Chemistry and Biology of the Maltepolides

• Applicant: Dr. Evgeny V. Prusov
• Subject Area: Biological and Biomimetic Chemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: from 2014 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 250797449

Natural products of various origins play an important role in drug development in areas such as infection control and cancer treatment. The maltepolides are a class of novel secondary metabolites isolated from the myxobacterium Sorangium cellulosum. These compounds were found to induce peculiar morphological changes in dividing transformed cell lines. Additionally, maltepolides exert cytostatic activities on the mouse fibroblasts cells L-929. The observed phenotype suggests that the maltepolides do not interact with established targets, but rather with a yet unknown regulatory or motor protein, which is crucial for mitosis. Our investigations of the biosynthesis of the maltepolides also revealed some unusual epoxide rearrangement/intramolecular epoxide opening transformations.A significant drawback of current syntheses of polyketides is that based on linear sequences only one molecule is produced at a time. This hampers significantly the biomedical exploration of natural products. Thus, the main objective of this project is to develop a diversity-oriented approach to maltepolide-like architectures starting from a central advanced intermediate. Inspired by the putative biosynthesis of maltepolide E, the epoxide rearrangement/intramolecular epoxide opening cascade will be studied as a key step for such transformations. For this purpose, several model epoxides mimicking the biosynthetic precursor of maltepolide E will be prepared. Then, the epoxide rearrangement cascade will be investigated in detail under anionic and cationic conditions. With optimized conditions in hand, simplification of the macrtolactone ring will be undertaken in order to demonstrate the broad applicability of the devised approach. This methodology will then be used to address two other goals of this project: a small library of stabilized and structurally-modified analogs of the maltepolids will be prepared for elucidation of the structure-activity relationships and specially designed and labeled molecular probes will be synthesized and used in the pull-down experiments and western blot assays for the identification of cellular target of maltepolides. Successful realization of this project will bring about not only a new way of synthesis of fused macrolactone structures, but may also result in the discovery of novel anti-cancer drug candidates.

• DFG Programme: Research Grants