"It was simply too difficult to use the native
blue-green algae for high-level production using traditional
fermentation approaches," said Sherman. But the compound, called
cryptophycin 1, held so much promise as an anti-cancer drug that
organic chemists got busy trying to find ways to make a synthetic form
of the compound in large enough quantities for clinical trials.
Developing an efficient synthetic route to natural
product compounds and their analogs is often an essential step in drug
development. With drugs such as penicillin and tetracycline, it can
easily be done, but cryptophycins present more of a challenge.
Sherman's team realized that with all cryptophycins, the most
difficult step came very late in the synthesis, at the point at which
a key part called an epoxide - a highly strained, three-membered ring
oxygen-containing group, crucial for the drug's anti-cancer activity -
becomes attached to the molecule.
The epoxide group can be attached in two
configurations, designated as alpha and beta. Scientists have known
for several years that the beta configuration was absolutely required
for the anti-cancer properties of the drug, but were unable to devise
efficient synthetic strategies that favored that configuration.
Sherman's team accomplished this by isolating the
entire set of biosynthetic genes and key enzymes and developing a new,
efficient method to manufacture the broad class of cryptophycin
natural products, including important analogs with clinical potential.
This included characterization of an enzyme, cytochrome P450, that
always introduces the epoxide in the desired beta configuration.
Sherman, who is also the John G. Searle Professor
of Medicinal Chemistry in the College of Pharmacy, believes that this
approach will allow effective new cryptophycin analogs with low levels
of side effects to be created for clinical trials.
"This issue represented an exciting target that
offered not only an interesting scientific problem, but the potential
to do something of practical importance in creating a promising
anti-cancer drug," he said. |