Journal article
Sustainable Syntheses of (-)-Jerantinines A & e and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site
CJ Smedley, PA Stanley, ME Qazzaz, AE Prota, N Olieric, H Collins, H Eastman, AS Barrow, KH Lim, TS Kam, BJ Smith, HM Duivenvoorden, BS Parker, TD Bradshaw, MO Steinmetz, JE Moses
Scientific Reports | NATURE PORTFOLIO | Published : 2018
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-(..
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Awarded by Association pour la Recherche sur le Cancer
Funding Acknowledgements
We thank La Trobe University (C.J.S.) and the University of Nottingham (P.A.S. and H.E.) for providing PhD scholarships. We are indebted to Takashi Tomizaki and Meitian Wang for excellent technical assistance with the collection of X-ray data at beamline X06SA of the Swiss Light Source (Paul Scherrer Institut, Villigen PSI, Switzerland). J.E.M. thanks the ARC for a Future Fellowship (FT170100156). B.S.P. thanks the NHMRC for funding (BSP 1127754). M.E.Q. thanks the Higher Committee for Education Development in Iraq (HCED) for sponsorship. This work was further supported by a grant from the Swiss National Science Foundation (31003A_166608; to M.O.S.). Coordinates of the X-ray crystal structures have been deposited in the RCSB PDB (www.rcsb.org) under accession number 6GF3 (tubulin-9).