title: In vitro antitumor structure-activity relationships of threo/trans/threo mono-tetrahydrofuranic acetogenins: correlations with their inhibition of mitochondrial complex I.
abstract: In this study we evaluated a mono-tetrahydrofuranic subgroup of natural acetogenins that had shown in previous enzyme inhibition studies different potency trends compared with the bis-tetrahydrofuranic acetogenin subgroup. The compounds were tested against colon, breast, lung, liver, and ovarian tumor cell lines. A drug-resistant ovarian cell line was also included in the panel. In general the compounds were more potent than doxorubicin. The goal was to determine how well the mitochondrial complex I inhibition correlates with the in vitro antitumor potency of these natural mono-tetrahydrofuranic acetogenins and of some derivatives. The results indicate that both the reduction of the terminal gamma-lactone after its translactonization and the introduction of an hydroxylimine group in the alkyl chain, near the mono-tetrahydrofuranic moiety, increased the antitumor activity, even against the doxorubicin-resistant cell line.
authors.affiliation: CIBE-Merck Research Laboratories, Merck, Sharp & Dohme de España S.A., C/Josefa Valcárcel, 38, Madrid 28027, Spain. jose_tormo@merck.com
authors.forename: José R
authors.initials: JR
authors.lastname: Tormo
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Royo
authors.forename: Teresa
authors.initials: T
authors.lastname: Gallardo
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Zafra-Polo
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; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005233:Fatty Alcohols / Q000737:chemistry* / Q000494:pharmacology*; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D054378:Acetogenins; D000970:Antineoplastic Agents; D005233:Fatty Alcohols; D005663:Furans; D007783:Lactones; D009097:Multienzyme Complexes; D013778:Tetrazolium Salts; D013844:Thiazoles; C018674:tetrahydrofuran; C053442:annonacin; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; C022616:thiazolyl blue