J Am Chem Soc. 2025 Dec 2. doi: 10.1021/jacs.5c16112. Online ahead of print.
ABSTRACT
We report the first total synthesis of (+)-verticillin A, over 50 years after the fungal metabolite was first isolated. Our initial strategy for sulfidation of a dimeric diketopiperazine (DKP) delivered the undesired stereochemistry for the epidithiodiketopiperazine (ETP) substructures of the alkaloid (+)-verticillin A. We later developed a protocol to directly introduce the disulfide with the correct relative stereochemistry on a complex DKP using benzhydryl hydrodisulfide prior to dimerization. Given the sensitivity of ETPs to carbon-centered radicals and UV irradiation, we developed a strategy to mask the disulfide as a pair of alkyl sulfides prior to an ambitious radical dimerization, fusing two bis-sulfide DKPs at the C3-C3′ linkage, followed by photochemical N1 desulfonylation. A final-stage unveiling of the ETP substructures furnished (+)-verticillin A, the first dimeric ETP natural product containing C12 oxygenation to be accessed by total synthesis. (+)-Verticillin A and its N1-sulfonylated derivatives demonstrated potent biological activity in cancer cell lines and effectively regulated histone lysine 27 trimethylation (H3K27me3) levels in the cell, leading to apoptosis. Treatment of cell lines expressing high levels of EZH inhibitory protein (EZHIP) with (+)-verticillin A led to the upregulation of H3K27me3, suggesting that (+)-verticillin A and its N1-sulfonylated derivatives interact with EZHIP. A thermal shift assay using cell lysates confirmed that N1-sulfonylated (+)-dideoxyverticillin A binds to EZHIP, whereas the structurally related ETP (+)-chaetocin A did not show any in-cell engagement with EZHIP. The interaction between (+)-verticillin A and its derivatives with EZHIP may be leveraged to treat pediatric cancers that are sensitive to H3K27me3 alteration.
PMID:41329819 | DOI:10.1021/jacs.5c16112
