title: Synthesis and cytotoxic activities of goniothalamins and derivatives.
abstract: Substituted goniothalamins containing cyclopropane-groups were efficiently prepared in high yields and good selectivity. Antiproliferative activity was measured on three human cancer cell lines (A549, MCF-7, HBL-100), to show which of the structural elements of goniothalamins is mandatory for cytotoxicity. We found that the configuration of the stereogenic centre of the δ-lactone plays an important role for cytotoxicity. In our studies only (R)-configured goniothalamins showed antiproliferative activity, whereby (R)-configuration accords to natural goniothalamin (R)-1. Additionally, the δ-lactone needs to be unsaturated whereas our results show that the vinylic double bond is not mandatory for cytotoxicity. Furthermore, with a two-fold in vitro and in vivo strategy, we determined the inhibitory effect of the compounds to the yeast protein Pdr5. Here, we clearly demonstrate that the configuration seems to be of minor influence, only, while the nature of the substituent of the phenyl ring is of prime importance.
authors.affiliation: Institut für Bioorganische Chemie (IBOC), Heinrich-Heine-Universität Düsseldorf im Forschungszentrum Jülich, Stetternicher Forst, Geb. 15.8, 52426 Jülich, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Weber
authors.affiliation: Institut für Biochemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Döhl
authors.affiliation: Bio-Pharmaceutical Chemistry and Molecular Pharmacology, Faculty of Applied Science, Technische Hochschule Köln, CHEMPARK, E39 51368 Leverkusen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Sachs
authors.affiliation: Institut für Bioorganische Chemie (IBOC), Heinrich-Heine-Universität Düsseldorf im Forschungszentrum Jülich, Stetternicher Forst, Geb. 15.8, 52426 Jülich, Germany.
authors.forename: Anja C M
authors.initials: ACM
authors.lastname: Nordschild
authors.affiliation: IBG-1: Biotechnologie, Forschungszentrum Jülich, 52428 Jülich, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Schröder
authors.affiliation: Bio-Pharmaceutical Chemistry and Molecular Pharmacology, Faculty of Applied Science, Technische Hochschule Köln, CHEMPARK, E39 51368 Leverkusen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kulik
authors.affiliation: BIO-MAR im Augenzentrum Friedrichstadt, Friedrichstraße 140, 40217 Düsseldorf, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Fischer
authors.affiliation: Institut für Biochemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
authors.forename: Lutz
authors.initials: L
authors.lastname: Schmitt
authors.affiliation: Bio-Pharmaceutical Chemistry and Molecular Pharmacology, Faculty of Applied Science, Technische Hochschule Köln, CHEMPARK, E39 51368 Leverkusen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Teusch
authors.affiliation: Institut für Bioorganische Chemie (IBOC), Heinrich-Heine-Universität Düsseldorf im Forschungszentrum Jülich, Stetternicher Forst, Geb. 15.8, 52426 Jülich, Germany; IBG-1: Biotechnologie, Forschungszentrum Jülich, 52428 Jülich, Germany. Electronic address: j.pietruszka@fz-juelich.de.
authors.forename: Jörg
authors.initials: J
authors.lastname: Pietruszka
mesh_terms: D000072283:A549 Cells; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007783:Lactones / Q000737:chemistry; D061986:MCF-7 Cells; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D007783:Lactones; D011753:Pyrones; C103280:goniothalamin
keywords: Asymmetric synthesis; Cytotoxicity; Multidrug exporter; Natural product; Stereoselectivity