New chemical reaction adds to ‘click-chemistry’ family, could speed drug discovery

The efficient amine-to-azide reaction can help chemists optimize potential new drugs with greater potency and fewer side effects.

October 04, 2019

LA JOLLA, CA A team including Nobel laureate chemist K. Barry Sharpless, PhD, of Scripps Research, has discovered an easy, efficient type of chemical reaction that could become widely useful in building potential new drug molecules and other valuable chemical products.

The reaction, described in Nature, transforms molecules called primary amines into a class of useful compounds called azides. It can be used alone or in combination with existing methods to quickly build “libraries” of thousands of variants of a single compound—variants that researchers can test to determine which one works best. Thus, the new reaction should make it easier for chemists to optimize potential new drugs, boosting their potency and reducing side effects—as well as to find the best variants of other, non-pharmaceutical chemical products.

The amine-to-azide technique is the latest addition to the “click chemistry” toolkit. The term “click chemistry,” coined by Sharpless more than two decades ago, refers to reactions that are simple to perform, high-yielding, work with a wide range of starting compounds, and have other properties that make them easy for any chemistry lab to use.

The team of chemists who made the discovery was led by a former postdoctoral researcher in Sharpless’s lab, Jiajia Dong, PhD, now a research professor at the Shanghai Institute of Organic Chemistry (SIOC), part of the Chinese Academy of Sciences.

“I expect that this newest click-chemistry reaction will be widely useful for drug discovery and development, materials science and other applications involving organic synthesis,” says Sharpless, who is the W.M. Keck Professor of Chemistry at Scripps Research, adjunct professor at SIOC and a co-recipient of the 2001 Nobel Prize for Chemistry.

The “diazotransfer” reaction method that the chemists discovered uses a special compound called fluorosulfuryl azide to convert widely available compounds called primary amines into azides—usually quickly, efficiently, and under simple, safe, room-temperature conditions. With prior methods, the formation of such azides had been much more cumbersome and limited in scope.

The new method also usually allows the newly made azides to be employed immediately—without the need for purification or other processing—to build larger compounds. The best known and most widely used click-chemistry technique, the Copper-catalyzed azide–alkyne cycloaddition (CuAAC), uses azides as building blocks to modify a class of compounds called alkynes, turning them into more complex molecules called triazoles. Many successful drug compounds are triazoles, and pharmaceutical chemists often convert drug compounds to triazole variants to see if that improves their properties.

“The availability of azides as building blocks to make triazoles in CuAAC reactions has been limited, owing to their potential toxicity and the risk of explosion involved in their preparation,” Sharpless says. “So this new method is a great tool for easily and safely generating azides to use in CuAAC reactions, including azides that were not even accessible before.”

To demonstrate, the team converted a group of 1,224 amine compounds into azides—about half of which were novel azides. They then used these azides, without any further processing, as building blocks in CuACC reactions to make a library of 1,224 triazole compounds.

The chemists are now employing the new technique to make variants of existing and new drug compounds for a variety of potential applications. For example, chemists at Scripps Research’s drug discovery and development arm, Calibr, recently used the technique to make triazole variants of a prospective new anti-tuberculosis drug—variants that in laboratory tests show more than 100 times greater potency, and better drug properties generally, compared with the original molecule.

The study’s authors, in addition to co-senior authors Dong and Sharpless, were co-lead-authors Genyi Meng, Taijie Guo, and Tiancheng Ma, and co-authors Jiong Zhang and Yucheng Shen, all of the Shanghai Institute of Organic Chemistry.

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