Diversely Functionalised Cytochalasins through Mutasynthesis and Semi‐Synthesis. Issue 60 (17th September 2020)

• Record Type: Journal Article
• Authors: Wang, Chongqing; Lambert, Christopher; Hauser, Maurice; Deuschmann, Adrian; Zeilinger, Carsten; Rottner, Klemens; Stradal, Theresia E. B.; Stadler, Marc; Skellam, Elizabeth J.; Cox, Russell J.
• Is Part Of: Chemistry. Volume 26:Issue 60(2020)
• Page Start: 13578
• Page End: 13583
• Publication Date: 2020-09-17
• Subjects: cytochalasins -- molecular tools -- mutasynthesis -- semi-synthesis; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202002241
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : Molecular toolbox : Unprecedented cytochalasins functionalised at the 4′‐position were produced by mutasynthesis. These compounds were then chemically diversified to produce a range of molecular tools without the need for protecting strategies. As a pertinent example the Texas‐red‐modified compound was synthesised in a single step from 4′‐azidocytochalasin and used to visualise sub‐micrometer actin microstructures in immobilised U2OS cells.