New reaction will make indoline scaffolds available for pharmaceutical development
From left to right, Prof. Donald A. Watson and doctoral students Feiyang Xu and Katerina Korch have found a new, easier way to make complex chemical structures known as indoline scaffolds that can be used in the development of new pharmaceuticals. Credit: Kathy F. Atkinson

New reaction makes indoline scaffolds for Pharma Development

Almost fifty years since the late Richard Heck discovered one of the powerful chemical reactions that led to the University of Delaware professor’s Nobel Prize 2010, currently, chemists around the world are still finding innovative and valuable ways to use this Heck Reaction.

Prof. Donald A. Watson is a part of the Department of Chemistry and Biochemistry where Heck taught during his time on University of Delaware ‘s faculty (1971-89). Donald Watson and his research team have just published new findings that could streamline the development as well as the production of small-molecule pharmaceuticals, which comprise the majority of drugs in use today. The active ingredient in these small-molecule drugs are typically delivered by a tablet or capsule and absorbed into the bloodstream.

Their recent research work, published in Angewandte Chemie, shows how the Heck Reaction, that uses palladium as a catalyst to bond carbon molecules, can make it very easier and more practical to produce indoline scaffolds structures that provide an important platform for new molecules useful in the pharmaceutical industry.

Indoline scaffolds are mainly found in many natural products as well as in the drugs used to treat diseases including cancer

, migraine headaches, hypertension, and other conditions.

But producing these indoline scaffolds has been challenging, especially when more complexity is required.

Watson and his research group saw a new way to deploy the Heck Reaction, using nitrogen to accomplish the assembly in previously unattempted ways and also make complex assemblies accessible. With nitrogen as a reagent, new possibilities have emerged.

Watson said that everything Heck focused on is based on carbon-based reagents. The team wanted to know whether this can be applied to other elements in the periodic table? The answer to that, in short, was yes. The team has looked at silicon, boron atoms and also nitrogen, which is directly relevant to the fabrication of various bioactive compounds.

A bioactive compound can provoke a specific biological response in a living organism and these compounds in medicines may be used to kill bacteria, lower blood pressure or even to kill cancer cells.

Watson credits doctoral student Feiyang Xu, who is the lead author of the article, with finding the path to this conversion processes.

Watson said that the team has been exploring the parameters of what’s allowed and also fleshing out the rules of how these new reactions actually work. There is a need to define and provide tools for other chemists to find where those tools will and will not work & also what you can do with those tools, he added.

The key to this process is forcing nitrogen to do the chemist’s bidding in a twist that chemists call “ümpole.”

Nitrogen is an electron hog naturally. In this process, the scientists have created elements where nitrogen doesn’t have enough electrons, steering it in the direction needed for this process.

Carbon is easy to do that with But getting nitrogen to behave in such a way in these types of reactions is the new thing that the team is trying to figure out how to exploit, he added.

As this work proceeds, Watson expects even more benefits.

He added that this chemistry of new reaction makes indoline scaffolds for Pharma is going to be very scalable and it uses readily available materials.

The Watson team uses the University of Delaware’s nuclear magnetic resonance (NMR) spectroscopy facilities to observe as well as to analyze the molecular structures of the materials.

There are a million ways you can do certain things, But sometimes some results or answers wind up better than previous ones. It may provide an easier way to prepare things, with more simple starting materials and streamlines how you can access more complex molecules, Watson said.

Murray Johnston who is an associate dean of the College of Arts and Sciences and professor of chemistry said it is gratifying to see Watson and his research team continuing to advance Heck’s science.

Johnston added that the groundwork laid by Professor Heck continues to thrive at UD.

Watson said that what gets all of the team up every day and motivates them to do is this; there are a lot of medical needs in the world; And the team tries to develop tools so that medicinal chemists who are developing new drugs have those tools to make the compounds they need to treat disease, he added.

Author: Ria Roy



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