Synthesis and evaluation of C2 functionalized analogs of the α-tubulin-binding natural product pironetin

David S. Huang; Henry L. Wong; Gunda I. Georg

doi:10.1016/j.bmcl.2017.10.057

Synthesis and evaluation of C2 functionalized analogs of the α-tubulin-binding natural product pironetin

David S. Huang, Henry L. Wong, Gunda I. Georg

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

5 Scopus citations

Abstract

Pironetin is an α-tubulin-binding natural product with potent antiproliferative activity against several cancer cell lines that inhibits cell division by forming a covalent adduct with α-tubulin via a Michael addition into the natural product's α,β-unsaturated lactone. We designed and prepared analogs carrying electron-withdrawing groups at the α-position (C2) of the α,β-unsaturated lactone with the goal to generate potent and selective binding analogs. We prepared derivatives containing halogens, a phenyl, and a methyl group at the C2 position to evaluate the structure-activity relationship at this position. Testing of the analogs in ovarian cancer cell lines demonstrated 100–1000-fold decreased antiproliferative activity.

Original language	English (US)
Pages (from-to)	2789-2793
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	28
Issue number	16
DOIs	https://doi.org/10.1016/j.bmcl.2017.10.057
State	Published - Sep 1 2018

Bibliographical note

Funding Information:
Support from the University of Minnesota through the Vince and McKnight Endowed Chairs (G.I.G.) and the College of Pharmacy is greatly appreciated. David Huang thanks the American Foundation for Pharmaceutical Education for a predoctoral fellowship. We thank Sara K. Coulup for performing the glutathione assay, Dr. Mathew E. Cuellar of the Institute for Therapeutics Discovery and Development for analytical support and Dr. Amy P.N. Skubitz in the Department of Laboratory Medicine and Pathology at the University of Minnesota for the OVCAR5 and A2780 cells.

Funding Information:
Support from the University of Minnesota through the Vince and McKnight Endowed Chairs (G.I.G.) and the College of Pharmacy is greatly appreciated. David Huang thanks the American Foundation for Pharmaceutical Education for a predoctoral fellowship. We thank Sara K. Coulup for performing the glutathione assay, Dr. Mathew E. Cuellar of the Institute for Therapeutics Discovery and Development for analytical support and Dr. Amy P.N. Skubitz in the Department of Laboratory Medicine and Pathology at the University of Minnesota for the OVCAR5 and A2780 cells.

Publisher Copyright:
© 2017 Elsevier Ltd

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

Cytotoxicity
Pironetin
Structure-activity
Synthesis
Tubulin

UN SDGs

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

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10.1016/j.bmcl.2017.10.057

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abstract = "Pironetin is an α-tubulin-binding natural product with potent antiproliferative activity against several cancer cell lines that inhibits cell division by forming a covalent adduct with α-tubulin via a Michael addition into the natural product's α,β-unsaturated lactone. We designed and prepared analogs carrying electron-withdrawing groups at the α-position (C2) of the α,β-unsaturated lactone with the goal to generate potent and selective binding analogs. We prepared derivatives containing halogens, a phenyl, and a methyl group at the C2 position to evaluate the structure-activity relationship at this position. Testing of the analogs in ovarian cancer cell lines demonstrated 100–1000-fold decreased antiproliferative activity.",

keywords = "Cytotoxicity, Pironetin, Structure-activity, Synthesis, Tubulin",

author = "Huang, {David S.} and Wong, {Henry L.} and Georg, {Gunda I.}",

note = "Funding Information: Support from the University of Minnesota through the Vince and McKnight Endowed Chairs (G.I.G.) and the College of Pharmacy is greatly appreciated. David Huang thanks the American Foundation for Pharmaceutical Education for a predoctoral fellowship. We thank Sara K. Coulup for performing the glutathione assay, Dr. Mathew E. Cuellar of the Institute for Therapeutics Discovery and Development for analytical support and Dr. Amy P.N. Skubitz in the Department of Laboratory Medicine and Pathology at the University of Minnesota for the OVCAR5 and A2780 cells. Funding Information: Support from the University of Minnesota through the Vince and McKnight Endowed Chairs (G.I.G.) and the College of Pharmacy is greatly appreciated. David Huang thanks the American Foundation for Pharmaceutical Education for a predoctoral fellowship. We thank Sara K. Coulup for performing the glutathione assay, Dr. Mathew E. Cuellar of the Institute for Therapeutics Discovery and Development for analytical support and Dr. Amy P.N. Skubitz in the Department of Laboratory Medicine and Pathology at the University of Minnesota for the OVCAR5 and A2780 cells. Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd Copyright: Copyright 2018 Elsevier B.V., All rights reserved.",

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N2 - Pironetin is an α-tubulin-binding natural product with potent antiproliferative activity against several cancer cell lines that inhibits cell division by forming a covalent adduct with α-tubulin via a Michael addition into the natural product's α,β-unsaturated lactone. We designed and prepared analogs carrying electron-withdrawing groups at the α-position (C2) of the α,β-unsaturated lactone with the goal to generate potent and selective binding analogs. We prepared derivatives containing halogens, a phenyl, and a methyl group at the C2 position to evaluate the structure-activity relationship at this position. Testing of the analogs in ovarian cancer cell lines demonstrated 100–1000-fold decreased antiproliferative activity.

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Synthesis and evaluation of C2 functionalized analogs of the α-tubulin-binding natural product pironetin

Abstract

Bibliographical note

Keywords

UN SDGs

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