Organic chemists at the University of California, Los Angeles (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.
The research team used a 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.
“The vast majority of medicines 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 quickly develop medicines and molecules with intricate chemical structures that benefit the world,” said Neil Garg, UCLA’s Kenneth N Trueblood Professor of Chemistry and Biochemistry and corresponding author of the study.
Overcoming chirality
A key factor complicating the development of these synthetic organic molecules, Garg said, is called chirality. Many molecules can exist in two distinct forms that are chemically identical but are 3D mirror images of each other. 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 Garg and his team employed cyclic allenes as an intermediate in their 12-step reaction process.
“Cyclic allenes have largely been 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,” Garg explained.
“By challenging conventional thinking, we have now learned how to make cyclic allenes and use them to make complicated molecules like lissodendoric acid A. We hope others will also be able to use cyclic allenes to make new medicines.”
Image shows: Lissodendoryx florida (PIBOC O47-283) by spongiologist Vladimir B Krasokhin. Provided by Sophia Kolesnikova of the Laboratory of Marine Natural Compounds Chemistry at the GB Elyakov Pacific Institute of Bioorganic Chemistry.
