Sustainable Syntheses of (−)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site

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 t...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/cd703e3a1db842d9bf536015c27b64dc
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spelling	oai:doaj.org-article:cd703e3a1db842d9bf536015c27b64dc2021-12-02T15:08:54ZSustainable Syntheses of (−)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site10.1038/s41598-018-28880-22045-2322https://doaj.org/article/cd703e3a1db842d9bf536015c27b64dc2018-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-28880-2https://doaj.org/toc/2045-2322Abstract 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.Christopher J. SmedleyPaul A. StanleyMohannad E. QazzazAndrea E. ProtaNatacha OliericHilary CollinsHarry EastmanAndrew S. BarrowKuan-Hon LimToh-Seok KamBrian J. SmithHendrika M. DuivenvoordenBelinda S. ParkerTracey D. BradshawMichel O. SteinmetzJohn E. MosesNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-7 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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 Sustainable Syntheses of (−)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site
description	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.
format	article
author	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
author_facet	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
author_sort	Christopher J. Smedley
title	Sustainable Syntheses of (−)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site
title_short	Sustainable Syntheses of (−)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site
title_full	Sustainable Syntheses of (−)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site
title_fullStr	Sustainable Syntheses of (−)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site
title_full_unstemmed	Sustainable Syntheses of (−)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site
title_sort	sustainable syntheses of (−)-jerantinines a & e and structural characterisation of the jerantinine-tubulin complex at the colchicine binding site
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/cd703e3a1db842d9bf536015c27b64dc
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Sustainable Syntheses of (−)-Jerantinines A & E and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site

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