[5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity

James L. Rushworth; Aditya R. Thawani; Elena Fajardo-Ruiz; Joyce C. M. Meiring; Constanze Heise; Andrew J. P. White; Anna Akhmanova; Jochen R. Brandt; Oliver Thorn-Seshold; Matthew J. Fuchter

doi:10.1021/jacsau.2c00435

[5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity

James L. Rushworth
, Aditya R. Thawani
, Elena Fajardo-Ruiz
, Joyce C. M. Meiring
, Constanze Heise
, Andrew J. P. White
, Anna Akhmanova
, Jochen R. Brandt
, Oliver Thorn-Seshold
, Matthew J. Fuchter

Cell Biology, Neurobiology and Biophysics

Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City Campus, 82 Wood Lane, London W12 OBZ, U.K.
Department of Pharmacy, Ludwig-Maximilians University of Munich, Munich 81377, Germany

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

Abstract

Helicenes are high interest synthetic targets with unique conjugated helical structures that have found important technological applications. Despite this interest, helicenes have had limited impact in chemical biology. Herein, we disclose a first-in-class antimitotic helicene, helistatin 1 (HA-1), where the helicene scaffold acts as a structural mimic of colchicine, a known antimitotic drug. The synthesis proceeds via sequential Pd-catalyzed coupling reactions and a π-Lewis acid cycloisomerization mediated by PtCl2. HA-1 was found to block microtubule polymerization in both cell-free and live cell assays. Not only does this demonstrate the feasibility of using helicenes as bioactive scaffolds against protein targets, but also suggests wider potential for the use of helicenes as isosteres of biaryls or cis-stilbenes─themselves common drug and natural product scaffolds. Overall, this study further supports future opportunities for helicenes for a range of chemical biological applications.

Original language	English
Pages (from-to)	2561-2570
Number of pages	10
Journal	JACS Au
Volume	2
Issue number	11
Early online date	19 Oct 2022
DOIs	https://doi.org/10.1021/jacsau.2c00435
Publication status	Published - 28 Nov 2022

Bibliographical note

Funding Information:
Funding for this work was provided by the Commonwealth Scientific and Industrial Research Organization (CSIRO), Imperial College London, the EPSRC (EP/L014580/1, EP/R00188X/1), and the German Research Foundation (DFG: Emmy Noether grant no. 400324123 and SFB 1032 project B09 number 201269156 to O.T.S.). J.C.M.M. acknowledges support from an EMBO Long Term Fellowship (ALTF 261-2019). The authors also acknowledge the funding support from “Laboratory for Synthetic Chemistry and Chemical Biology” under the Health@InnoHK Program launched by Innovation and Technology Commission, The Government of Hong Kong Special Administrative Region of the People’s Republic of China.

Publisher Copyright:
© 2022 The Authors. Published by American Chemical Society.

UN SDGs

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

SDG 3 Good Health and Well-being

Keywords

DNA
antiproliferative
cancer
cell cycle
helicene
mitosis
tubulin

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Cite this

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title = "[5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity",

abstract = "Helicenes are high interest synthetic targets with unique conjugated helical structures that have found important technological applications. Despite this interest, helicenes have had limited impact in chemical biology. Herein, we disclose a first-in-class antimitotic helicene, helistatin 1 (HA-1), where the helicene scaffold acts as a structural mimic of colchicine, a known antimitotic drug. The synthesis proceeds via sequential Pd-catalyzed coupling reactions and a π-Lewis acid cycloisomerization mediated by PtCl2. HA-1 was found to block microtubule polymerization in both cell-free and live cell assays. Not only does this demonstrate the feasibility of using helicenes as bioactive scaffolds against protein targets, but also suggests wider potential for the use of helicenes as isosteres of biaryls or cis-stilbenes─themselves common drug and natural product scaffolds. Overall, this study further supports future opportunities for helicenes for a range of chemical biological applications.",

keywords = "DNA, antiproliferative, cancer, cell cycle, helicene, mitosis, tubulin",

author = "Rushworth, \{James L.\} and Thawani, \{Aditya R.\} and Elena Fajardo-Ruiz and Meiring, \{Joyce C. M.\} and Constanze Heise and White, \{Andrew J. P.\} and Anna Akhmanova and Brandt, \{Jochen R.\} and Oliver Thorn-Seshold and Fuchter, \{Matthew J.\}",

