(Bio)Syntheses of chondramides and related cyclodepsipeptides

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Myxobacteria produce a wealth of bioactive natural products including cyclic peptides and depsipeptides such as the chondramides and miuraenamides. The chondramides mainly interact with the actin cytoskeleton, but only sporadic experiments have been carried out with the miuraenamides and related peptides, probably because not enough material is available for biological testing. Therefore, our aim is to develop a highly flexible protocol for the synthesis of miuraenamides and related peptides, based on peptide modification. This concept would allow us to generate libraries of similar compounds easily by introducing relevant side chains in the last step of the synthesis. Compound libraries of these cyclic depsipeptides and related compounds shall be screened in various cell-based and in vitro biological assays in order to establish structure-activity relationships. Furthermore, targeted approaches shall be developed and applied to elucidate putative molecular targets and to characterize protein-ligand interactions. A further aim of the project is the production and biological evaluation of novel chondramide variants, which exhibit, based on structural variations, a more cancer cell specific mode of action than the original analogs. In initial studies with novel natural derivatives of this compound class, found in an alternative producer strain during the first funding period, it has already been shown that specific derivatizations of the core structure lead to higher cytotoxicity towards cancer cell lines. Overall, these studies implied a putative cellular target other than actin (off-target), which shall be identified and investigated in further studies. To ensure sufficient supply of test substances synthetic approaches which should be accomplished by biotechnological onsets are planned. To guarantee for a sustainable supply the original chondramide producer strain will be genetically engineered, thereby allowing fermentative production of the novel chondramides plus further derivatives. The targeted manipulation of the biosynthesis gene cluster shall furthermore allow the incorporation of synthesized precursors to enable mutasynthetic onsets to produce desired structural variants. Also the fermentative biotechnological production process will be optimized and adapted to the specific requirements.