Chemistry: A successful (+)-verticillin A synthesis 55 years after its discovery

In 1970 researchers isolated the fungal compound (+)-verticillin A. They tested it and found it to be active against some cancer cell lines in vitro. However, chemists could not figure out a way to synthesize the compound. Chemically, it is a real stinker to synthesize. It was never moved into human clinical trials. There just wasn't enough of the compound to do clinical trials. In mouse cancer testing using nanoparticle-encapsulated verticillin A, tumor burden was significantly reduced in high-grade serous ovarian cancer xenograft models. 

As one can easily see from its chemical structure, this beast isn't easy to synthesize. 

As we can all imagine, the chemists were stumped for 55 years at how to form that nasty C3-C3' carbon-carbon covalent bond that links the two 4-ring monomers into the dimer. Obviously, the disulfide bonds (-S-S-) are not stable under conditions needed to form the C3-C3' bond. But chemists at MIT finally figured a way to do it. A complicated way, but it works.

Next thing is to refine the synthesis and scale it up for expanded pre-clinical testing. Assuming the compound turns out to be promising enough, it will get put into human cancer trials, apparently for treating aggressive pediatric cancers. 

All that said, the clinical success rate starting from the current data set for most new drug candidates is low, probably on the order of ~1% or less. Probably less. It's pretty easy to treat cancer in rodents like mice, but damned hard to do it in humans.

For new drug development, failure is the overwhelming norm, success the rare exception. 

It is worth noting that once a chemical tough nut like this gets cracked, chemists can usually figure out ways to make analogs of the original compound. They will be looking for chemical modifications that increase the clinical safety and/or efficacy compared to the original compound. That is also on the agenda for next steps.

And that is how drug discovery and development often goes. Slow and messy.

By Germaine: Interested in the synthesis of stinkers