The natural diterpene tonantzitlolone A and its synthetic enantiomer inhibit cell proliferation and kinesin-5 function

authored by

Tobias J. Pfeffer, Florenz Sasse, Christoph F. Schmidt, Stefan Lakämper, Andreas Kirschning, Tim Scholz

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.

Organisation(s)

Institute of Organic Chemistry
Centre of Biomolecular Drug Research (BMWZ)

External Organisation(s)

Hannover Medical School (MHH)
Helmholtz Centre for Infection Research (HZI)
University of Göttingen
ETH Zurich

Type

Article

Journal

European Journal of Medicinal Chemistry

Volume

112

Pages

164-170

No. of pages

7

ISSN

0223-5234

Publication date

13.04.2016

Publication status

Published

Peer reviewed

Yes

ASJC Scopus subject areas

Pharmacology, Drug Discovery, Organic Chemistry

Sustainable Development Goals

SDG 3 - Good Health and Well-being

Electronic version(s)

https://doi.org/10.1016/j.ejmech.2016.02.022 (Access: Closed)