Total Synthesis and Anticancer Study of (+)-Verticillin A

Area of Science:

• Organic Chemistry
• Natural Product Synthesis
• Chemical Biology

Background:

• (+)-Verticillin A is a fungal metabolite belonging to the epidithiodiketopiperazine (ETP) class.
• ETPs are known for their biological activities but their complex structures pose synthetic challenges.
• The C12 oxygenation and dimeric nature of (+)-verticillin A make it a particularly challenging synthetic target.

Purpose of the Study:

• To achieve the first total synthesis of (+)-verticillin A.
• To explore the biological activity and mechanism of action of (+)-verticillin A and its derivatives.
• To investigate the potential therapeutic applications of (+)-verticillin A in cancer treatment.

Main Methods:

• Developed a novel synthetic strategy involving disulfide masking and radical dimerization.
• Utilized benzhydryl hydrodisulfide for stereoselective disulfide introduction.
• Photochemical desulfonylation and final-stage unveiling of ETP substructures.
• Assessed biological activity in cancer cell lines and measured H3K27me3 levels.
• Employed thermal shift assays to confirm EZHIP binding.

Main Results:

• Successfully synthesized (+)-verticillin A, the first dimeric ETP natural product with C12 oxygenation via total synthesis.
• (+)-Verticillin A and its N1-sulfonylated derivatives exhibit potent anti-cancer activity.
• These compounds regulate H3K27me3 levels, induce apoptosis, and interact with EZHIP.
• N1-sulfonylated (+)-dideoxyverticillin A binds to EZHIP, while (+)-chaetocin A does not.

Conclusions:

• The total synthesis of (+)-verticillin A provides access to a valuable natural product.
• The interaction with EZHIP suggests a novel therapeutic strategy for H3K27me3-sensitive cancers, including pediatric malignancies.
• Further research into (+)-verticillin A derivatives could lead to new cancer therapies.