Overview: Researchers have successfully created a synthetic version of a small molecule found in a recently discovered sea sponge that appears to have therapeutic benefits for Parkinson’s disease.
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 conditions. The molecule, known as lissodendoric acid A, appears to counteract other molecules that can damage DNA, RNA and proteins, and even destroy entire cells.
And in an interesting twist, the research team used an unusual, long-neglected compound called a cyclic alone to control a critical step in the chain of chemical reactions needed to produce a useful version of the molecule in the laboratory – an advancement they believe could prove beneficial in developing other complex molecules for pharmaceutical research.
Their findings are published in the journal Science.
“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 intricate chemical structures that will change the world. benefit,” said Neil Garg, UCLA’s Kenneth N. Trueblood Professor of Chemistry and Biochemistry and corresponding author of the study.
A key factor complicating the development of these synthetic organic molecules, Garg said, is called chirality, or “handedness.” Many molecules – including lissodendoric acid A – can exist in two different forms that are chemically identical but are 3D mirror images of each other, such as a right and left hand. Each version is known as an enantiomer.
When used in pharmaceuticals, one enantiomer of a molecule can have beneficial therapeutic effects, while the other does nothing at all – or can even prove to be dangerous. Unfortunately, making organic molecules in the lab often produces a mixture of both enantiomers, and chemically removing or inverting the unwanted enantiomers adds difficulty, cost, and delays to the process.
To meet this challenge and quickly and efficiently produce only the enantiomer of lissodendoric acid A that occurs 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 make molecules of such complexity.
“Cyclic allenes,” Garg said, “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 found that they could exploit the compounds’ unique properties to generate one particular chiral version of cyclic allenes, which in turn led to chemical reactions that eventually almost exclusively produced the desired enantiomer of the lissodendoric acid A molecule.
While the ability to synthetically produce an analog of lissodendoric acid A is the first step in testing whether the molecule has suitable properties for future therapies, the method of synthesizing the molecule is something that could immediately benefit other scientists. involved in pharmaceutical research, the chemists said.
“By challenging conventional thinking, we’ve now learned how to make cyclic allenes and use them to make complicated molecules like lissodendoric acid A,” Garg said. “We hope that others can also use cyclic alones to make new drugs.”
Co-authors on the study were UCLA doctoral students Francesca Ippoliti (now a postdoctoral researcher at the University of Wisconsin), Laura Wonilowicz and Joyann Donaldson (now of Pfizer Oncology Medicinal Chemistry); UCLA postdoctoral researchers Nathan Adamson and Evan Darzi (now CEO of the startup ElectraTect, a spinoff of Garg’s lab); and Daniel Nasrallah, an assistant adjunct professor of chemistry and biochemistry at UCLA.
About this Parkinson’s disease research news
Writer: Holly Waiter
Contact: Holly Waiter–UCLA
Image: The image is in the public domain
Original research: Closed access.
“Total synthesis of lissodendoric acid A via stereospecific capture of a tense cyclic alone” by Neil Garg et al. Science
Total synthesis of lissodendoric acid A via stereospecific capture of a strained cyclic alone
Small rings containing single ones are unconventional temporary connections that have been known since the 1960s.
Despite being discovered around the same time as benzyne and offering a number of synthetically advantageous properties, strained cyclic allenes are relatively little used in chemical synthesis.
We report a concise total synthesis of the manzamine alkaloid lissodendoric acid A, which depends on the development of a regioselective, diastereoselective and stereospecific capture of a volatile cyclic-only intermediate.
This key step rapidly assembles the azadecalin framework of the natural product, allows for a concise synthetic endgame, and enables a total synthesis in 12 steps (longest linear sequence; 0.8% overall yield).
These studies demonstrate that strained cyclic alones are versatile building blocks in chemical synthesis.