A team of Yale Univ.
scientists has, for the first time, synthesized a chemical compound called
lomaiviticin aglycon, leading to the development of a new class of molecules
that appear to target and destroy cancer stem cells.
Chemists worldwide have been interested in
lomaiviticin’s potential anticancer properties since its discovery in 2001. But
so far, they have been unable to obtain significant quantities of the compound,
which is produced by a rare marine bacterium that cannot be easily coaxed into
creating the molecule. For the past decade, different groups around the world
have been trying instead to synthesize the natural compound in the lab, but
without success.
Now a team at Yale, led by chemist Seth Herzon, has
managed to create lomaiviticin aglycon for the first time, opening up new
avenues of exploration into novel chemotherapies that could target cancer stem
cells, thought to be the precursors to tumors in a number of different cancers
including ovarian, brain, lung, prostate, and leukemia. Their discovery appears
online 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,”
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, Herzon’s team
also created smaller, similar molecules that have proven extremely effective in
killing ovarian stem cells, said Gil Mor, M.D., a researcher at the Yale School
of Medicine who is collaborating with Herzon to test 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 notoriously 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,” 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.”
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 a year on just one
step of the process involving the creation of a carbon-carbon bond. It was an
achievement that many researchers deemed impossible, 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,” Herzon said. “After that, the rest of the process
was relatively easy.”
Next, the team will continue to analyze the
compound to better understand what’s 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,” 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.”
Other authors of the paper include Liang Lu,
Christina M. Woo, and Shivajirao L. Gholap, all of Yale Univ.
