Characterization of Novel Colchicine Derivatives to Selectively Inhibit Tubulin Polymerization in Humans

Microtubules are cylindrical protein filaments formed by dimers of tubulin. They are fundamental in many cellular functions, such as mitosis, which is a key process in the cellular multiplication. Because of this central role, they are an interesting target of pharmacological treatment, as it is possible to block the mitotic process by altering the dynamic equilibrium between microtubule’s polymerization and depolymerization. From this perspective, it is interesting to design and develop antitumoral drugs able to selectively bind the tubulin in the tumoral cells, in order to lead them to apoptosis. There are several tubulin isotypes: in particular, tumoral cells are characterized by an overexpression of αβIII tubulin, so a drug able to specifically target this dimer can be assumed as a good drug to target tumoral cells. Computational modelling may help to develop and test several drugs. The present study focuses on the design and the evaluation of 60 colchicine derivative compounds on different tubulin dimer isotypes using various computational tools. Indeed, colchicine is an interesting compound because it has a strong antimitotic-activity which differs among different tubulin isotypes, but it is quite toxic for the organism, so the purpose of designing its derivatives is both to enhance the antitumoral activity and both to reduce its poisonous side effects. Overall, computational results presented here show that one of these drugs, the compound C19, can be a specific αβIII tubulin targeting agent, potentially whit better characteristics compared to the colchicine.