Diversely Functionalised Cytochalasins through Mutasynthesis and Semi‐Synthesis
Chongqing Wang, Christopher Lambert, Maurice Hauser, Adrian Deuschmann, Carsten Zeilinger, Klemens Rottner, Theresia E. B. Stradal, Marc Stadler, Elizabeth Skellam, Russell J. Cox
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.