To produce lissodendoric acid A, the team used a method they believe could help speed up the drug discovery process.

Organic chemists at UCLA 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 lissodendoric acid A, appears to thwart 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-overlooked compound called 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. they. could prove interesting 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 by synthetic organic chemistry, and one of our roles in academia is to establish new chemical reactions that could be used to rapidly develop drugs and molecules with structures complex chemicals that benefit the world,” said Neil Garg. , UCLA Kenneth N. Trueblood Professor of Chemistry and Biochemistry and corresponding author of the study.

A key factor complicating the development of these synthetic organic molecules, Garg said, is called chirality, or “laterality.” Many molecules, including lissodendoric acid A, can exist in two distinct forms that are chemically identical but are 3D mirror images of each other, such as a right hand and a left 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 or even prove 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 enantiomer of lissodendoric acid A that is found almost exclusively in nature, Garg and his team used cyclic allenes as an intermediate in their 12-step reaction process. First discovered in the 1960s, these highly reactive compounds had never before been used to make molecules of such complexity.

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

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

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

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

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

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