As the population continues to age, a pandemic of Parkinson’s disease (PD) is emerging, with conservative estimates of over 14 million victims globally by 2040. While PD patients display a wide range of non-motor features, the defining symptoms are progressive motor deficits due to striatal dopaminergic insufficiency secondary to loss of dopaminergic nigral neurons.
Current treatments are symptomatic, mostly focused on ameliorating motor deficits, but no therapy arrests or reverses the disease 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 counteract other molecules that can damage DNA, RNA and proteins and even destroy whole cells.
And in an interesting twist, the research team used an unusual, 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, an advance they say could prove advantageous in developing other complex molecules for pharmaceutical research.
What is the challenge ?
Neil Garg, UCLA’s Kenneth N. Trueblood Professor of Chemistry and Biochemistry, and his team, found a key factor complicating the development of these synthetic organic molecules, iis called chirality, or “handedness. Many molecules , including lissodendoric acid A, can exist in two distinct forms that are chemically identical but are 3D mirror images of each other, like a right and 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 at all , or even prove dangerous. Unfortunately, creating organic molecules in the laboratory often yields a mixture of both enantiomers, and chemically removing or reversing the unwanted enantiomers adds difficulties, costs and delays 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 employed cyclic allenes as an intermediate in their 12-step reaction process.
The team discovered that they could harness the compounds’ unique qualities to generate one 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 possess suitable qualities for future therapeutics, the method for synthesizing the molecule is something that could immediately benefit other scientists involved in pharmaceutical research.
Francesca M. Ippoliti, Nathan J. Adamson, Laura G. Wonilowicz, Daniel J. Nasrallah, Evan R. Darzi, Joyann S. Donaldson, Neil K. Garg. Total synthesis of lissodendoric acid A via stereospecific trapping of a strained cyclic allene. Sc ience, January 19 , 2023; 379 (6629): 261 DOI: 10.1126/science.ade0032