Good news! Cancer is history (soon)! Memories of the miracle drug penicillin revived?
"For the first time in 55 years, scientists from MIT and Harvard Medical School successfully synthesized a fungal compound with cancer-fighting potential that was previously impossible to produce in the lab."
"The fungal compound verticillin A, discovered more than 50 years ago, has long been regarded for its potential cancer-fighting capabilities. Scientists have now managed to artificially synthesize the compound for the first time, meaning they can study it in more detail and potentially develop new cancer treatments.
Being able to produce verticillin A on demand in the lab is a major step forward. In nature, it's found only in small amounts in a microscopic fungus and is very difficult to extract. ..."
"... Killing cancer cells
Once the researchers had successfully completed the synthesis, they were also able to tweak it to generate derivates of verticillin A. Researchers at Dana-Farber then tested these compounds against several types of diffuse midline glioma (DMG), a rare brain tumor that has few treatment options.
The researchers found that the DMG cell lines most susceptible to these compounds were those that have high levels of a protein called EZHIP. This protein, which plays a role in the methylation of DNA, has been previously identified as a potential drug target for DMG. ...
The verticillin derivatives appear to interact with EZHIP in a way that increases DNA methylation, which induces the cancer cells to undergo programmed cell death. The compounds that were most successful at killing these cells were N-sulfonylated (+)-11,11'-dideoxyverticillin A and N-sulfonylated verticillin A. N-sulfonylation — the addition of a functional group containing sulfur and oxygen — makes the molecules more stable. ..."
From the 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."
MIT chemists synthesize a fungal compound that holds promise for treating brain cancer (original news release) "Preliminary studies find derivatives of the compound, known as verticillin A, can kill some types of glioma cells."
Total Synthesis and Anticancer Study of (+)-Verticillin A (no public access)
