Professor Sherman and Colleagues Isolate Anti-cancer Compounds From Blue-green Algae

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rom sea sediment to the insides of sponges, John G. Searle Professor of Medicinal Chemistry David H. Sherman, PhD, has probed some unusual places looking for compounds with potential cancer-fighting properties. With fellow U-M Life Sciences Institute researcher Zachary Q. Beck and others, Sherman has turned his attention to yet another potential source of anticancer drugs: blue-green algae

By combining synthetic chemistry techniques with a knowledge of the properties and actions of enzymes, Sherman’s research group has isolated and manufactured cryptophycin 1 using a novel chemoenzymatic approach. Cryptophycin 1, the prototypic member of the class of lichen cyanobacterial symbiont Nostoc sp. ATCC 53789 and its close relative Nostoc sp. GSV 224, has shown potential as a potent tubulin-depolymerizing agent, and several semisynthetic derivatives are being developed as anticancer therapeutics.

“It was simply too difficult to use the native blue-green algae for high-level production using traditional fermentation approaches,” explains Sherman, who is director of the Center for Chemical Genomics at the U-M Life Sciences Institute in addition to his medicinal chemistry appointment. “But cryptophycin 1, as well as a group of select analogs, holds so much promise as an anticancer drug that we had to find a way to create sufficient quantities for clinical trials.”

With drugs such as penicillin and tetracycline, developing an efficient synthetic route to natural product compounds and their analogs is fairly straightforward, Sherman says. But cryptophycins present more of a challenge. Late in the synthesis process, an epoxide group can be attached in two configurations: alpha and beta. Scientists knew that the beta configuration was essential to create a compound with requisite anticancer properties, but until now, scientists were unable to devise efficient synthetic strategies favoring that particular 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

“The late-stage epoxidation 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 anticancer drug,” Sherman states

The article describing this study, “Biosynthetic Characterization and Chemoenzymatic Assembly of the Cryptophycins: Potent Anticancer Agents from Nostoc Cyanobionts,” was featured on the cover of the January 2007 issue of the journal, ACS Chemical Biology. E-mail: davidhs@umich.edu.