Automated Complex Molecular printer for making organic small molecules could speed drug development

A new molecule-making machine could do for chemistry what 3-D printing did for engineering: Make it fast, flexible and accessible to anyone.

Chemists at the University of Illinois, led by chemistry professor and medical doctor Martin D. Burke, built the machine to assemble complex small molecules at the click of a mouse, like a 3-D printer at the molecular level. The automated process has the potential to greatly speed up and enable new drug development and other technologies that rely on small molecules.

“We wanted to take a very complex process, chemical synthesis, and make it simple,” said Burke, a Howard Hughes Medical Institute Early Career Scientist. “Simplicity enables automation, which, in turn, can broadly enable discovery and bring the substantial power of making molecules to nonspecialists.”

Photo by L. Brian Stauffer. A machine in University of Illinois chemistry professor Martin Burke’s lab assembles complex small molecules out of simple chemical building blocks, like a 3-D printer on the molecular level.

A block-by-block way to manufacture molecules

Carbon-based small molecules involved in biochemistry and drug design exhibit extraordinary structural diversity. But can we come up with a general set of building blocks from which a machine could put most of them together, in assembly-line fashion? Li et al. present progress toward this goal by showcasing the range of structures available via coupling reactions of fragments bearing a specific type of boronate group. They successfully made complex polycyclic structures by stringing together a linear precursor and then coaxing it to fold back on itself. They also developed a purification method that facilitates automation of the reaction and product isolation.

Science – Synthesis of many different types of organic small molecules using one automated process

“Small molecules” are a specific class of complex, compact chemical structures found throughout nature. They are very important in medicine – most medications available now are small molecules – as well as in biology as probes to uncover the inner workings of cells and tissues. Small molecules also are key elements in technologies like solar cells and LEDs.

However, small molecules are notoriously difficult to make in a lab. Traditionally, a highly trained chemist spends years trying to figure out how to make each one before its function can even be explored, a slowdown that hinders development of small-molecule-based medications and technologies.

“Up to now, the bottleneck has been synthesis,” Burke said. “There are many areas where progress is being slowed, and many molecules that pharmaceutical companies aren’t even working on, because the barrier to synthesis is so high.”

The main question that Burke’s group seeks to answer: How do you take something very complex and make it as simple as possible?

The group’s strategy has been to break down the complex molecules into smaller building blocks that can be easily assembled. The chemical building blocks all have the same connector piece and can be stitched together with one simple reaction, the way that a child’s interconnecting plastic blocks can have different shapes but all snap together. Many of the building blocks Burke’s lab has developed are available commercially.

See a video of Burke explaining the process.

To automate the building-block assembly, Burke’s group devised a simple catch-and-release method that adds one building block at a time, rinsing the excess away before adding the next one. They demonstrated that their machine could build 14 different classes of small molecules, including ones with difficult-to-manufacture ring structures, all using the same automated building-block assembly.

“Dr. Burke’s research has yielded a significant advance that helps make complex small molecule synthesis more efficient, flexible and accessible,” said Miles Fabian of the National Institutes of Health’s National Institute of General Medical Sciences, which partially funded the research. “It is exciting to think about the impact that continued advances in these directions will have on synthetic chemistry and life science research.”

The automated synthesis technology has been licensed to REVOLUTION Medicines, Inc., a company that Burke co-founded that focuses on creating new medicines based on small molecules found in nature. The company initially is focusing on anti-fungal medications, an area where Burke’s research has already made strides.

“It is expected that the technology will similarly create new opportunities in other therapeutic areas as well, as the industrialization of the technology will help refine and broaden its scope and scalability,” Burke said.

“Perhaps most exciting, this work has opened up an actionable roadmap to a general and automated way to make most small molecules. If that goal can be realized, it will help shift the bottleneck from synthesis to function and bring the power of making small molecules to nonspecialists.”

Abstract

Small-molecule synthesis usually relies on procedures that are highly customized for each target. A broadly applicable automated process could greatly increase the accessibility of this class of compounds to enable investigations of their practical potential. Here we report the synthesis of 14 distinct classes of small molecules using the same fully automated process. This was achieved by strategically expanding the scope of a building block–based synthesis platform to include even Csp3-rich polycyclic natural product frameworks and discovering a catch-and-release chromatographic purification protocol applicable to all of the corresponding intermediates. With thousands of compatible building blocks already commercially available, many small molecules are now accessible with this platform. More broadly, these findings illuminate an actionable roadmap to a more general and automated approach for small-molecule synthesis.

105 pages of supplemental material

SOURCES- University of Illinois, Journal Science, Youtube

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