Tubulysin Derivatives

The tubulysins (1) are a family of nine secondary metabolites produced by several strains of myxobacteria. They are among a handful of natural products which interact with the eukaryotic cytoskeleton, inhibiting the polymerization of tubulin at very low concen­trations (<50 pg mL-1). Notably, their ability to suppress the growth of cancerous cells exceeds that of other tubulin modifiers, including the epothilones, vinblastine and taxol.

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Pretubulysin (2), a biosynthetic precursor of the tubulysins, shows potent biological activity in the subnanomolar range towards various tumor cell lines. Its activity is only slightly reduced relative to the structurally more complex tubulysins. Pretubulysin induces apoptosis and inhibits cancer cell migration and tubulin assembly in vitro. With a straightforward synthesis in hand, pretubulysin is an ideal lead structure for the development of tubulysin-based anti-cancer drugs.

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