A new set of molecular building blocks aims to make complex chemistry as easy and accessible as a toy construction kit.
Researchers at the University of Illinois at Urbana-Champaign and collaborators at Revolution Medicines Inc. have developed a new class of chemical building blocks that simply snap together to form 3D molecules with intricate twists, and a machine automated to assemble the blocks like a 3D printer for molecules.
This automation could enable chemists and non-chemists alike to develop new pharmaceuticals, materials, diagnostic probes, catalysts, fragrances, sweeteners and more, said study leader Dr. Martin D. Burke, Professor in Chemistry at Illinois and Fellow of Carle Illinois College. of medicine, as well as a doctor. The researchers reported their findings in the journal Nature.
“It makes very complex 3D molecules in a very simple way,” Burke said. “This has been the secret chamber that only card-holding chemists with decades of experience can enter. This new advancement blows that door wide open. Now anyone can enter and play in the sandbox, because these very complex molecules become very accessible.”
For more than 15 years, Burke’s group has pioneered the development of simple chemical building blocks called MIDA boronates, which fit together sequentially using a simple reaction to build small molecules. His lab and collaborators at Revolution Medicines have developed a molecule-making machine that automates chemical synthesis using these building blocks. However, MIDA blocks are largely limited to making flat 2D molecules.
The new set of building blocks, called TIDA boronates, unlocks the missing third dimension, incorporating specific twists and 3D structures directly into the blocks.
“It’s all about function. Three-dimensionality equals function,” Burke said. “The first generation was like those square and rectangular brick kits for kids that can fit together to build a nice, simple toy house. It’s like the cool, intricate brick kits for adults that let you build the Batmobile.”
To demonstrate the capability of the TIDA blocks and the novel second-generation molecule-making machine, researchers synthesized two antimicrobial natural products with specific 3D characteristics, including a cyclic structure, as well as an array of smaller representative structures found in different types of molecules. .
“Nature is very good at creating three-dimensional objects in very precise ways,” said postdoctoral researcher Daniel Blair, first author and co-corresponding author of the paper. “Many of the molecules we use as inspiration to make many of our drugs are natural products, and those with these 3D structures tend to perform better in clinical applications. Yet, until now, it has been very difficult to capture these structures in modular construction. The goal is to help more people make more molecules as simply as possible.”
The modular approach to making molecules has many advantages for chemists and non-chemists alike, the researchers said. Typically, chemists spend a lot of time and effort making a single target molecule, Blair said.
“Three-dimensionality hampers the preparation of different derivatives of a molecule to explore its function,” Blair said. “By capturing a lot of that three-dimensionality up front in modular building blocks, we can easily build a target molecule. Then we can swap out unique building blocks to directly access the derivatives, and then see how that affects the molecular functions.”
In addition to incorporating more functions, TIDA boronate building blocks are up to 1000 times more stable than MIDA boronate blocks in important reaction parameters. They are also very stable in water, allowing the simple synthesis of even more classes of chemicals under a wider range of conditions.
“MIDA had this loose place where the connector part was. When we switched to TIDA, that connector part twisted like a screw, and it’s like tightening a bolt and a nut. And now it’s is surprisingly stable,” Burke said.
Researchers are working to expand the library of TIDA boronate building blocks and plan to make them as widely commercially available as possible, using the success of MIDA boronates as a roadmap. MIDA boronates are now widely used: About 270 are commercially available and more than 250 academic and industrial labs have used them to make discoveries leading to more than 750 publications and 200 patent applications, Burke said.
“One of the things we’re so excited about now is that we can make molecular construction kits for really complex molecules. Since a plastic block kit has all the specialized parts and you put them together, we can now imagine kits for complex and large molecules, and then make it accessible to non-chemists. I think it’s a chance for us to break down some of those barriers that have traditionally limited who can innovate at the molecular level.
The National Institutes of Health, National Science Foundation, Damon-Runyon Cancer Research Foundation, Henry Luce Foundation, ACS Division of Organic Chemistry, and Austrian Science Fund supported this work. READ. of I. has filed patent applications for the boronates MIDA and TIDA. Burke is founder, shareholder and consultant of Revolution Medicines Inc., which provided additional support for this research in the form of the TIDA reagent.