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

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

Research output: Contribution to journalArticleResearchpeer-review

2 Citations (Scopus)

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.

Original languageEnglish
Article number10617
Pages (from-to)1-7
Number of pages7
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018
Externally publishedYes

Cite this

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. / Sustainable Syntheses of (-)-Jerantinines A & e and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site. In: Scientific Reports. 2018 ; Vol. 8, No. 1. pp. 1-7.
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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.",
author = "Smedley, {Christopher J.} and Stanley, {Paul A.} and Qazzaz, {Mohannad E.} and Prota, {Andrea E.} and Natacha Olieric and Hilary Collins and Harry Eastman and Barrow, {Andrew S.} and Lim, {Kuan Hon} and Kam, {Toh Seok} and Smith, {Brian J.} and Duivenvoorden, {Hendrika M.} and Parker, {Belinda S.} and Bradshaw, {Tracey D.} and Steinmetz, {Michel O.} and Moses, {John E.}",
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Smedley, CJ, Stanley, PA, Qazzaz, ME, Prota, AE, Olieric, N, Collins, H, Eastman, H, Barrow, AS, Lim, KH, Kam, TS, Smith, BJ, Duivenvoorden, HM, Parker, BS, Bradshaw, TD, Steinmetz, MO & Moses, JE 2018, 'Sustainable Syntheses of (-)-Jerantinines A & e and Structural Characterisation of the Jerantinine-Tubulin Complex at the Colchicine Binding Site', Scientific Reports, vol. 8, no. 1, 10617, pp. 1-7. https://doi.org/10.1038/s41598-018-28880-2

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.

In: Scientific Reports, Vol. 8, No. 1, 10617, 01.12.2018, p. 1-7.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Prota, Andrea E.

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AU - Barrow, Andrew S.

AU - Lim, Kuan Hon

AU - Kam, Toh Seok

AU - Smith, Brian J.

AU - Duivenvoorden, Hendrika M.

AU - Parker, Belinda S.

AU - Bradshaw, Tracey D.

AU - Steinmetz, Michel O.

AU - Moses, John E.

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