Organic chemists at UCLA have created the first synthetic version of a molecule recently discovered in sea sponges that may have therapeutic benefits for Parkinson’s disease and similar disorders. The molecule, known as A-lysodonic acid, appears to counteract other molecules that can damage DNA, RNA and proteins, and even destroy entire cells.
And in an intriguing twist, the research team used an unusual, long-neglected compound called cyclic alliin to control a critical step in the chain of chemical reactions needed to produce a usable version of the molecule in the laboratory — an advance they say could be useful in developing other complex molecules for pharmaceutical research.
Their findings have been published in the journal Sciences.
“The vast majority of drugs today are made by synthetic organic chemistry, and one of our roles in academia is to create new chemical reactions that can be used to rapidly develop drugs and molecules with complex chemical structures that benefit the world,” said Neil Garg. Professor of Chemistry and Biochemistry, Kenneth N. Trueblood UCLA and corresponding author of the study.
The main factor complicating the development of these synthetic organic molecules is called chirality, or “hands,” Garg said. Many molecules—including A-lysodenuric acid—can exist in two distinct forms that are chemically identical but are three-dimensional mirror images of each other, like right and left hands. Each version is known by an identical name.
When used in pharmaceuticals, one nanoparticle may have beneficial therapeutic effects while another may do nothing at all — or even prove dangerous. Unfortunately, the formation of organic molecules in the laboratory often results in a mixture of both homologues, and chemically removing or inverting undesirable variants adds difficulties, costs, and delays to the process.
To meet this challenge and quickly and efficiently produce a homologue of lysodenuric acid A that is found almost exclusively in nature, Garg and his team used cyclic alines as intermediates in their 12-step reaction process. First discovered in the 1960s, these highly reactive compounds had never before been used to make molecules of this complexity.
“Cyclic allenes have been largely forgotten since they were discovered more than half a century ago,” Garg said. “This is because they have unique chemical structures and are only present for a split second when they are generated.”
The team discovered that they could harness the compounds’ unique qualities to generate one particular copy of the cyclic allenes, which in turn triggered chemical reactions that eventually produced the required homologous end of the molecule A-lysodenuric acid almost exclusively.
While the ability to produce a synthetic analogue of lysodenuric acid A is the first step in testing whether the molecule might possess qualities suitable for future therapies, the method for synthesizing the molecule is something that could immediately benefit other scientists involved in pharmaceutical research, the chemists said.
“By challenging conventional thinking, we have now learned how to make cyclic allenes and use them to make complex molecules such as A-lysodenuric acid,” Garg said. “We hope that others will also be able to use cycloallenes to make new medicines.”
Co-authors on the paper were UCLA doctoral students Francesca Ippoliti (now a postdoctoral researcher at the University of Wisconsin), Laura Wenilovich and Joanne Donaldson (currently in Oncology Medicinal Chemistry at Pfizer); UCLA postdoctoral researchers Nathan Adamson and Evan Darzi (now CEO of startup ElectraTect, an offshoot of Garg Lab); and Daniel Nasrallah, assistant professor of chemistry and biochemistry at the University of California, Los Angeles.