Scientists introduce innovative hook-and-slide method to improve drug discovery

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Historically, one of the main ways organic chemists have studied and created compounds is by constructing a carbon skeleton and making modifications to its structure. But instead of building a carbon skeleton from scratch to make new compounds, the UChicago scientists developed a new method in which they can insert atoms into an already existing carbon framework.

The innovation comes from a paper recently published in Science, by Rui Zhang, a fifth-year student in the Guangbin Dong lab. Zhang, with help from graduate student Tingting Yu, developed a new hook-and-slide strategy that promises to optimize medicinal chemistry.

“This can lead to rapid access to various drug candidates and therefore save a lot of time in the drug discovery process,” Zhang said.

Homologation

Back in May 2021, Zhang started working on a problem related to how scientists create new molecules.

By tuning the structure of molecules in a systematic way, scientists can study how these changes affect the properties of the substances they are working with, providing a useful tool for tailoring molecules to specific needs in different applications. This is especially important in areas such as drug development, where the identification of a new lead can potentially save lives.

Specifically, Zhang wanted to successfully realize the homologation process with amides, a difficulty that had plagued the field and that had not yet been solved.

Homologation is one of the most important molecular modification strategies.

In homology, scientists build a family of related molecules where each member has a longer structure than the last. Once identified, they add specific building blocks, often called methylene groups. As efficient as this process is, for years when researchers tried to homologate amides, a compound found in proteins and great polymers like plastics, they were met with resistance and difficulty. Compared to other functional groups, amides have proven difficult because they are succinctly inert, making them difficult to activate and thus manipulate.

Inspired by the technical challenge, Zhang is not satisfied with simply overcoming the difficulty, but finds new ways to do it well.

“There are no existing methods to homologate amides,” said Professor Guangbin Dong, also an author of the study. “Our goal was to provide a tunable homology so that we could insert a carbon unit of almost any length.”

Pin and drag

When previous methods failed to achieve the desired results, Zhang was able to complete the process and then some.

With what Dong describes as a “hook-and-slide strategy,” they found the key to not only enabling the connection, but also making the homologation process tunable.

After Zhang developed the activation method, he spent another two years refining the project, reviewing different conditions and finding more efficient ways to activate and create connections.

With the publication in Sciencenow he feels his work has finally paid off.

“We have gained new knowledge about how to break this very inert carbon-carbon bond, and we hope that this may inspire the field to explore more of the activation of this inert chemical bond,” Zhang said. “Hopefully this tells the community that if you design the strategy well and it has a great catalyst, even an inert relationship can be manipulated.”

More info:
Rui Zhang et al, Rhodium-Catalyzed Tunable Homologation of Amides via a Hook-and-Slide Strategy, Science (2023). DOI: 10.1126/science.adk1001

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