Abstract EN:

The system tubulin/microtubules plays a key-role during mitosis and disturbing its dynamic equilibrium can prevent cell division and induce apoptosis. Antitubulin agents are divided into two classes: those that bind to microtubules, stabilizing them and preventing their depolymerization, and those that bind to tubulin dimer, preventing the formation of microtubules. Most of the known antitubulin agents are characterized by a very complex structure, and therefore are relatively hard to synthesize. We planned to use dynamic combinatorial chemistry combined with the reversible formation of imines in water to identify new potential antitubulin agents. This approach is based on the reversible connection between different building blocks to form a chemical library under thermodynamic equilibrium. In the presence of a target, the distribution of the library may be altered, with an amplification for the best binders, which can be detected by an adequate analytical method after fixation of the library’s distribution. We have demonstrated that dynamic combinatorial chemistry is applicable to the dynamic macromolecular system tubulin/microtubules. Using adequate conditions, we have shown that it is possible to target either the tubulin dimer or microtubules. Then we have designed and synthesized two types of scaffolds in order to use them in dynamic libraries. Among the numerous dynamic libraries we prepared some amplifications were identified. Analogues of amplified imines were synthesized and tested on tubulin. Therefore we were able to identify a new class of microtubules ligands and to show that the orientation of two aromatic moieties plays a key role for the type of activity.