A schematic
shows a trioxacarcin C molecule, whose structure was revealed for
the first time
through a new process developed by the Rice lab of synthetic organic
chemist K.C.
Nicolaou. Trioxacarcins are found in bacteria but synthetic versions are
needed to study
them for their potential as medications. Trioxacarcins have anti-cancer
properties.
(Credit: Nicolaou Group/Rice University)
(March 11, 2016) Trioxacarcin
molecules bind to the DNA of targeted cells and prevent them from replicating
A team led by Rice University synthetic organic chemist K.C.
Nicolaou has developed a new process for the synthesis of a series of potent
anti-cancer agents originally found in bacteria.
The Nicolaou lab finds ways to replicate rare, naturally
occurring compounds in larger amounts so they can be studied by biologists and
clinicians as potential new medications. It also seeks to fine-tune the
molecular structures of these compounds through analog design and synthesis to
improve their disease-fighting properties and lessen their side effects.
Such is the case with their synthesis of trioxacarcins,
reported this month in the Journal of the American Chemical Society.
“Not only does this synthesis render these valuable
molecules readily available for biological investigation, but it also allows
the previously unknown full structural elucidation of one of them,” Nicolaou
said. “The newly developed synthetic technologies will allow us to construct
variations for biological evaluation as part of a program to optimize their
pharmacological profiles.”
At present, there are no drugs based on trioxacarcins, which
damage DNA through a novel mechanism, Nicolaou said.
Trioxacarcins were discovered in the fermentation broth of
the bacterial strain Streptomyces bottropensis. They disrupt the replication of
cancer cells by binding and chemically modifying their genetic material.
“These molecules are endowed with powerful anti-tumor
properties,” Nicolaou said. “They are not as potent as shishijimicin, which we
also synthesized recently, but they are more powerful than taxol, the widely
used anti-cancer drug. Our objective is to make it more powerful through
fine-tuning its structure.”