Details
| Original language | English |
|---|---|
| Pages (from-to) | 13578-13583 |
| Number of pages | 6 |
| Journal | Chemistry - A European Journal |
| Volume | 26 |
| Issue number | 60 |
| Early online date | 2 Jun 2020 |
| Publication status | Published - 29 Oct 2020 |
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.
Keywords
- cytochalasins, molecular tools, mutasynthesis, semi-synthesis
ASJC Scopus subject areas
- Chemical Engineering(all)
- Catalysis
- Chemistry(all)
- Organic Chemistry
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In: Chemistry - A European Journal, Vol. 26, No. 60, 29.10.2020, p. 13578-13583.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Diversely Functionalised Cytochalasins through Mutasynthesis and Semi-Synthesis
AU - Wang, Chongqing
AU - Lambert, Christopher
AU - Hauser, Maurice
AU - Deuschmann, Adrian
AU - Zeilinger, Carsten
AU - Rottner, Klemens
AU - Stradal, Theresia E.B.
AU - Stadler, Marc
AU - Skellam, Elizabeth J.
AU - Cox, Russell J.
N1 - Funding Information: This work was supported by the Chinese Scholarship Council [C.W. (201608310143)] and the German Research Foundation (DFG) [grants numbers: CO 1328/ 2‐1, INST 187/ 621‐1, INST 187/ 686‐1)]. T.E.B.S. and K.R. acknowledge support through intramural funding from the Helmholtz Society. Open access funding enabled and organized by Projekt DEAL.
PY - 2020/10/29
Y1 - 2020/10/29
N2 - 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.
AB - 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.
KW - cytochalasins
KW - molecular tools
KW - mutasynthesis
KW - semi-synthesis
UR - http://www.scopus.com/inward/record.url?scp=85091155661&partnerID=8YFLogxK
U2 - 10.1002/chem.202002241
DO - 10.1002/chem.202002241
M3 - Article
C2 - 32484589
AN - SCOPUS:85091155661
VL - 26
SP - 13578
EP - 13583
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 0947-6539
IS - 60
ER -