Tuning microtubule dynamics: synthesis of bifunctional drugs targeting tubulins Microtubule-associated proteins (MAPs) regulate growth or shrinkage of microtubule in a dynamic polimerization process through a conformational recognition not completely elucidated of the tubulin heterodimers. MAPs Microtubules are essential for intracellular organization, cellular division and for correct neuronal functions. Targeting tubulin founds new interesting application in neurodegenerative diseases to ensure stabilization of microtubule using agents that promote or destabilize polymerization, because in some of these pathologies tau-MAP becomes defective and no longer stabilize microtubules properly. MT stabilizing agent Tubulin targeted anticancer chemotherapy MT destabilizing agent Applications in neurodegenerative diseases 1

Aim of the project TUBULINE DYNAMICS Establish the correlation between drug induced structural change and observed biological effect sintetizing drug-based on maytansine DRUG LINKER MAYTANSINOL 12-14 atoms TUBULINE DYNAMICS Biochemical activities: Neurology department of University of Osnabrück (Prof. Brandt) Crystallographic structure: Center of Biological Investigation of Madrid (Doc. Diaz) Docking study: Chemistry department of University of Milan (Prof. Pieraccini) Synthesis: (Prof. Passarella) 2 Eribulin