The natural diterpene tonantzitlolone A and its synthetic enantiomer inhibit cell proliferation and kinesin-5 function.
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.
['Pfeffer|Tobias J|TJ|', 'Sasse|Florenz|F|', 'Schmidt|Christoph F|CF|', 'Lakämper|Stefan|S|', 'Kirschning|Andreas|A|', 'Scholz|Tim|T|']
D000818:Animals D002460:Cell Line D045744:Cell Line, Tumor D049109:Cell Proliferation D004224:Diterpenes D019665:Euphorbiaceae D006801:Humans D016547:Kinesins D047028:Macrocyclic Compounds D051379:Mice D008870:Microtubules D008938:Mitosis D008958:Models, Molecular D013237:Stereoisomerism
Diterpene Cytostatic Inhibitor Cancer Kinesin spindle protein Monoaster