Long-Sought Anticancer Agent Synthesized

Chemists worldwide have been interested in lomaiviticin's potential anticancer properties since its discovery in 2001. But up to now, they have been unable to obtain enough quantities of the compound, which is produced by a rare marine bacterium that cannot be easily persuaded into creating the molecule. For the past 10 years, different groups around the world have been trying instead to synthesize the natural compound in the lab, but without success.

Now a team from Yale University (New Haven, CT, USA), led by chemist Dr. Seth Herzon, has managed to create lomaiviticin aglycon for the first time, opening up new ways to explore innovative chemotherapies that could target cancer stem cells, believed to be the precursors to tumors in a number of different cancers including ovarian, brain, lung, prostate, and leukemia. Their study's findings were published online February 1, 2011, in the Journal of the American Chemical Society. "About three quarters of anticancer agents are derived from natural products, so there's been lots of work in this area,” Dr. Herzon said. "But this compound is structurally very different from other natural products, which made it extremely difficult to synthesize in the lab.”

In addition to lomaiviticin aglycon, the investigators also created smaller, similar molecules that have been shown to be extremely effective in killing ovarian stem cells, according to Gil Mor, MD, a researcher at the Yale School of Medicine who is collaborating with Dr. Herzon to assess the new class of molecules' potential as a cancer therapeutic.

The scientists are particularly excited about lomaiviticin aglycon's potential to kill ovarian cancer stem cells because the disease is very resistant to Taxol and Carboplatin, two of the most common chemotherapy drugs. "Ovarian cancer has a high rate of recurrence, and after using chemotherapy to fight the tumor the first time, you're left with resistant tumor cells that tend to keep coming back,” Dr. Mor explained. "If you can kill the stem cells before they have the chance to form a tumor, the patient will have a much better chance of survival--and there aren't many potential therapies out there that target cancer stem cells right now.”

Dr. Herzon's team, which managed to synthesize the molecule in just 11 steps starting from basic chemical building blocks, has been working on the problem since 2008 and spent more than one year on just one step of the process involving the creation of a carbon-carbon bond. It was an accomplishment that many researchers thought not possible, but while others tried to work around having to create that bond by using other techniques, the team's persistence paid off. "A lot of blood, sweat, and tears went into creating that bond,” Dr. Herzon said. "After that, the rest of the process was relatively easy.”

Next, the team will continue to study the compound to determine better what is happening to the stem cells at the molecular level. The team hopes to begin testing the compounds in animals shortly. "This is a great example of the synergy between basic chemistry and the applied sciences,” Dr. Herzon said. "Our original goal of synthesizing this natural product has led us into entirely new directions that could have broad impacts in human medicine.”

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