title: The natural diterpene tonantzitlolone A and its synthetic enantiomer inhibit cell proliferation and kinesin-5 function.
abstract: Tonantzitlolone A, a diterpene isolated from the Mexican plant Stillingia sanguinolenta, shows cytostatic activity. Both the natural product tonantzitlolone A and its synthetic enantiomer induce monoastral spindle formation in cell experiments which indicates inhibitory activity on kinesin-5 mitotic motor molecules. These inhibitory effects on kinesin-5 could be verified in in vitro single-molecule motility assays, where both tonantzitlolones interfered with kinesin-5 binding to its cellular interaction partner microtubules in a concentration-dependent manner, yet with a larger effect of the synthetic enantiomer. In contrast to kinesin-5 inhibition, both tonantzitlolone A enantiomers did not affect conventional kinesin-1 function; hence tonantzitlolones are not unspecific kinesin inhibitors. The observed stronger inhibitory effect of the synthetic enantiomer demonstrates the possibility to enhance the overall moderate anti-proliferative effect of the lead compound tonantzitlolon A by chemical modification.
authors.affiliation: Molecular and Cell Physiology, Hannover Medical School (MHH), Carl-Neuberg-Str. 1, D-30625 Hannover, Germany.
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Pfeffer
authors.affiliation: Chemical Biology, Helmholtz Centre for Infection Research (HZI), Inhoffenstraße 7, D-38124 Braunschweig, Germany.
authors.forename: Florenz
authors.initials: F
authors.lastname: Sasse
authors.affiliation: Drittes Physikalisches Institut, Georg-August University Göttingen, Friedrich-Hund-Platz 1, D-37077 Göttingen, Germany.
authors.forename: Christoph F
authors.initials: CF
authors.lastname: Schmidt
authors.affiliation: Drittes Physikalisches Institut, Georg-August University Göttingen, Friedrich-Hund-Platz 1, D-37077 Göttingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lakämper
authors.affiliation: Institute of Organic Chemistry and Center of Biomolecular Drug Research (BMWZ), Leibniz University Hannover, Schneiderberg 1B, D-30167 Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Kirschning
authors.affiliation: Molecular and Cell Physiology, Hannover Medical School (MHH), Carl-Neuberg-Str. 1, D-30625 Hannover, Germany. Electronic address: scholz.tim@mh-hannover.de.
authors.forename: Tim
authors.initials: T
authors.lastname: Scholz
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology*; D019665:Euphorbiaceae / Q000737:chemistry*; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047028:Macrocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D008958:Models, Molecular; D013237:Stereoisomerism
chemical_list: D004224:Diterpenes; C500506:KIF5A protein, human; D047028:Macrocyclic Compounds; C510266:tonantzitlolone; D016547:Kinesins
keywords: Cancer; Cytostatic; Diterpene; Inhibitor; Kinesin spindle protein; Monoaster