Cancer worldwide remains one of the most important cause of death. Tumors that recur after an initial response to chemotherapy easily become resistant to multiple drugs, making more difficult the cancer treatment. The present research project aims to design and synthesize new anticancer drugs targeting tubulin. Arylthioindoles and aroylindoles are a modern class of tubulin polymerization inhibitors that proved effective in inhibiting many cancer cells lines. Derivatives bearing a cyclic substituent at the position 2 of the indole inhibit tubulin assembly by binding the colchicine site of tubulin at submicromolar concentration and cell growth at low nanomolar concentrations. In this research project, will be carried out exhaustive structure activity relationship studies mainly focusing on positions 6-7 of the indole nucleus by introducing an aromatic or heteroaromatic ring to identify new potent tubulin polymerization inhibitors.
Microtubules (MTs) represent a key target for anticancer therapy because MTs are essential for cell division and cancer is featured by an out of control cells growing. MTs are also crucial for the cell shape maintenance, cell motility and intracellular transport. MTs are highly dynamic cylindrical structures principally composed of alpha,beta-tubulin heterodimers. During their assembly, MTs continuously undergo regulated transitions between polymerization and depolymerization, by the adding or deletion of tubulin heterodimers in a process called dynamic instability. Since inhibition of tubulin polymerization/depolymerization increases the number of cells in metaphase arrest, tubulin is the most important molecular target for anticancer therapeutics. The vinca alkaloids, taxol, colchicine and combretastatin A4 are examples of tubulin interfering agents. These drugs act by binding to different sites on the tubulin dimer or at different positions within the microtubule. Taxol and vinca alkaloids are clinically important chemotherapeutic drugs and are used for the treatment of different types of tumours. Restrictions due to toxicity, complex formulation and limited bioavailability highlight the need for new tubulin inibitors.
The major limitation of using microtubule-targeting agents clinically is innate and acquired drug resistance. The most common form of clinical resistance is overexpression of the MDR1 gene, which encodes the P-glycoprotein (Pgp) drug efflux pump. Over-expression of Pgp decreases intracellular drug levels, consequently limiting drug cytotoxicity. In addition, over-expression of Pgp is associated with poor response to microtubule-targeted agents including taxanes and vinca alkaloids and subsequent treatment failure. Besides over-expression of ABC transporters, other significant mechanisms of resistance include mutations in tubulin and overexpression of ßIII-tubulin isoform. Among eight identified ß-tubulin isotypes in human, overexpression of class III ß-tubulin is an indicator of resistance to tubulin targeting agents such as paclitaxel and vinorelbine. Therefore, the clinical development of a microtubule-targeting agent that circumvents both of these drug resistance mechanisms could have advantages for patients with drug resistant tumours. Fueled by the purpose of developing novel tubulin inhibitors as anticancer agents and since ATIs not only show greater anticancer profiles but also have smaller molecular weight with chemically accessible structures with respect to both taxanes and Vinca alkaloids, we will develop new ATIs bearing an aromatic or heteroaromatic ring at the position 6 or 7 of the indole for achieving improved pharmacokinetic properties and efficacy as well as reduced toxicity hoping to make a difference in the field of new anticancer drug discovery.