Affiliations 

  • 1 La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia
  • 2 School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD, UK
  • 3 Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, CH-5232, Villigen PSI, Switzerland
  • 4 School of Pharmacy, University of Nottingham Malaysia Campus, Jalan Broga, 43500, Semenyih, Selangor, Malaysia
  • 5 Department of Chemistry, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia
  • 6 La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia. J.Moses@latrobe.edu.au
Sci Rep, 2018 Jul 13;8(1):10617.
PMID: 30006510 DOI: 10.1038/s41598-018-28880-2

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.