New Metal Catalyst Can Help Diversify Drug Development Options

A team of researchers from the University of Illinois led by chemistry professor M. Christina White have created a new manganese-based catalyst that can alter the structure of drug-like molecules to produce new drugs, advancing the pace and efficiency of drug development. Their findings have been published in the journal Nature Chemistry.

Chemistry professor M. Christina White, right, and graduate student Jinpeng Zhao developed a new catalyst that has the potential to advance the pace and efficiency of drug development. (Photo by Fred Zwicky)

A number of pharmaceuticals contain aliphatic and aromatic carbon-hydrogen scaffolds to which chemists add oxygen atoms in precise locations to regulate the behavior of the drug. Aliphatic molecules have carbon-hydrogen bonds that are robust, ubiquitous, and tough to manipulate without influencing other, more reactive parts of the molecule. For instance, aromatics have a type of bond that is frequently more reactive than aliphatic carbon-hydrogen bonds.

Nature tells us in examples of drugs such as erythromycin and Taxol that by swapping out specific hydrogen atoms with oxygen atoms at strategic locations, chemists can control the function of a drug. However, carbon-hydrogen bonds in aliphatic structures are some of the strongest in nature, and our previously developed methods to convert them to carbon-oxygen bonds—a process called oxidation—tend not to tolerate aromatics, which also are very prevalent in drugs.

M. Christina White, Chemistry Professor, University of Illinois

“We have developed a synthetic manganese catalyst that can oxidize aliphatic scaffolds in the presence of aromatics that serve as frameworks for most drugs,” White said. White repeatedly refers to what her team does as “molecular surgery.” Imagine this manganese catalyst as similar to a saw that can cut the skull without touching the brain, she said.

“Our new catalyst does the work of a complex enzyme, but is a simple substance that uses basic principles and can be stored in a refrigerator,” she said. “It will allow drug developers to replace a hydrogen atom with an oxygen atom without having to make a new drug from scratch.”

The team has used the new manganese catalyst to successfully show oxidation in 50 molecules, four of which are drug scaffolds, with the potential to quickly make derivatives having various biological activities or metabolites. This is crucial because metabolites—the byproducts of metabolizing a drug—at times cause side effects or are more active than the original drug, White said.

Moving forward, we believe this catalyst may enable chemists to expedite the drug discovery process by producing new drugs from old ones and identifying metabolites without having to do new syntheses.

M. Christina White, Chemistry Professor, University of Illinois

This study was supported by the National Institutes of Health, Uehara Memorial Foundation, and the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico.

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