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Diversely Functionalised Cytochalasins through Mutasynthesis and Semi-Synthesis.

Wang, Chongqing
; 
Lambert, Christopher
; 
Hauser, Maurice
; 
Deuschmann, Adrian
; 
Zeilinger, Carsten
; 
Rottner, Klemens
; ; 
Stadler, Marc
; 
Skellam, Elizabeth J
; 
Cox, Russell J
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Issue Date
2020-06-02
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Abstract
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.
Citation
Chemistry. 2020 Jun 2. doi: 10.1002/chem.202002241.
Affiliation
HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
Publisher
Wiley-VCH
Journal
Chemistry (Weinheim an der Bergstrasse, Germany)
URI
http://hdl.handle.net/10033/622546
DOI
10.1002/chem.202002241
PubMed ID
32484589
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Article
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en
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1521-3765
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Attribution-NonCommercial-ShareAlike 4.0 International
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publications of the research group of microbial drugs (MWIS)
publications of the research group cell biology (ZBIO)
publications of the Research group: molecular cell biology (MZBI)