Synthesis of the seco-Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor

David M. Pinkerton; Sharon Chow; Nada H. Eisa; Kashish Kainth; Timothy J. Vanden Berg; Jed M. Burns; Luke W. Guddat; G. Paul Savage; Ahmed Chadli; Craig M. Williams

doi:10.1002/chem.201805420

Synthesis of the seco-Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor

David M. Pinkerton, Sharon Chow, Nada H. Eisa, Kashish Kainth, Timothy J. Vanden Berg, Jed M. Burns, Luke W. Guddat, G. Paul Savage, Ahmed Chadli, Craig M. Williams

Cardiology

Research output: Contribution to journal › Article › peer-review

15 Scopus citations

Abstract

D-Ring-seco-limonoids (tetranortriterpenoids), such as gedunin and xylogranin B display anti-cancer activity, acting via inhibition of Hsp90 and/or associated chaperon machinery (e.g., p23). Despite this, these natural products have received relatively little attention, both in terms of an enabling synthetic approach (which would allow access to derivatives), and as a consequence their structure–activity relationship (SAR). Disclosed herein is a generally applicable synthetic route to the BCD ring system of the seco-D-ring double bond containing limonoids. Furthermore, cell based assays revealed the first skeletal fragment that exhibited inhibition of the p23 enzyme at a level which was equipotent to that of gedunin, despite being much less structurally complex.

Original language	English (US)
Pages (from-to)	1451-1455
Number of pages	5
Journal	Chemistry - A European Journal
Volume	25
Issue number	6
DOIs	https://doi.org/10.1002/chem.201805420
State	Published - Jan 28 2019

Keywords

BCD ring
Hsp90p23
gedunin
limonoids
medicinal chemistry
natural products

ASJC Scopus subject areas

Catalysis
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/chem.201805420

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title = "Synthesis of the seco-Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor",

abstract = "D-Ring-seco-limonoids (tetranortriterpenoids), such as gedunin and xylogranin B display anti-cancer activity, acting via inhibition of Hsp90 and/or associated chaperon machinery (e.g., p23). Despite this, these natural products have received relatively little attention, both in terms of an enabling synthetic approach (which would allow access to derivatives), and as a consequence their structure–activity relationship (SAR). Disclosed herein is a generally applicable synthetic route to the BCD ring system of the seco-D-ring double bond containing limonoids. Furthermore, cell based assays revealed the first skeletal fragment that exhibited inhibition of the p23 enzyme at a level which was equipotent to that of gedunin, despite being much less structurally complex.",

keywords = "BCD ring, Hsp90p23, gedunin, limonoids, medicinal chemistry, natural products",

author = "Pinkerton, {David M.} and Sharon Chow and Eisa, {Nada H.} and Kashish Kainth and {Vanden Berg}, {Timothy J.} and Burns, {Jed M.} and Guddat, {Luke W.} and Savage, {G. Paul} and Ahmed Chadli and Williams, {Craig M.}",

note = "Funding Information: We thank the University of Queensland (UQ) and the Australian Research Council (DP130103858) for financial support. C.M.W. gratefully acknowledges the Australian Research Council for a Future Fellowship award (FT110100851). T.J.V. thanks the Australian Government for a Research Training Program Scholarship, and Dr. Aidan Brock for assistance with collecting X-ray crystallographic data. We also thank Dr. Nick Meanwell (Bristol-Myers Squibb Research and Development, USA) for productive discussions regarding the biological activity of chloroacetates. Publisher Copyright: {\textcopyright} 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim",

year = "2019",

month = jan,

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doi = "10.1002/chem.201805420",

language = "English (US)",

volume = "25",

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journal = "Chemistry - A European Journal",

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T1 - Synthesis of the seco-Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor

AU - Pinkerton, David M.

AU - Chow, Sharon

AU - Eisa, Nada H.

AU - Kainth, Kashish

AU - Vanden Berg, Timothy J.

AU - Burns, Jed M.

AU - Guddat, Luke W.

AU - Savage, G. Paul

AU - Chadli, Ahmed

AU - Williams, Craig M.

N1 - Funding Information: We thank the University of Queensland (UQ) and the Australian Research Council (DP130103858) for financial support. C.M.W. gratefully acknowledges the Australian Research Council for a Future Fellowship award (FT110100851). T.J.V. thanks the Australian Government for a Research Training Program Scholarship, and Dr. Aidan Brock for assistance with collecting X-ray crystallographic data. We also thank Dr. Nick Meanwell (Bristol-Myers Squibb Research and Development, USA) for productive discussions regarding the biological activity of chloroacetates. Publisher Copyright: © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

PY - 2019/1/28

Y1 - 2019/1/28

N2 - D-Ring-seco-limonoids (tetranortriterpenoids), such as gedunin and xylogranin B display anti-cancer activity, acting via inhibition of Hsp90 and/or associated chaperon machinery (e.g., p23). Despite this, these natural products have received relatively little attention, both in terms of an enabling synthetic approach (which would allow access to derivatives), and as a consequence their structure–activity relationship (SAR). Disclosed herein is a generally applicable synthetic route to the BCD ring system of the seco-D-ring double bond containing limonoids. Furthermore, cell based assays revealed the first skeletal fragment that exhibited inhibition of the p23 enzyme at a level which was equipotent to that of gedunin, despite being much less structurally complex.

AB - D-Ring-seco-limonoids (tetranortriterpenoids), such as gedunin and xylogranin B display anti-cancer activity, acting via inhibition of Hsp90 and/or associated chaperon machinery (e.g., p23). Despite this, these natural products have received relatively little attention, both in terms of an enabling synthetic approach (which would allow access to derivatives), and as a consequence their structure–activity relationship (SAR). Disclosed herein is a generally applicable synthetic route to the BCD ring system of the seco-D-ring double bond containing limonoids. Furthermore, cell based assays revealed the first skeletal fragment that exhibited inhibition of the p23 enzyme at a level which was equipotent to that of gedunin, despite being much less structurally complex.

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Synthesis of the seco-Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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