Drug candidates: maximising potential through the synthesis of three-dimensional and chiral molecules

Any chemist tackling the design of new drugs aims to synthesise new therapeutic molecules that we know will have a good chance of being selective and effective. In his scientific article Escape from flatland, published in 2009, American chemist Franck Lovering presented a statistical study of molecules tested as potential drugs in clinical phases 1 to 3. This research resulted in two main recommendations for the design of candidate molecules capable of optimising their efficacy and selectivity as drugs. The CUBIC project (Chiral building blocks with bridged polycyclic structures), led by Aurélien de la Torre and winner of an ERC Consolidator Grant worth two million euros over five years, is part of this dynamic: CUBIC aims to develop a chemical synthesis method that meets the recommendations put forward by Franck Lovering and his study.
 

The emergence of three-dimensionality

Prior to this study, most of the candidate molecules synthesised were aromatic compounds, i.e. geometrically flat cyclic structures in which all the atoms lie in the same plane. Relatively easy to synthesise, this type of compound also has the advantage of yielding very diverse molecules, making large-scale testing possible. However, Franck Lovering's study shows that this strategy is not effective: the molecules with the best chances of being used as drugs are not flat. On the contrary, they have a three-dimensional geometry, and their atoms are aligned in different planes. This is the first recommendation from Lovering's study: "Drug candidates must have a higher proportion of sp3 carbon compared to sp2 carbon and sp carbon."

The designations sp, sp2 and sp3 refer to the spatial geometry of the molecule's carbon atoms. They denote the hybridisation of the atom's atomic orbitals, which are three-dimensional mathematical expressions that describe the most likely location of the electrons orbiting the atom's nucleus. An sp carbon has two orbitals, an sp2 carbon has three and an sp3 carbon has four. As orbitals tend to adopt the most symmetrical geometry possible, the two atomic orbitals of an sp carbon create a line, while the four orbitals of an sp3 carbon are distributed in space with an angle of 109.5° between them, forming a tetrahedron. This spatial arrangement is what makes them three-dimensional.

Bridging together polycyclic organic molecules whose carbon atoms have an sp3 structure results in cage-like molecules. "Since drugs often target the active sites of receptors located in or around cells, which are not flat, it's understandable that three-dimensional molecules are more effective and, above all, more selective," explains Aurélien de la Torre.

Lovering's first recommendation was the driving force behind many advances in organic chemistry: it led to new syntheses, new patented molecules, new drugs and even the creation of new companies.
 

Chiral molecule synthesis yet to be explored

While Lovering's first recommendation has given rise to a great deal of research, the second has been much less explored, no doubt because of its complex application. It refers to the asymmetry of the molecules synthesised: "Drug candidates need to have a greater number of stereocentres," Franck Lovering said. To understand this recommendation, we need to look at the notion of chirality in molecules.

An object is said to be chiral if it cannot be superimposed on its mirror image. The most common and familiar example is our hands: when we place them side by side and try to superimpose one on top of the other, the thumb of one hand ends up on top of the little finger of the other. In chemistry, for a molecule to be chiral, it must have what's known as a stereocentre, i.e. a grouping of atoms in which two elements are swapped around, resulting in two different arrangements of the molecule. This molecule then exists in the form of two enantiomers, which are mirror images of each other and cannot be superimposed. These two mirror molecules have exactly the same properties, except that they diffract light differently, making them difficult to distinguish when you need to identify them after synthesising, for example.

In the living world, the majority of molecules are chiral, but in most cases only one of the molecule's two enantiomers is found. For example, amino acids, the building blocks of proteins, naturally exist only in the so-called L conformation, for left. However, the active sites of receptors, the targets of drug molecules, are also chiral, so equipping candidate molecules with stereocentres increases their chances of being selective. "The aim of the CUBIC project is to respond to Lovering's two recommendations by developing organic synthesis methods that can synthesise bridged or cage-like polycyclic molecules that are also chiral," explains Aurélien de la Torre.
 

The challenges of enantioselective synthesis

Over the past two years, a number of laboratories have succeeded in synthesising chiral bridged polycyclic molecules. However, these syntheses were all racemic, which means that the process produced equal quantities of the two enantiomers of the molecule. The challenge that Aurélien de la Torre is facing is to develop an enantioselective synthesis that favours one of the two enantiomers. The chemist's idea is to use a common synthetic platform – based on the same precursor – to enantioselectively produce a variety of chemical molecules.

The researcher wants to start with an alpha-pyrone, a flat monocyclic organic molecule. "In the laboratory, we have shown that we can activate this precursor with a chiral Lewis acid (a compound that is electron deficient, but is capable of accepting a pair of electrons). It binds to the pyrone [a heterocycle of five carbon atoms, one of which is part of an ester functional group, and one oxygen atom], accepting its electrons. This in turn makes the pyrone more electrophilic." As the Lewis acid used is chiral, it only interacts with the pyrone on one of its two sides.

This reaction not only improves the pyrone's electrophilicity, giving it the ability to form a new bond with another compound, but also blocks one of its faces, with the new bond only being made on one side. This first step in the synthesis leads to a chiral compound, and favours one of the two enantiomers. "We then include this compound in other cascade reactions, giving rise to bridged or cage-like polycyclic molecules," concludes Aurélien de la Torre. Using this new approach, the chemist and his colleagues have already succeeded in synthesising a few grams of a natural compound, in quantities that are relatively significant for this kind of synthesis.

The advantage of this approach is that it makes it possible to form stereocentres from all the carbon atoms of the pyrone heterocycle, thus generating a wide variety of compounds. Once optimised, this new synthesis method will be put to work in the search for new therapeutic molecules, as well as in other fields of study such as the development of new materials.
 

Reference:
Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success, F. Lovering, Jack Bikker, Christine Humblet, J. Med. Chem, 2009.