Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F

Guanghui Zong; Zhijian Hu; Kwabena Baffour Duah; Lauren E. Andrews; Jianhong Zhou; Sarah O'Keefe; Lucas Whisenhunt; Joong Sup Shim; Yuchun Du; Stephen High; Wei Q. Shi

doi:10.1021/acs.joc.0c01659

Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F

Guanghui Zong, Zhijian Hu, Kwabena Baffour Duah, Lauren E. Andrews, Jianhong Zhou, Sarah O'Keefe, Lucas Whisenhunt, Joong Sup Shim, Yuchun Du, Stephen High, Wei Q. Shi

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

Abstract

Two new ring-size-varying analogues (2 and 3) of ipomoeassin F were synthesized and evaluated. Improved cytotoxicity (IC50: from 1.8 nM) and in vitro protein translocation inhibition (IC50: 35 nM) derived from ring expansion imply that the binding pocket of Sec61α (isoform 1) can accommodate further structural modifications, likely in the fatty acid portion. Streamlined preparation of the key diol intermediate 5 enabled gram-scale production, allowing us to establish that ipomoeassin F is biologically active in vivo (MTD: μ3 mg/kg).

Original language	English
Journal	Journal of Organic Chemistry
Volume	85
Issue number	24
Pages (from-to)	16226-16235
Number of pages	10
ISSN	0022-3263
DOIs	https://doi.org/10.1021/acs.joc.0c01659
Publication status	Published - 18 Dec 2020
Externally published	Yes
MoE publication type	A1 Journal article-refereed

Bibliographical note

Funding Information:
This work was supported by Grant No. 2R15GM116032-02A1 from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) and a Ball State University (BSU) Provost Startup Award (to W.Q.S.), together with Wellcome Trust Investigator Award in Science ref no. 204957/Z/16/Z (to S.H.). L.E.A. is the recipient of BSU honors college research grants from 01/2020–12/2020.

Publisher Copyright:
© 2020 American Chemical Society.

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title = "Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F",

abstract = "Two new ring-size-varying analogues (2 and 3) of ipomoeassin F were synthesized and evaluated. Improved cytotoxicity (IC50: from 1.8 nM) and in vitro protein translocation inhibition (IC50: 35 nM) derived from ring expansion imply that the binding pocket of Sec61α (isoform 1) can accommodate further structural modifications, likely in the fatty acid portion. Streamlined preparation of the key diol intermediate 5 enabled gram-scale production, allowing us to establish that ipomoeassin F is biologically active in vivo (MTD: μ3 mg/kg).",

author = "Guanghui Zong and Zhijian Hu and Duah, {Kwabena Baffour} and Andrews, {Lauren E.} and Jianhong Zhou and Sarah O'Keefe and Lucas Whisenhunt and Shim, {Joong Sup} and Yuchun Du and Stephen High and Shi, {Wei Q.}",

note = "Funding Information: This work was supported by Grant No. 2R15GM116032-02A1 from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) and a Ball State University (BSU) Provost Startup Award (to W.Q.S.), together with Wellcome Trust Investigator Award in Science ref no. 204957/Z/16/Z (to S.H.). L.E.A. is the recipient of BSU honors college research grants from 01/2020–12/2020. Publisher Copyright: {\textcopyright} 2020 American Chemical Society.",

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doi = "10.1021/acs.joc.0c01659",

language = "English",

volume = "85",

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T1 - Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F

AU - Zong, Guanghui

AU - Hu, Zhijian

AU - Duah, Kwabena Baffour

AU - Andrews, Lauren E.

AU - Zhou, Jianhong

AU - O'Keefe, Sarah

AU - Whisenhunt, Lucas

AU - Shim, Joong Sup

AU - Du, Yuchun

AU - High, Stephen

AU - Shi, Wei Q.

N1 - Funding Information: This work was supported by Grant No. 2R15GM116032-02A1 from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) and a Ball State University (BSU) Provost Startup Award (to W.Q.S.), together with Wellcome Trust Investigator Award in Science ref no. 204957/Z/16/Z (to S.H.). L.E.A. is the recipient of BSU honors college research grants from 01/2020–12/2020. Publisher Copyright: © 2020 American Chemical Society.

PY - 2020/12/18

Y1 - 2020/12/18

N2 - Two new ring-size-varying analogues (2 and 3) of ipomoeassin F were synthesized and evaluated. Improved cytotoxicity (IC50: from 1.8 nM) and in vitro protein translocation inhibition (IC50: 35 nM) derived from ring expansion imply that the binding pocket of Sec61α (isoform 1) can accommodate further structural modifications, likely in the fatty acid portion. Streamlined preparation of the key diol intermediate 5 enabled gram-scale production, allowing us to establish that ipomoeassin F is biologically active in vivo (MTD: μ3 mg/kg).

AB - Two new ring-size-varying analogues (2 and 3) of ipomoeassin F were synthesized and evaluated. Improved cytotoxicity (IC50: from 1.8 nM) and in vitro protein translocation inhibition (IC50: 35 nM) derived from ring expansion imply that the binding pocket of Sec61α (isoform 1) can accommodate further structural modifications, likely in the fatty acid portion. Streamlined preparation of the key diol intermediate 5 enabled gram-scale production, allowing us to establish that ipomoeassin F is biologically active in vivo (MTD: μ3 mg/kg).

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DO - 10.1021/acs.joc.0c01659

M3 - Article

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EP - 16235

JO - Journal of Organic Chemistry

JF - Journal of Organic Chemistry

IS - 24

ER -

Ring Expansion Leads to a More Potent Analogue of Ipomoeassin F

Abstract

Bibliographical note

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