A new technique allows researchers to more quickly create new molecules by easily swapping nitrogen atoms in the place of carbonyl groups, which may help speed the process of drug discovery
Image Credit: Scientific Frontline
Scientific Frontline: Extended "At a Glance" Summary: Carbonyl-to-Nitrogen Atom Swapping
The Core Concept: A novel chemical technique that enables researchers to customize molecules by directly swapping carbon-oxygen pairs (carbonyl groups) for nitrogen atoms.
Key Distinction/Mechanism: Unlike traditional structural modifications that require up to ten labor-intensive steps to construct a new molecular iteration, this method utilizes an ingredient called NAHA to cleave the carbonyl bond and directly insert a nitrogen atom into the empty space.
Major Frameworks/Components:
- Small-Molecule Scaffold Modification: Editing pre-existing molecular structures instead of building entirely from scratch.
- NAHA-Mediated Cleavage: Utilizing specific reagents to selectively break paired carbon-oxygen bonds.
- Functional Group Tolerance: Maintaining the stability and successful integration of other complex chemical attachments during the nitrogen substitution process.
Branch of Science: Synthetic Organic Chemistry, Medicinal Chemistry, Pharmacology.
Future Application: Accelerating the design, synthesis, and testing of small-molecule drugs by allowing researchers to rapidly generate structural variations and precisely position nitrogen atoms to optimally interact with active sites in the human body.
Why It Matters: By streamlining molecular synthesis from up to ten steps down to one or two, this innovation drastically reduces the time, cost, and complexity of developing new therapeutics for a wide range of diseases.
One of the most common types of medicine belongs to a category called small-molecule drugs. This category includes the pills patients are accustomed to taking, such as ibuprofen, but it also covers drugs for everything from eczema to cancer.
However, when researchers want to create a new small-molecule drug to treat a disease, the process is long and complex, and it begins with synthesizing the compound itself for testing.
A new breakthrough by University of Chicago chemists demonstrates how to easily customize molecules by swapping carbon-oxygen pairs for nitrogen atoms. In some cases, the process can be reduced from ten steps down to just one or two.
“This is another strong tool in the box for the goal of being able to imagine a molecule and then make it—to assemble a molecule as a wish,” said chemist Zining Zhang, a graduate student at UChicago and the first author of the paper.
Structure Matters
Creating molecules from scratch is difficult. It is not like reaching into a box of loose Lego bricks. It is more like starting with a box of partly assembled Lego builds and cobbling those together into the desired structure—with very strict rules regarding how and when pieces can be taken apart.
The structure being created matters significantly. When synthesizing a drug, tiny changes—such as moving a single nitrogen atom—can have huge implications for the final product. That single atom could mean the difference between a drug that successfully latches onto the target proteins in the body and one that fails.
But when researchers want to test different versions of a molecule to determine which one works best, they must laboriously figure out how to synthesize each new iteration.
“So the question we try to address is, can we find a quicker way to introduce many different structural variations that contain nitrogen atoms?” said Guangbin Dong, the Weldon G. Brown Professor of Chemistry at UChicago and the senior author of the paper.
In this case, the scientists wanted to determine whether they could devise a way to easily substitute nitrogen atoms for carbonyl groups, which are a common feature of small molecules and consist of paired carbon and oxygen atoms.
Previously, the Dong lab discovered a method to move these carbonyl groups more easily when developing a new drug. But they also wanted to give researchers the ability to place nitrogen wherever it is needed.
“The location of the nitrogen is important because it is often the piece that interacts with the active site in your body, so we want to be able to move it easily,” explained Zhang.
The group discovered a simpler method using a reagent called NAHA, which grabs the carbonyl and cleaves its bond. Then, through a series of moves akin to choreographed dancers switching partners, the empty space is filled with nitrogen.
The process is simple, effective, and inexpensive, the scientists said. They also noted that the technique's design allows many different types of attachments, known as functional groups, to be compatible—even those that are normally tricky to integrate successfully.
“This was kind of a dream reaction,” said Zhang, “so it was really gratifying to see it work.”
Dong added that the group plans to continue pursuing this direction.
“We’d like to be able to swap carbonyl to all of the possible important atoms,” he said.
The other authors of the paper were visiting undergraduate student Zhehan Liang and graduate student Rong Ye.
Funding: National Institute of General Medical Sciences, Bristol Myers Squibb fellowship.
Published in journal: Science
Title: Scanning nitrogen in sp³-rich scaffolds enabled by carbonyl-to-nitrogen atom swap
Authors: Zining Zhang, Zhehan Liang, Rong Ye, and Guangbin Dong
Source/Credit: University of Chicago | Louise Lerner
Reference Number: chm050526_01