note = "Funding Information: Funding for this work was provided by the Commonwealth Scientific and Industrial Research Organization (CSIRO), Imperial College London, the EPSRC (EP/L014580/1, EP/R00188X/1), and the German Research Foundation (DFG: Emmy Noether grant no. 400324123 and SFB 1032 project B09 number 201269156 to O.T.S.). J.C.M.M. acknowledges support from an EMBO Long Term Fellowship (ALTF 261-2019). The authors also acknowledge the funding support from “Laboratory for Synthetic Chemistry and Chemical Biology” under the Health@InnoHK Program launched by Innovation and Technology Commission, The Government of Hong Kong Special Administrative Region of the People{\textquoteright}s Republic of China. Publisher Copyright: {\textcopyright} 2022 The Authors. Published by American Chemical Society.",

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AU - Rushworth, James L.

AU - Thawani, Aditya R.

AU - Fajardo-Ruiz, Elena

AU - Meiring, Joyce C. M.

AU - Heise, Constanze

AU - White, Andrew J. P.

AU - Akhmanova, Anna

AU - Brandt, Jochen R.

AU - Thorn-Seshold, Oliver

AU - Fuchter, Matthew J.

N1 - Funding Information: Funding for this work was provided by the Commonwealth Scientific and Industrial Research Organization (CSIRO), Imperial College London, the EPSRC (EP/L014580/1, EP/R00188X/1), and the German Research Foundation (DFG: Emmy Noether grant no. 400324123 and SFB 1032 project B09 number 201269156 to O.T.S.). J.C.M.M. acknowledges support from an EMBO Long Term Fellowship (ALTF 261-2019). The authors also acknowledge the funding support from “Laboratory for Synthetic Chemistry and Chemical Biology” under the Health@InnoHK Program launched by Innovation and Technology Commission, The Government of Hong Kong Special Administrative Region of the People’s Republic of China. Publisher Copyright: © 2022 The Authors. Published by American Chemical Society.

PY - 2022/11/28

Y1 - 2022/11/28

N2 - Helicenes are high interest synthetic targets with unique conjugated helical structures that have found important technological applications. Despite this interest, helicenes have had limited impact in chemical biology. Herein, we disclose a first-in-class antimitotic helicene, helistatin 1 (HA-1), where the helicene scaffold acts as a structural mimic of colchicine, a known antimitotic drug. The synthesis proceeds via sequential Pd-catalyzed coupling reactions and a π-Lewis acid cycloisomerization mediated by PtCl2. HA-1 was found to block microtubule polymerization in both cell-free and live cell assays. Not only does this demonstrate the feasibility of using helicenes as bioactive scaffolds against protein targets, but also suggests wider potential for the use of helicenes as isosteres of biaryls or cis-stilbenes─themselves common drug and natural product scaffolds. Overall, this study further supports future opportunities for helicenes for a range of chemical biological applications.

AB - Helicenes are high interest synthetic targets with unique conjugated helical structures that have found important technological applications. Despite this interest, helicenes have had limited impact in chemical biology. Herein, we disclose a first-in-class antimitotic helicene, helistatin 1 (HA-1), where the helicene scaffold acts as a structural mimic of colchicine, a known antimitotic drug. The synthesis proceeds via sequential Pd-catalyzed coupling reactions and a π-Lewis acid cycloisomerization mediated by PtCl2. HA-1 was found to block microtubule polymerization in both cell-free and live cell assays. Not only does this demonstrate the feasibility of using helicenes as bioactive scaffolds against protein targets, but also suggests wider potential for the use of helicenes as isosteres of biaryls or cis-stilbenes─themselves common drug and natural product scaffolds. Overall, this study further supports future opportunities for helicenes for a range of chemical biological applications.

KW - DNA

KW - antiproliferative

KW - cancer

KW - cell cycle

KW - helicene

KW - mitosis

KW - tubulin

UR - https://www.scopus.com/pages/publications/85141060895

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DO - 10.1021/jacsau.2c00435

M3 - Article

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VL - 2

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JF - JACS Au

IS - 11

ER -

[5]-Helistatins: Tubulin-Binding Helicenes with Antimitotic Activity

Abstract

Bibliographical note

UN SDGs

Keywords

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