💊 When a drug's mirror reflection is a poison, and vice versa

A team from UNIGE and the University of Pisa has designed surprisingly stable molecular assemblies, paving the way for new drug configurations and materials with controlled geometry.


Can one imagine that a molecule could save lives while its "twin" is a deadly poison? As surprising as it may seem, this chemical reality is known as "chirality".

Like a right hand and a left hand, two molecules can have the same composition but different shapes and images in space. This difference can change everything. Understanding and controlling this phenomenon is crucial for drug design. A team from the University of Geneva (UNIGE), in collaboration with the University of Pisa, has developed a new family of chiral molecules with remarkable stability. This work opens new perspectives for designing drugs with controlled geometry. It is published in the Journal of the American Chemical Society.

A molecule, or any object, is chiral if it cannot be superimposed on its mirror image by any combination of rotations, translations, and geometric changes. Much like our two hands which appear identical but cannot be superimposed when viewed from the back or palm side. This universal molecular asymmetry requires chemists to design chiral molecules capable of interacting precisely with living systems.

This new way of organizing molecular space opens a whole new degree of freedom and imagination in chemical synthesis.

Within a molecule, chirality often arises from the presence of one or more asymmetry centers, called stereogenic centers. They typically consist of a central carbon atom, itself bonded to four different groups or chains of atoms, most often carbon as well. The group of Jérôme Lacour, full professor in the Department of Organic Chemistry of the Section of Chemistry and Biochemistry at the UNIGE Faculty of Science, has created a new type of stereogenic center. This time, the central carbon atom is not surrounded by carbon or hydrogen chains, but solely by oxygen and nitrogen atoms. A first in the field of chemistry.

"Molecules possessing this new type of stereogenic center had never been isolated in stable three-dimensional form before. Their synthesis and characterization mark a major conceptual and experimental advance," explains Jérôme Lacour.

Exceptional stability

The stability of chiral molecules is a particularly important parameter. Indeed, mirror molecule pairs are structurally very similar, and in many cases spontaneous conversion from one to the other is possible, for example under the effect of temperature. As if a left hand suddenly transformed into a right hand. One could thus go from a drug to an inactive, or even toxic molecule! The new molecular structures developed by the UNIGE team exhibit exceptional chiral stability, meaning the conversion from one molecule to its mirror sister is particularly difficult to occur spontaneously.

Olivier Viudes, PhD student and first author of the study, explains: "using dynamic chromatography techniques and quantum chemistry calculations, scientists have shown that for one of the developed molecules, it would take 84,000 years at room temperature for half of a sample to transform into its mirror molecule". For a drug, such stability duration guarantees safe storage without requiring specific conditions. For the second molecule, this duration was estimated at 227 days at 25°C (77°F).

The new stereogenic centers developed by the Geneva team should enable the design of stable and controlled three-dimensional chiral molecules. These structures open new possibilities for drug design, or the creation of new materials. "These new kinds of stereogenic centers offer a new way to organize molecular space. They open a whole new degree of freedom and imagination in chemical synthesis," concludes Gennaro Pescitelli, professor at the University of Pisa and co-principal investigator of this paper.