To produce lysodendoric acid A, the team used a method that they say may help speed up the drug discovery process — ScienceDaily

To produce lysodendoric acid A, the team used a method that they say may help speed up the drug discovery process — ScienceDaily

UCLA organic chemists have created the first synthetic version of a molecule recently discovered in a sea sponge that may have therapeutic benefits for Parkinson’s disease and similar disorders. The molecule, known as lysodendoric acid A, appears to counteract other molecules that can damage DNA, RNA, and proteins and even destroy entire cells.

And in an interesting twist, the research team used an unusual and long-neglected compound called a cyclic allene to control a crucial step in the chain of chemical reactions needed to produce a usable version of the molecule in the lab, a breakthrough they say. it could prove advantageous in the development of other complex molecules for pharmaceutical research.

Their findings are published in the journal Science.

“The vast majority of drugs today are made using synthetic organic chemistry, and one of our roles in academia is to establish new chemical reactions that can be used to rapidly develop drugs and molecules with complex chemical structures that benefit the world,” said Neil Garg. , Kenneth N. Trueblood Professor of Chemistry and Biochemistry at UCLA and corresponding author of the study.

A key factor complicating the development of these synthetic organic molecules, Garg said, is called chirality, or “hand.” Many molecules, including lysodendoric acid A, can exist in two distinct forms that are chemically identical but are 3D mirror images of each other, like a left and right hand. Each version is known as an enantiomer.

When used in pharmaceuticals, one enantiomer of a molecule may have beneficial therapeutic effects, while the other may do nothing at all, or even be dangerous. Unfortunately, the creation of organic molecules in the laboratory often produces a mixture of both enantiomers, and the chemical removal or inversion of unwanted enantiomers adds difficulty, cost, and delay to the process.

To address this challenge and quickly and efficiently produce only the lysodendoric acid A enantiomer found almost exclusively in nature, Garg and his team used cyclic allenes as intermediates in their 12-step reaction process. First discovered in the 1960s, these highly reactive compounds have never before been used to make molecules of such complexity.

“Cyclic allenes,” Garg said, “have been largely forgotten since their discovery more than half a century ago. This is because they have unique chemical structures and only exist for a fraction of a second when they are generated.”

The team found that they could harness the unique qualities of the compounds to generate a particular chiral version of cyclic allenes, which in turn led to chemical reactions that ultimately produced the desired enantiomer of the lysodendoric acid A molecule almost exclusively.

While the ability to synthetically produce a lysodendoric acid A analog is the first step in testing whether the molecule may possess qualities suitable for future therapies, the method of synthesizing the molecule is something that could immediately benefit other scientists involved in the research. pharmaceutical, chemists said.

“By challenging conventional thinking, we have now learned how to make cyclic allenes and use them to make complicated molecules like lysodendoric acid A,” Garg said. “We hope that others will also be able to use cyclic allenes to make new drugs.”

Co-authors on the research were UCLA doctoral students Francesca Ippoliti (now a postdoctoral fellow at the University of Wisconsin), Laura Wonilowicz and Joyann Donaldson (now of Pfizer Oncology Medicinal Chemistry); UCLA postdocs Nathan Adamson and Evan Darzi (now CEO of startup ElectraTect, a spinoff of Garg’s lab); and Daniel Nasrallah, UCLA adjunct associate professor of chemistry and biochemistry.

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