Diversely Functionalised Cytochalasins through Mutasynthesis and Semi-Synthesis.

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.

SUBMITTER: Wang C 

PROVIDER: S-EPMC7692911 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature