A recently discovered molecule which exists naturally in the sea sponge Lissodendoryx florida that may have therapeutic benefits for Parkinson’s disease, has been synthesized by organic chemists at UCLA, and in the process, may have uncovered a method to solve the challenge of chirality, which has hampered producing usable versions of lab-developed drug candidates.
“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, a professor of chemistry and biochemistry at and corresponding author of the study.
The compound, known as lissodendoric acid A has shown promise in counteracting molecules that cause damage to DNA, RNA, and proteins and even those that destroy entire cells. The findings, published in the journal Science, also detail the team’s surprising finding of a long-neglected compound called a cyclic allene that is used to control a key step in the chain of chemical reactions needed to create a usable version of the molecule in the lab.
Their method appears to have solved the complications of producing usable chemicals for pharmaceutical research related to chirality—molecules that exist in two, distinct mirror image forms (or “handedness”). Each version is known as an enantiomer, and while one enantiomer may have therapeutic benefits, its mirror image may have no effect, or even be toxic. Quite often, when attempting to create organic molecules in the lab, the process will yield a mixture of both enantiomers and finding ways to remove or reverse the unwanted enantiomers is complicated and adds costs and delays to production.
For their work, Garg and his research team at UCLA discovered a much quicker and efficient method, that only produces the enantiomer of lissodendoric acid A found in the sea sponge via the use of cyclic allenes as an intermediate in the 12-step reaction they developed to create the molecule. First discovered in the 1960s, cyclic allenes are highly reactive and had never before been used to synthesize such complex molecules.
“Cyclic allenes have largely been forgotten since their discovery more than half a century ago,” Garg noted. “This is because they have unique chemical structures and only exist for a fraction of a second when they are generated.”
Beyond the potential of discovering a technique for synthesizing the correct enantiomer of lissodendoric acid A that can now be used for research as a potential treatment for Parkinson’s disease, the UCLA team noted that the method they used employing cyclic allenes could be more broadly applied by chemists seeking to produce only one enantiomer of promising therapeutic candidates.
“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 medicines.”
