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Parkinson’s disease is a progressive neurological disorder that affects movement and mobility. It is caused by the degeneration of dopamine-producing neurons in the brain, leading to symptoms such as tremors, stiffness, slow movements and impaired balance and coordination.
The team used a technique they believe could speed up the drug discovery process in the production of lissodendoric acid A.
Organic chemists at the University of California, Los Angeles (UCLA) have synthesized the first artificial form of a molecule found in a marine sponge that has potential therapeutic benefits for Parkinson’s disease and similar disorders. The molecule, called lissodendoric
Their findings are published in the journal Science.
“The vast majority of drugs today are made from 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 intricate chemical structures that benefit the world,” said Neil Garg,
When used in pharmaceuticals, one enantiomer of a molecule may have beneficial therapeutic effects, while the other may do nothing at all—or even prove dangerous. Unfortunately, making organic molecules in the laboratory often yields a mixture of both enantiomers, and chemically removing or reversing the unwanted enantiomers adds difficulty, cost, and delay to the process.
To meet 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. These highly reactive compounds were first discovered in the 1960s, and had never before been used to create molecules of such complexity.
“Cyclic allenes,” said Garg, “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 discovered that they could exploit the compounds’ unique properties to generate a particular chiral version of cyclic allenes, which in turn led to chemical reactions that ultimately produced the desired enantiomer of the lissodendoric acid A molecule almost exclusively.
While the ability to synthetically produce an analog of lissodendoric acid A is the first step in testing whether the molecule may have suitable qualities for future therapy, the method of synthesizing the molecule is something that can immediately benefit other researchers involved in pharmaceutical research, the chemists so.
“By 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 others will also be able to use cyclic allenes to make new drugs.”
Reference: “Total synthesis of lissodendoric acid A via stereospecific trapping of a strained cyclic allene” by Francesca M. Ippoliti, Nathan J. Adamson, Laura G. Wonilowicz, Daniel J. Nasrallah, Evan R. Darzi, Joyann S. Donaldson, and Neil K. Garg, January 19, 2023, Science.
DOI: 10.1126/science.ade0032
