Molecule-Making Device Synthesizes Small Molecules

With molecular weights under 900 Daltons, small molecules are the fundamental chemical building blocks for most medicines on the market today — drugs that can enter body cells more quickly, have improved bioavailability, and can cross the brain-blood barrier.

Because of their complexity, these densely packed small molecules have been  notoriously difficult to synthesize in the research lab.  The classic method for creating small molecules requires a great deal of simulation and prediction by highly trained specialists, a lengthy series of chemical reactions and a heavy dose of patience. This results in a research bottleneck that impedes, and sometimes prevents, the development of promising medications and technologies.

This extremely time-consuming process, however, may soon be replaced with an automated "molecule-making" machine developed by Martin D. Burke, M.D., Ph.D., a member of Howard Hughes Medical Institute and professor at  the University of Illinois. Using the 3-D printing technology model, Burke and his colleagues are on the verge of revolutionizing small molecule manufacturing with a machine that can rapidly assemble chemical building blocks with a few clicks of the mouse.

The team set out to simplify this complex chemical synthesis process and make it "fast, flexible and accessible to anyone." "Simplicity enables automation, which, in turn, can broadly enable discovery and bring the substantial power of making molecules to nonspecialists," states Burke.

In his own research, Burke had been exploring the potential of small molecules found plants, animals and microbes to treat disease, and he experienced firsthand the challenges of making target modifications.  To streamline the synthesis process, his team began to analyze the structure of thousands of natural products. They discovered that small molecules were inherently modular configurations comprised of a number of simpler building blocks linked in a repetitive fashion.

With this understanding, the team identified and developed hundreds of the simpler chemical structures common to many small molecules. Using these chemical building blocks in a small molecule synthesizer, researchers successfully created 14 different organic small molecules with configurations ranging from basic linear structures to complex folded arrangements with several rings.  In essence, the machine connected the blocks in a LEGO® like fashion, induced chemical reactions, and rinsed away the unwanted reaction byproducts to create the final small molecule.

In a matter of hours using customized chemical "recipes," the molecule maker will be able to synthesize from scratch small molecules  that may have previously  taken months or even years in the lab. Burke has licensed the technology and believes it's poised to be a game changer in creating the next generation of complex therapeutic drugs and technological tools with the push of a button.