Total synthesis and semi synthetic derivatization of [13]cytochalasans

• Applicant: Professor Dr. Philipp Klahn
• Subject Area: Biological and Biomimetic Chemistry ; Organic Molecular Chemistry - Synthesis and Characterisation
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 438841444

Cytochalasans comprise a diverse group of fungal polyketide-amino acid hybrid metabolites with a wide range of biological functions. A hallmark of the cytochalasans is their tricyclic core structure in which a size-variable macrocycle is fused to a bicyclic isoindolone system derived from an amino acid. The eleven known subclasses of the cytochalasan natural product family differ in the size of the fused macrocycle and its oxidation pattern as well as the oxidation pattern in the 6-membered ring of the isoindolone core. In some representatives of the respected subclasses additional structural diversity is achieved by fusion of the macrocycle into polycyclic frameworks and even non-macrocyclic Cytochalasans are known. Despite all available biological data on cytochalasans, a comprehensive picture of the structure-activity relationships (SAR) for specific activities or of the correlation between the structural motives (ring sizes, oxidation pattern, substituents) of the respected cytochalasan subclasses and the different biological targets addressed by them is still missing. Although, several total syntheses for specific representatives of known cytochalasan subclasses have been published, none of them has been targeting the subclass of [13]cytochalasans. As access to natural cytochalasans is limited, only very few semi-synthetic derivatization studies have been made, only limited to [11]cytochalasans. Thus, there are no comprehensive synthetic studies on [13]cytochalasans enabling the elucidation of SAR of incorporated amino acid, oxidation pattern or macrocycle size on the biological activities and target selectivity.Furthermore, considering the biosynthetic pathways leading to cytochalasans already elucidated, we can expect that there are formally missing cytochalasan subclasses existing in nature, which could be formed from a biosynthetically perspective, but have not been isolated from natural sources yet. Thus, there might be even more hidden biological activity to discover from the cytochalasan natural product family.Within the present project, on the one hand, we plan to derivatize natural [13]cytochalasans obtained by fermentation and on the other hand develop an efficient, convergent and variable synthetic access to the subclass of [13]cytochalasans via a late-stage derivatization strategy and generate several [13]cytochalasan derivatives. Furthermore, we aim to synthetically access the formally missing subclass of 23-oxa-[13]cytochalasans based on the developed synthesis. Thus, we will provide appropriate [13]cytochalasan derivatives for biological evaluation, target identification and imaging purposes and enable systematic comprehensive SAR studies for specific biological activities by different collaboration partners within the envisaged DFG Researcher Group CytoLabs.

• DFG Programme: Research Units
• Subproject of: FOR 5170: CytoLabs – Systematic Investigation and Exploitation of Cytochalasans
• International Connection: Sweden