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Diversely Functionalised Cytochalasins through Mutasynthesis and Semi‐Synthesis

Mutasynthesis of pyrichalasin H from Magnaporthe grisea NI980 yielded a series of unprecedented 4′‐substituted cytochalasin analogues in titres as high as the wild‐type system (≈60 mg L(−1)). Halogenated, O‐alkyl, O‐allyl and O‐propargyl examples were formed, as well as a 4′‐azido analogue. 4′‐O‐Pro...

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Autores principales: Wang, Chongqing, Lambert, Christopher, Hauser, Maurice, Deuschmann, Adrian, Zeilinger, Carsten, Rottner, Klemens, Stradal, Theresia E. B., Stadler, Marc, Skellam, Elizabeth J., Cox, Russell J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692911/
https://www.ncbi.nlm.nih.gov/pubmed/32484589
http://dx.doi.org/10.1002/chem.202002241
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author Wang, Chongqing
Lambert, Christopher
Hauser, Maurice
Deuschmann, Adrian
Zeilinger, Carsten
Rottner, Klemens
Stradal, Theresia E. B.
Stadler, Marc
Skellam, Elizabeth J.
Cox, Russell J.
author_facet Wang, Chongqing
Lambert, Christopher
Hauser, Maurice
Deuschmann, Adrian
Zeilinger, Carsten
Rottner, Klemens
Stradal, Theresia E. B.
Stadler, Marc
Skellam, Elizabeth J.
Cox, Russell J.
author_sort Wang, Chongqing
collection PubMed
description Mutasynthesis of pyrichalasin H from Magnaporthe grisea NI980 yielded a series of unprecedented 4′‐substituted cytochalasin analogues in titres as high as the wild‐type system (≈60 mg L(−1)). Halogenated, O‐alkyl, O‐allyl and O‐propargyl examples were formed, as well as a 4′‐azido analogue. 4′‐O‐Propargyl and 4′‐azido analogues reacted smoothly in Huisgen cycloaddition reactions, whereas p‐Br and p‐I compounds reacted in Pd‐catalysed cross‐coupling reactions. A series of examples of biotin‐linked, dye‐linked and dimeric cytochalasins was rapidly created. In vitro and in vivo bioassays of these compounds showed that the 4′‐halogenated and azido derivatives retained their cytotoxicity and antifungal activities; but a unique 4′‐amino analogue was inactive. Attachment of larger substituents attenuated the bioactivities. In vivo actin‐binding studies with adherent mammalian cells showed that actin remains the likely intracellular target. Dye‐linked compounds revealed visualisation of intracellular actin structures even in the absence of phalloidin, thus constituting a potential new class of actin‐visualisation tools with filament‐barbed end‐binding specificity.
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spelling pubmed-76929112020-12-08 Diversely Functionalised Cytochalasins through Mutasynthesis and Semi‐Synthesis Wang, Chongqing Lambert, Christopher Hauser, Maurice Deuschmann, Adrian Zeilinger, Carsten Rottner, Klemens Stradal, Theresia E. B. Stadler, Marc Skellam, Elizabeth J. Cox, Russell J. Chemistry Communications Mutasynthesis of pyrichalasin H from Magnaporthe grisea NI980 yielded a series of unprecedented 4′‐substituted cytochalasin analogues in titres as high as the wild‐type system (≈60 mg L(−1)). Halogenated, O‐alkyl, O‐allyl and O‐propargyl examples were formed, as well as a 4′‐azido analogue. 4′‐O‐Propargyl and 4′‐azido analogues reacted smoothly in Huisgen cycloaddition reactions, whereas p‐Br and p‐I compounds reacted in Pd‐catalysed cross‐coupling reactions. A series of examples of biotin‐linked, dye‐linked and dimeric cytochalasins was rapidly created. In vitro and in vivo bioassays of these compounds showed that the 4′‐halogenated and azido derivatives retained their cytotoxicity and antifungal activities; but a unique 4′‐amino analogue was inactive. Attachment of larger substituents attenuated the bioactivities. In vivo actin‐binding studies with adherent mammalian cells showed that actin remains the likely intracellular target. Dye‐linked compounds revealed visualisation of intracellular actin structures even in the absence of phalloidin, thus constituting a potential new class of actin‐visualisation tools with filament‐barbed end‐binding specificity. John Wiley and Sons Inc. 2020-09-17 2020-10-27 /pmc/articles/PMC7692911/ /pubmed/32484589 http://dx.doi.org/10.1002/chem.202002241 Text en © 2020 The Authors. Published by Wiley-VCH GmbH This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Communications
Wang, Chongqing
Lambert, Christopher
Hauser, Maurice
Deuschmann, Adrian
Zeilinger, Carsten
Rottner, Klemens
Stradal, Theresia E. B.
Stadler, Marc
Skellam, Elizabeth J.
Cox, Russell J.
Diversely Functionalised Cytochalasins through Mutasynthesis and Semi‐Synthesis
title Diversely Functionalised Cytochalasins through Mutasynthesis and Semi‐Synthesis
title_full Diversely Functionalised Cytochalasins through Mutasynthesis and Semi‐Synthesis
title_fullStr Diversely Functionalised Cytochalasins through Mutasynthesis and Semi‐Synthesis
title_full_unstemmed Diversely Functionalised Cytochalasins through Mutasynthesis and Semi‐Synthesis
title_short Diversely Functionalised Cytochalasins through Mutasynthesis and Semi‐Synthesis
title_sort diversely functionalised cytochalasins through mutasynthesis and semi‐synthesis
topic Communications
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692911/
https://www.ncbi.nlm.nih.gov/pubmed/32484589
http://dx.doi.org/10.1002/chem.202002241
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