; D005663:Furans; D007783:Lactones; D042967:Electron Transport Complex I