Image and mirror image

This article was originally published in April 2014.
Published on 15/06/2020

Botany is Eric Francotte’s second passion after chemistry. “Every time I see a blossom, I immediately have to go up and smell it so I can experience its fragrance,” he admits. It therefore comes as no surprise that after completing his post-doc in 1980 at the University of Geneva on the total synthesis of the natural substance lysergic acid, a derivative of ergot, Francotte, who comes from Belgium, toyed with the idea of becoming a perfumer. “Many of the aromatic substances used in industry originally came from nature.” However, because the focus would then have been more on his excellent nose than his flair for chemistry, he finally decided to look for a different kind of job and ended up joining what was then Ciba-Geigy. There, too, certain natural substances were soon the focus of his work. Today, 30 years later, this chemist is still working for Novartis, where he is now Executive Director of GDC Preparations & Separations.

The same and yet quite different

At Ciba-Geigy, Francotte first had to navigate some unknown territory. He was one of the first pharmaceutical chemists in the 1980s to research what is known as the chirality of molecules. This means that two molecules behave towards each other as do an image and mirror image, but without being congruent, that is, without it being possible to superimpose one on top of the other. Even larger objects can be chiral, for example our two hands. If you were to place a mirror between them, the mirror image of the left hand would look like the right hand. However, you become keenly aware that both hands are not congruent when you attempt to put the right glove on the left hand. In chemical molecules, these two “mirror images” are described as enantiomers.

Although they have the same chemical properties, enantiomers frequently differ in their effect on the human body – such as by having a different odor or taste. For instance, the natural substance limonene exists in two versions: One enantiomer tends to smell like an orange, while the other smells more like a lemon or even a terpene.

Interestingly, in most cases nature forms only one of the two enantiomers, and the other mirror image rarely occurs, if at all. This applies in particular to such important groups of natural substances as amino acids and carbohydrates. Why does nature select only one particular chiral form? This is something researchers do not know for certain. “This selectivity could be purely coincidental or even have an extraterrestrial origin,” according to Francotte.

Sorting the good from the bad

This selectivity of nature, though, poses a problem for pharmaceutical research. While one enantiomer that interacts with the organism can be a potential medicine, its mirror image is very frequently ineffective – and sometimes even harmful.

This situation often arises in the laboratory. As opposed to the human body, where selective enzymes control metabolic processes, conventional chemical processes are not able to distinguish between a substance’s image and its mirror image. Chemical synthesis as a rule thus creates a mixture of enantiomers. To find out which enantiomer is responsible for the desired effect, researchers must separate the two forms in order to investigate them independently of each other.

For a long time there were no suitably efficient and general methods to perform this separation. This is where Francotte made a key contribution in the 1990s at Ciba-Geigy: With his research, he soon became a pioneer in the identification and separation of enantiomer mixtures. The principle of his chromatographic process is simple: “To recognize chirality, you need a chiral instrument,” he explains. For this purpose, nature is known to draw from enzymes. Francotte also finds his instruments in nature: He takes the two chiral carbohydrates amylose (starch) and cellulose (from the cell walls of plants or cotton) and employs them in a chemically modified form as carrier materials in chromatography. If you add a mixture of enantiomers, the carrier material interacts with the two enantiomers in different ways – often one sticks well to the carrier material and the other hardly at all. This way they are separated from each other and can easily be isolated and identified.

Wide application

Francotte has been honored several times for his achievements: in 1995 with the Ciba Fellow Award, in 1998 with an award from the University of Geneva, and then in 2000 with the prestigious Novartis Distinguished Scientist Award. Today his process is of major importance in pharmaceutical research and has contributed significantly to the development of countless products at Novartis. “The pharmaceutical industry can today no longer afford to bring a mixture of enantiomers onto the market,” says Francotte. “One medication with a single mirror image is significantly safer and has fewer side effects.” Chiral rugs appear on the market today primarily as “enantiomerically pure” products.

For example, Francotte’s laboratory recently made a major contribution to the development of KAE609, an extremely promising candidate for treating malaria. The malaria parasite is starting to show resistance to the established substance artemisinin (Coartem) and we therefore need alternatives. KAE609 is especially promising because it attacks the parasites with a mechanism that differs from that of artemisinin. This new drug was developed in 2007 at the Novartis Institute for Tropical Diseases (NITD) in Singapore – and it was soon clear that the synthetic material consisted of two enantiomers. The researchers in Singapore approached Francotte’s team in Basel and asked them to determine which of the two forms of KAE609 was responsible for the antimalarial effect. With this knowledge, the researchers could then separate the two enantiomers following synthesis. A new synthesis method is now being developed that in future should make it possible to manufacture just the active enantiomer of KAE609 and avoid having to dispose of large amounts of the wrong enantiomer. In parallel with this, KAE609 is currently undergoing Phase II clinical trials.

Chirality is everywhere

“Our method is not the only separation process on the market,” notes Francotte, “but it is broadly applicable, and we produce the highest yields and the lowest volume of waste products.” The process was patented in 1996, licensed to the Japanese company Daicel Chemical Industries in 1998 and is now deployed around the world, even on an industrial production scale.

So what is Francotte doing now, after many decades in chirality research at Novartis, the successful propagation of his life’s work and a number of distinguished awards? “Every application can always be perfected further,” he says modestly. At present he is working on replacing the organic solvent in chromatography with liquid CO2, which is more environmentally friendly. He also devotes time to his passion in his private life. He photographs chiral objects wherever he runs into them: Columns with spiral patterns, snail shells, animals, pieces of art – and his favorite, of course, the fragrant, helical blossoms of plants.