Yale chemists are working to prevent cancer.
Assistant chemistry professor Seth Herzon and his team of researchers have synthesized a molecule which has led to the discovery of new agents that could be used to prevent the recurrence of ovarian cancer. The molecule, called lomaiviticin aglycon, has been known for a decade, but scientists have since struggled to reproduce it in the laboratory. Herzon’s team recently succeeded in reproducing the molecule, and Herzon spoke to the News Tuesday about the journey that led to the discovery.
Q When and why did you start this project?
A We started in the summer of 2008, right when I started at Yale. Primarily, we were interested in these molecules because of their structures. The focus of our research is natural product synthesis, which is where we recreate in the laboratory molecules that occur in nature. Lomaiviticin, which we have been working on, is unique compared to known natural products. It contains a natural functionality that is unusual and that in simpler molecules is explosive. Lomaiviticin aglycon doesn’t explode, though, so there is something special about it.
Q What were your initial goals?
A We got into it for the challenge — no one could synthesize it. In the long term, we were interested in exploring the molecule’s biological effects. The scientists who originally isolated lomaiviticin in 2001 tested it against cancer cell lines. These tests showed that it was a potent anticancer agent. So that gave us long-term direction. Lomaiviticin is produced in nature by bacteria, but in practice it’s hard to tease the bacteria into making useful quantities of it. Consequently, the biology was a bit of a black box because no one could get access to it very easily. In the short term, though, we just wanted to make the molecule.
Q Did your team face any obstacles in this research?
A There was one obstacle that was 80 percent of the problem, and it couldn’t be more esoteric. There was one carbon-carbon bond that we needed to make. Lomaiviticin aglycon is a symmetrical dimer, which means that one half of the molecule is identical to the other half. The dimers are linked together by this single carbon-carbon bond. In terms of thinking about how it’s naturally produced, we figured that nature makes one half of the molecule and then has a way of making that key bond to connect the two halves. Our strategy in the lab was to emulate this natural pathway by making the symmetrical monomers, then generating the bond. We spent a year working on the bond-generation step — three people working full-time. It was really quite a challenge.
Q Have other groups been working on this problem?
A There were several other groups trying to make lomaiviticin. Quite reasonably, some of these groups adopted strategies where they made this key bond earlier in the synthesis. The issue, though, is that these molecules are exceedingly unstable and delicate, and if you take that type of approach, you’re just swapping problems. We decided first to build the halves and then tackle the bond.
Q How is this compound special?
A Lomaiviticin exhibits very powerful anticancer activity, which is exciting. The thing that we’re most excited about, though, is an ongoing collaboration with Dr. Gil Mor, at the School of Medicine. Gil is one of the world experts on what are called cancer stem cells. The idea is that when you get a tumor, the bulk of the tumor consists of what you might call normal cancerous tissue, but there are a small subpopulation of cells — the stem cells — that are key to survival of the tumor. These cells are highly resistant to chemotherapy and they can regenerate the tumor on their own, which is why they’re called “stem cells.” We sent Gil a sample of some simple lomaiviticin-like molecules, and they turned out to be pretty potent. Now that we have lomaiviticin itself, we are anxious to evaluate it against this cell line. In the long term, we would like to study the molecular mechanisms underlying the anti-stem cell activity of these molecules. This could open up new avenues for inhibiting cancer stem cell growth.
Q What have been the reactions among your colleagues?
A Everyone is pretty excited; the organic group is thrilled. This molecule has been foundering in the literature for a long time. It’s a tough molecule to recreate, and we’re happy to get it done. Now we’re on to more trials and experiments.
Q How does this compare to your other research projects — is it your magnum opus?
A Hopefully not. I think it sets the bar high in terms of what we need to be accomplishing. But we try to choose our projects carefully in terms of the challenges they present and the impact our studies could have. Going forward, the project will be a source of motivation, and we’ll try to emulate the work we were able to accomplish here.