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OSU Scientists Unlock Less Wasteful Way to Synthesize Drugs

A new method of synthesizing molecule arrangements in medicine could change the way many drugs, including the PARP inhibitor Zejula, a treatment for ovarian cancer, are produced.

Organic chemists working out of Ohio State University uncovered a new way to synthesize the most common molecule arrangement in medicine that could cut down on the amount of waste that is common with medication production. The research was published in the journal Chem. In a statement from the university, the discovery will provide drug developers with a “crucial building block” in their manufacturing efforts.

David Nagib, the study's senior author and assistant professor in the Department of Chemistry and Biochemistry at Ohio State, said the discovery his team made could potentially allow drug developers to create the building block in one step. Nagib pointed to the fact that the molecules within a drug must be designed to act “in just the right way” with molecules inside the body. He likened it to a lock and key.

Currently, the most common arrangement of molecules used in the development of drugs so they can interact effectively with human molecules is called a chiral piperidine, the OSU researchers noted. Drugmakers synthesize this molecule arrangement using a circuitous process that ultimately creates a mixture. And currently, about half that mixture is tossed out, creating waste. Zuxiao Zhang, the study's lead author and a postdoctoral researcher in Nagib's lab, said the OSU team figured out a way to swap a single carbon-hydrogen bond for a carbon-carbon bond through free radicals.

According to OSU, the discovery relies on chemical bonds that make up a molecule. During the course of their research, the OSU team focused on GlaxoSmithKline’s Zejula, a PARP inhibitor developed by Tesaro, which GSK acquired for $5.1 billion in 2018. Zejula was the first PARP inhibitor approved by the U.S. Food and Drug Administration that does not require BRCA mutation or other biomarker testing.

The manufacture of Zejula is currently done with a chiral piperidine, the OSU team said. During its production, the drug’s makers must “create a number of symmetric mixtures, then strip parts away until they get to the asymmetric molecule necessary to make the drug effective.”

It may sound simple to those versed in these processes, but the OSU team says otherwise. Creating that chiral six-sided ring synthetically was a problem that had troubled chemists for decades, the Ohio State team said. In fact, Nagib said the process was so tricky that when he was first approached about it by Zhang, he was not sure it was the “right problem to solve.”

“The success of this chemistry was entirely thanks to Zuxiao's courage and ambition to tackle such a hard problem,” Nagib said in a statement.

Now that it has been done at OSU, Nagib hopes it could be used to across the drug making process to make medications easier.

Written by: Alex Keown

Published on: Oct 18, 2019

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