2. Academic Validation
  3. Synthesis and cytotoxic activities of goniothalamins and derivatives

Synthesis and cytotoxic activities of goniothalamins and derivatives

  • Bioorg Med Chem. 2017 Nov 15;25(22):6115-6125. doi: 10.1016/j.bmc.2017.02.004.
Anja Weber 1,  Katja Döhl 2,  Julia Sachs 3,  Anja C M Nordschild 1,  Dennis Schröder 4,  Andrea Kulik 3,  Thomas Fischer 5,  Lutz Schmitt 2,  Nicole Teusch 3,  Jörg Pietruszka 6
Affiliations

Affiliations

  • 1 Institut für Bioorganische Chemie (IBOC), Heinrich-Heine-Universität Düsseldorf im Forschungszentrum Jülich, Stetternicher Forst, Geb. 15.8, 52426 Jülich, Germany.
  • 2 Institut für Biochemie, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany.
  • 3 Bio-Pharmaceutical Chemistry and Molecular Pharmacology, Faculty of Applied Science, Technische Hochschule Köln, CHEMPARK, E39 51368 Leverkusen, Germany.
  • 4 IBG-1: Biotechnologie, Forschungszentrum Jülich, 52428 Jülich, Germany.
  • 5 BIO-MAR im Augenzentrum Friedrichstadt, Friedrichstraße 140, 40217 Düsseldorf, Germany.
  • 6 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.
PMID: 28214230 DOI: 10.1016/j.bmc.2017.02.004
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.

Keywords

Asymmetric synthesis; Cytotoxicity; Multidrug exporter; Natural product; Stereoselectivity.

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