Total Synthesis and Biological Evaluation of Leptosphaerone B and Derivatives of Microketide A
Year: 2026
Type: article
Abstract: Microketide A and B are fungal polyketides reported to display potent activity against Gram-negative pathogens, yet the lack of synthetic access has prevented detailed investigation of their mode of action and structure-activity relationship (SAR). Here, we report the first total synthesis of two close analogs of microketide A, dihydro-MikA and 11-deoxy-MikA, as well as of racemic leptosphaerone B, another member of this cyclohexenone-based natural product family. Our route features a modular assembly of highly functionalized fragments and enables divergent access to analogs through selective dihydroxylation and late-stage fragment fusion. Despite extensive exploration of multiple C-C bond-forming strategies, unfavorable sterics and competing eliminations prevented successful connection of the fragments required for microketide A. The synthesized compounds leptosphaerone B, dihydro-MikA, and 11-deoxy-MikA were evaluated for antibacterial activity and human cytotoxicity but showed no effects up to 200 μM. Competitive residue-specific chemoproteomics and in vitro nucleophile-trapping experiments further revealed no covalent protein engagement, indicating that these scaffolds are intrinsically weak electrophiles. Our findings suggest that microketide A possesses a restrictive SAR, in which even subtle modifications abolish biological function. The synthetic strategy described herein provides a robust platform for in-depth structure activity relationship studies assessing the biological potential of this natural product.
Source: Journal of Natural Products
Authors: Martin F. Köllen, Stephan A. Sieber
Institution: Technical University of Munich
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Awards: G4051244481, G8711866317
OpenAlex ID: W7128812476