Drug Designer’s Cup of Tea

Posted on December 12th, 2012 by Dr. Francis Collins

Medicinal chemists are the molecular architects of the drug development world—they do whatever it takes to design and build compounds with therapeutic potential. They are precise, they handle toxic chemicals under extreme conditions, they are continuously developing new structures, and they don’t rest until the job is done.

These chemists begin with an organic chemical “scaffold” (generally made up of carbon, hydrogen, oxygen, nitrogen, and a few other atoms) and then tinker; they often create hundreds of incrementally different versions of the same structure, adding a side chain of additional atoms here or there, to improve the potency or selectivity of the drug. It is painstaking, costly research.

That’s why the new “toolkit” developed by NIH-supported researchers at The Scripps Research Institute in La Jolla, CA, and featured in the November 28^th issue of Nature, is such a big hit [1]. The researchers have created a collection of 10 new recipes that can be used to modify “heterocycles”—flat, ring shaped molecules made of carbon and nitrogen that are the building blocks for many drugs. The presence of nitrogen traditionally makes these heterocycles very uncooperative—they are difficult to dissolve and frequently deactivate the reagents or catalysts with which they are supposed to react. Until now adding a branch to one of these molecules could take days or even weeks, at the cost of thousands of dollars per gram (just for comparison, a gram of gold is currently worth about $55).

The Scripps researchers have exploited the hidden romantic tendencies of heterocyclic molecules—their love and attraction for radicals (highly reactive compounds). They have created a toolkit of “zinc salts” that morph into superhero radical molecules under the right conditions and react with the heterocycle, slyly attaching the desired chemical group to these rings as the two mingle. These zinc salts are particularly handy for attaching fluorine atoms, which can help a drug absorb into the bloodstream and remain in circulation longer. The practical implication is that a patient might need less of a drug or need to take it less frequently.

The toolkit has been very successful in multiple applications, and medicinal chemists at several pharmaceutical companies, including the world’s biggest, Pfizer, are already using these salts in their quest to speed up drug development. That’s vital because developing a drug from scratch takes on average about 14 years.

A spinoff from this basic research is that chemists from all fields who work with heterocycles will benefit from this cheap and easy short cut, which can now be performed in any lab.

Another advantage of these new tools is that they can complete their mission under many conditions – even in chemically complicated, or what scientists might call “dirty,” surroundings. To demonstrate this point, the Scripps team turned to oolong tea, which is a complex brew of hundreds of chemicals. They filled a paper cup with oolong tea and then, instead of stirring in a teaspoon of sugar, they added one of the new zinc salts. To their delight, the zinc-based salt formed a radical and zeroed in on the caffeine molecules in the tea, altering their structure. The tool kit is simple, practical, and cheap—just the right cup of tea for drug design!

[1] Practical and innate carbon–hydrogen functionalization of heterocycles. Fujiwara Y et al. Nature (2012) November 28.