Syntheses of pretubulysin derivatives for targeted tumor therapies

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Myxobacteria produce a wealth of bioactive natural products such as the tubulin-binding linear tetra peptides tubulysins and their biosynthetic precursors, the pretubulysins. New derivatives of pretubulysin will be synthesized with functionalized side chains on the tubuvaline nitrogen, allowing the connection of a wide range of functionalities required e.g. for target fishing, bioimaging and tumor targeting. For tumor-targeted delivery pretubulysin will be conjugated to sequence-defined oligoaminoamides containing PEG and targeting ligands. These prodrugs will display triple responsiveness (cleavage of pH-labile bonds, protonation of carrier amines in endosomes resulting in endosomolytic property, and cleavage of disulfides in the cytosol of the target cell, necessary for efficient cytosolic delivery and intracellular release of pretubulysin. Biodistribution in vivo (NIR bioimaging) and therapeutic efficacy will be evaluated in human hepatocellular carcinoma and breast cancer xenograft models.