We are a twisted species, and so are our molecules. Many organic molecules are not symmetrical: they bulge, lean, branch or twist to the left or the right. Nature generally makes only one form of the molecule, but laboratory synthesis for drug research frequently produces both left-handed and right-handed variants of the same molecule. These (usually manufactured) mirror images of each other are called enantiomers or isomers. One such chiral twin may be beneficial to humans, while the other is highly toxic. For instance, one form of thalidomide is a sedative and reduces morning sickness, while the other causes fetal deformities. So it is vital to separate enantiomers, but until 30 years ago, it was difficult to do so.
Enter NIBR’s Eric Francotte, Executive Director in Global Discovery Chemistry – and master of chirality. In the late 1980s, Francotte worked for the Novartis predecessor, Ciba-Geigy, in its Central Research Lab. He and his group began working on ways to separate enantiomers. “Our bodies are chiral,” he says. “Our biological receptors are chiral, so it’s natural that they respond best to one form of a molecule, where there’s better selectivity and more interaction. The drug is the key, the target is the lock, and one enantiomer better fits the target receptor.”
Eric Francotte: Master of ytilarihC – Photo by Marta Sanchez-Oro
“Thalidomide was the ‘big bang’ of chirality for the pharmaceutical industry,” Francotte says. “The undesirable isomer produced those terrible results. Then the whole pharmaceutical industry knew they would have to systematically separate drug stereoisomers and test them separately. There was no choice anymore.”
It was a great challenge. The breakthrough came when Francotte began using chiral materials in a chromatography column to discriminate between the two chiral forms of a molecule. He says, “To recognize chirality you need a chiral instrument.” Francotte found that materials based on cellulose and amylose could best distinguish between the isomers: the lefties, say, would stick to the material while the righties would not.
Our hands are familiar macro examples of chiral twins: indeed, the word “chiral” is derived from “cheir,” Greek for hand. To see how you react to molecules which are different only in orientation, you need go no further than your fruit bowl. Molecules of the same chemical composition produce both the scent of lemon and the scent of orange. They are naturally occurring chiral twins, and your nose, like a chromatography column, can easily distinguish between the two enantiomers.
Francotte describes enantioselective chromatography as being “at the interface of chemistry, separation sciences, and physics.” Today, his chromatography columns, continuously improved, have become ubiquitous throughout the industry. Novartis out-licenses them to other companies which commercialized the technology. “I’m quite happy it has reached this level of usefulness,” Francotte says. A pioneer in the field of separations, in 2006, he edited Chirality in Drug Research, which has become the standard book on the subject. Because of the process that he helped develop, Francotte has contributed to Novartis drugs countering hypertension, asthma, and multiple sclerosis. He recently collaborated with a team of scientists from Singapore on an anti-malarial molecule. And he has the satisfaction of knowing that today all drug manufacturers work to achieve enantiomic purity before their products hit the market.
As a boy growing up in Belgium, Francotte walked along the beach collecting seashells, noting that the spiral shells invariably twisted up and to the right. He went to college in Brussels and continued his chemistry studies at the University of Louvain, where he received a BS and PhD. He moved to Geneva for a postdoc, and his passion shifted from seashells to flowers, which, in Switzerland, are easier to find – and more interesting and delightful to smell. Francotte has a keen nose and at one point considered working for the perfume industry. Flowers, too, are often chiral, twisting in one direction only, as evidenced by gardenias, mandevillas, oleanders and some orchids. After inhaling their perfume, which in most cases consists of chiral molecules, Francotte takes exquisite photographs of the blossoms, adding to his impressive image collection of chiral objects, both natural and man-made.