Single-Handed Medicine Compounds
Getting It Left or Getting It Right?
Making chemicals in the lab isn't quite the same thing as cooking up a pot of spaghetti, in which you simply boil the pasta, heat up the sauce, and voila! It's not so easy to make molecules from a laboratory recipe. The thing is, many small molecules— created by scientists or by Nature— come in two, mirror-image forms, a "left" and a "right." The molecules that make up sugars and DNA conform to this principle, called "chirality," which is actually rooted in the laws of physics. Chemical bonds— the physical forces that attract or repel atoms in molecules— rotate in space two ways, giving rise to two complementary, mirror-image molecular forms. These are sort of like a left hand and a right hand— put them together and they match up, but they'll never align when placed atop each other. Put another way, a right hand will never fit into a left-handed glove.
Why should any of this matter when it comes to drugs? Well— take the case of a small-molecule drug that does its job in the body by nestling snugly into a particular cavity of a certain protein receptor. The left-handed version of this drug might fit perfectly into the correct space inside the receptor, whereas its right-handed counterpart couldn't squeeze in, no matter what. And in some instances, both "hands" of a drug (each called an "enantiomer") fit into a biological spot, but one might help treat a symptom while the other causes the body harm!
A terrible tragedy occurred when this happened with a drug called thalidomide, which was used in the 1960s to treat morning sickness in pregnant women. Scientists found out too late that one of thalidomide's two hands caused horrific birth defects. What's more, researchers discovered that removing the "bad" hand from a dose of thalidomide didn't take care of the problem— the body can itself make the harmful hand from the "good" one.
Another two-faced drug in this regard was a popular allergy medicine called Seldane®, which the Food and Drug Administration removed from the market in 1997 because in combination with a certain antibiotic it caused life-threatening heart rhythm problems. Scientists determined that neither enantiomer of a breakdown product of Seldane— now marketed as a medicine called Allegra®— interacts the same way with the antibiotic, and Allegra is now used by millions of Americans.
To manufacture products quickly and cost-effectively, traditionally pharmaceutical companies have chemically cooked up medicines that contain equal portions of the left and right hands. That is because it is usually much less efficient and more expensive to produce only one hand of a drug. Over time, however, chemists in industry and elsewhere have come to realize the importance of making single-handed compounds. There are those especially troubling cases in which one enantiomer is toxic. But in the vast majority of cases, most drugs produced as left-and right-handed mixtures are only half as strong as they could be, because one hand does nothing more than dilute the medicine produced. Chemist Eric Jacobsen of Harvard University spent years perfecting a laboratory tool— a "chiral catalyst"— that can purposefully produce one and only one enantiomer of a particular type of molecule, eliminating the waste inherent in the process of making a left-and right-handed mix, or in separating the two enantiomers from each other after manufacturing. The pharmaceutical company Merck recognized the value of Jacobsen's tool and has used it successfully for the production of a widely used AIDS drug called Crixivan®. Other scientists, such as K. Barry Sharpless of the Scripps Research Institute, have tailor-made chemical reactions that produce a single enantiomer. The method is sort of like stripping the "random" part out of a coin toss so that the quarter always comes up heads. Sharpless' reactions, which give rise to one-handed chemical intermediates, have been important for the production of a variety of medically useful chemicals, including certain antibiotics, heart medicines, and antidepressants.
By paying more attention to getting it "right" (or "left," as the case may be) today's chemists have enormous opportunity for improving existing medicines— by eliminating dose-related side effects, for instance— as well as for streamlining the process of making the most effective new medicines