Skip to main content

Research Repository

See what's under the surface

Advanced Search

Sustainable syntheses of (−)-jerantinines A & E and structural characterisation of the jerantinine-tubulin complex at the colchicine binding site

Smedley, Christopher J.; Stanley, Paul A.; Qazzaz, Mohannad E.; Prota, Andrea E.; Olieric, Natacha; Collins, Hilary; Eastman, Harry; Barrow, Andrew S.; Lim, Kuan-Hon; Kam, Toh-Seok; Smith, Brian J.; Duivenvoorden, Hendrika M.; Parker, Belinda S.; Bradshaw, Tracey D.; Steinmetz, Michel O.; Moses, John E.

Authors

Christopher J. Smedley

Paul A. Stanley

Mohannad E. Qazzaz

Andrea E. Prota

Natacha Olieric

Hilary Collins

Harry Eastman

Andrew S. Barrow

Kuan-Hon Lim

Toh-Seok Kam

Brian J. Smith

Hendrika M. Duivenvoorden

Belinda S. Parker

Tracey D. Bradshaw

Michel O. Steinmetz

John E. Moses



Abstract

The jerantinine family of Aspidosperma indole alkaloids from Tabernaemontana corymbosa are potent microtubule-targeting agents with broad spectrum anticancer activity. The natural supply of these precious metabolites has been significantly disrupted due to the inclusion of T. corymbosa on the endangered list of threatened species by the International Union for Conservation of Nature. This report describes the asymmetric syntheses of (−)-jerantinines A and E from sustainably sourced (−)-tabersonine, using a straight-forward and robust biomimetic approach. Biological investigations of synthetic (−)-jerantinine A, along with molecular modelling and X-ray crystallography studies of the tubulin—(−)-jerantinine B acetate complex, advocate an anticancer mode of action of the jerantinines operating via microtubule disruption resulting from binding at the colchicine site. This work lays the foundation for accessing useful quantities of enantiomerically pure jerantinine alkaloids for future development.

Journal Article Type Article
Publication Date Dec 1, 2018
Journal Scientific Reports
Print ISSN 2045-2322
Electronic ISSN 2045-2322
Publisher Nature Research
Peer Reviewed Peer Reviewed
Volume 8
Article Number 10617
APA6 Citation Smedley, C. J., Stanley, P. A., Qazzaz, M. E., Prota, A. E., Olieric, N., Collins, H., …Moses, J. E. (2018). Sustainable syntheses of (−)-jerantinines A & E and structural characterisation of the jerantinine-tubulin complex at the colchicine binding site. https://doi.org/10.1038/s41598-018-28880-2
DOI https://doi.org/10.1038/s41598-018-28880-2
Publisher URL https://www.nature.com/articles/s41598-018-28880-2
;