Pellets of silvery-colored nickel sit in a pile.

The newly developed complex includes a nickel atom.

Credit: iStock.com/RHJ

Accelerating drug discovery with a nickel-based catalyst

The new complex is inexpensive to produce, and its unique architecture makes chemical reactions integral to drug discovery more stable and efficient.
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A new chemical complex that helps glue molecules together more efficiently could simplify the search for new drug molecules, suggests a new study (1). Researchers, led by Christo Sevov, a chemist at Ohio State University, detailed a chemical complex that could make unpredictable and hard-to-control chemical reactions more stable. Chemists could apply the tool to a wide range of chemical synthesis reactions, bringing high-throughput approaches to previously pedestrian organic synthesis assays and accelerating the discovery phase that often slows new pharmaceutical development.

To build small-molecule pharmaceuticals, drug developers often combine organic molecules in a process called cross-coupling. These reactions can create desirable three-dimensional drug molecules, but researchers have long sought a process that will generate these complex structures reliably. A 3D structure will help drugs bind to enzymes and other biological targets more effectively. “Everybody in the pharmaceutical industry wants to escape flatland,” said Sevov. If researchers could reliably cross-couple 3D alkyl fragments, it would open up an unexplored chemical space, said Sevov.  

In many cross-coupling reactions, the fit between two molecules isn’t perfect. Chemists use metals such as palladium in an intermediate step to bond the fragments. The discovery of palladium-catalyzed coupling reactions won Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki the 2010 Nobel Prize for Chemistry (2). Nickel-based catalysis has become more popular in the last decade (3). “People are trying to get away from palladium, which is a lot less abundant,” said Peter O’Brien, a chemist at the University of York who was not involved in the study. 

Catalysts have so far proved unable to accelerate alkyl cross-coupling. The central problem is an issue of selectivity. Given two molecules — alkyl X and alkyl Y — cross-coupling reactions aim to produce a new molecule that combines the two — alkyl XY. But because alkyls all look very similar, the reaction instead will produce many alkyl XX or YY molecules, ruining the reaction’s purity. 

One potential solution is to create an intermediate complex in which one alkyl molecule attaches to a metal-containing complex. A researcher could combine this intermediate molecule with the second alkyl in a highly specific reaction. Sevov said that previous attempts to make such intermediates produced molecules that fell apart within microseconds, making them impossible to use. 

Sevov and his team’s innovation solved this problem.      

The nickel intermediate in the researchers’ new paper doesn’t disintegrate. It owes this property to an additional ligand made of thionitrile and aminopyridine. This ligand has a three-point structure that occupies three of nickel’s four binding sites. When the alkyl fragment of interest binds to the final site, the complex becomes geometrically stable. The ligand’s negative charge also balances out the nickel’s positive charge. “It's a perfect balance of electronic, geometric effects,” said Sevov. 

The new approach may also bring stability to chemistry laboratories’ budgets. Sevov’s team made the complex from inexpensive starting materials. The total cost of the whole structure, including the nickel and the components that make up the ligand, came to roughly $0.55 per gram, said Sevov. In comparison, tert-butyl bipyridine — a common ligand used in nickel catalysis — can cost $10 per gram, he added. 

The structure’s primary use will be in discovery chemistry, where researchers try and create new compounds under various experimental conditions. What makes the technique so valuable in this setting, said Sevov, is that many organic synthesis assays require researchers to assemble a nickel-alkyl complex as an intermediate structure. Combined with the added stability offered by the complex, this innovation opens up countless chemical possibilities. “You can do reactions in a parallel fashion for high-throughput experimentation,” he said. In the study, the researchers used the technique to build complex molecules from natural products such as the sugars galactose and ribose and from several amino acids like serine and lysine.  

“It’s a significant step forward,” said O’Brien.

At this stage, said Sevov, the process is unfeasible for use on a large scale. The complex should allow researchers to explore how alkyl substrates perform, allowing scientists to select ideal conditions for industrial-size reactions. The true impact of this innovation might be how it helps other chemists in their day-to-day work. “It is [a] mechanistic tool to build the foundation of this field,” said Sevov. 

References

  1. Zubaydi, S.A. et al. Reductive alkyl-alkyl coupling from isolable nickel-alkyl complexes. Nature  634, 585-591 (2024).
  2. Negishi, E. A profile of Professor Richard F. Heck: Discovery of the Heck reaction. J Organomet Chem  576, xv-xvi (1999).
  3. Diccianni, J.B. & Diao, T. Mechanisms of Nickel-Catalyzed Cross-Coupling Reactions. Trends Chem  1, 830-844 (2019).
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