A ring-closing metathesis (RCM)-based approach to mycolactones A/B

Area of Science:

• Organic Chemistry
• Synthetic Biology
• Chemical Biology

Background:

• Mycolactones A/B are toxic compounds produced by Mycobacterium ulcerans.
• Understanding the structure-activity relationship of mycolactones is crucial for developing therapeutic strategies against M. ulcerans infections.
• Total synthesis provides a reliable method for obtaining pure mycolactones for biological studies.

Purpose of the Study:

• To achieve the total synthesis of mycolactones A/B.
• To investigate the biological activity of synthetic mycolactones A/B and their analogues.
• To establish a synthetic route amenable to analogue preparation for structure-activity relationship studies.

Main Methods:

• The synthesis strategy centered on constructing the mycolactone core via ring-closing metathesis using the Grubbs second-generation catalyst.
• Key reactions included modified Suzuki coupling for the upper side chain and Yamaguchi esterification for the lower side chain.
• Biological activity was assessed using fluorescence microscopy and flow cytometry to evaluate apoptosis-inducing and cytopathic effects.

Main Results:

• The 12-membered macrocyclic core of mycolactones A/B was successfully synthesized in 60-80% yield.
• Synthetic mycolactones A/B demonstrated comparable apoptosis-inducing and cytopathic effects to naturally occurring mycolactones A/B.
• A simplified analogue with truncated side chains was found to be biologically inactive, highlighting the importance of the complete structure.

Conclusions:

• The total synthesis of mycolactones A/B was successfully accomplished, validating the proposed synthetic strategy.
• The synthetic mycolactones A/B are biologically active and mimic the effects of their natural counterparts.
• This synthetic route provides a platform for generating analogues to further probe the biological mechanisms of mycolactone toxicity.