Carnegie Mellon University
July 01, 2021

Mechanism Guided Chemoenzymatic Synthesis of Quinolone Alkaloids

By Ben Panko

New research from Carnegie Mellon University chemists sheds light on how complex natural products could be more effectively made through mechanism guided chemoenzymatic synthesis. The work was published in the latest issue of the journal ACS Catalysis, and was featured as a supplementary journal cover. The cover was designed by Mellon College of Science Publications Manager and Graphic Designer Rachel Keeney.

Quinoline and quinolone alkaloids are organic compounds from which many potentially valuable products with anti-cancer, antiviral and antibacterial properties can be derived, said Associate Professor of Chemistry Yisong (Alex) Guo.

"People will naturally want to know how you will make more of this," Guo said.

Naturally, these products are most often found to be synthesized by plants and some microorganisms using a variety of protein catalysts called enzymes. While processes have been previously developed to synthetically create some of the products, the complexity and variety of the functional groups being attached to the molecules in question makes the processes labor intensive and inefficient.

Guo has long worked to better understand and leverage the power of enzymes in synthetic chemical reactions — in research published last year in the Journal of the American Chemical Society, he and his collaborators looked specifically at the mechanisms of the non-heme-iron oxygenase enzyme AsqJ, which is a critical enzyme in the biosynthesis of quinolone alkaloids.

An important reaction catalyzed by AsqJ is epoxidation, which comprises putting a three-atom ring containing oxygen called an epoxide onto a molecule. This epoxide acts as a functional group for the molecule, allowing it to participate in a variety of chemical reactions including the generation of the core molecular structure of quinolone alkaloids.

In this latest work, Guo and his collaborators built on those mechanistic insights into AsqJ-catalyzed epoxidation by showing how the enzyme could be used to help prepare quinoline and quinolone alkaloid analogues more robustly and efficiently.

"This is the first demonstration of applying this chemoenzymatic synthesis for this family of alkaloids by using non-heme-iron oxygenases," Guo noted.

With the assistance of molecular dynamics simulations performed by Carnegie Mellon Associate Professor of Chemistry Maria Kurnikova and Visiting Researcher Igor Kurnikov and quantum chemical calculations by Guo, Guo and his long-time collaborator, Wei-chen Chang at North Carolina State University, were able to test a range of potential substrate analogues that AsqJ could catalyze into variants of the quinolone viridicatin. Using these analogue substrates, the researchers then synthesized a wide variety of viridicatin products, including some rarely found in nature.

"Overall, using both enzymes and chemical synthesis with a simple Lewis acid treatment, we can create a library of these man-made compounds at a gram scale," Guo said.

In addition to Guo, Chan, Kurnikova and Kurnikov, the other researchers on this study were Yijie Tang of Carnegie Mellon; Haoyu Tang of North Carolina State University and Hsuan Jen-Liao and Nei-Li Chan of National Taiwan University.

Funding for the study was provided by a grant (GM125924) from the National Institutes of Health.