3-Aroyl-1,4-diarylpyrroles (ARDAPs) are potent inhibitors of tubulin polymerization and cancer cell growth by binding the colchicine site of tubulin, recently developed by our research group. Preliminary results suggested that the introduction of a heterocycle at position 4 of the pyrrole ring, and the simultaneous presence of a 3-aminophenyl group at position 1 increase both tubulin polymerization and anticancer activity. However, the new compounds, such as colchicine, showed a low solubility in water. Starting from these data, this research project aims to optimise the pharmacokinetic profile of ARDAP derivates. In particular, we will try to improve the water solubility by introducing linear chains, bearing various combinations of amino acids residues, on the amino group on the 3-aminophenyl group at position 1 of the pyrrole nucleus.
Colchicine, an alkaloid extracted from the poisonous meadow saffron Colchicum autumnale L., is the first identified tubulin destabilizing agent. It has been used for many years as an unapproved drug to treat gout, familial Mediterranean fever, pericarditis and Behcet's disease. In 2009, U.S. Food and Drug Administration (FDA) approved colchicine as a monotherapy drug to treat familial Mediterranean fever and acute gout flares. Colchicine can effectively inhibit mitosis, and since cancer cells undergo mitosis at a significantly increased rate they are more susceptible to colchicine poisoning than normal cells. Therefore, colchicine is also being investigated as an anticancer drug. However, colchicine shows a limited clinical application for treating cancer because of its low therapeutic index and toxic effects such as neutropenia, gastrointestinal upset, bone marrow damage and anaemia. Although colchicine is not employed as an anticancer agent, there have been multiple efforts to clinically develop colchicine-binding site inhibitors (CBSIs). As microtubules are important regulators of endothelial cell biology, one advantage of the mechanism of actions of CBSIs is targeting the tumour vasculature. Another favourable factor is that most of these drugs have no multidrug resistance (MDR) issues. The major limitation of using microtubule-targeting agents clinically is innate and acquired drug resistance. In addition, the colchicine exhibits another important limitation; in fact, it has a low bioavailability. Therefore, the clinical development of a microtubule-targeting agent that able to overcome the aforementioned problems, could be an excellent goal. Fueled by the purpose of developing novel chemotherapeutics and with the aim of establishing the benefits of tubulin inhibition, we have recently develop 3-aroyl-1,4-diarylpyrroles (ARDAPs) as modern and potent CBSIs of tubulin polymerization and cancer cell growth [1]. The new ARDAPs not only show greater anticancer profiles but also have smaller molecular weight with chemically accessible structures with respect to both taxanes and Vinca alkaloids; this makes them attractive chemical classes to work with for achieving improved pharmacokinetic properties, in particular the water solubility. Therefore, the project proposed here is an ambitious medicinal chemistry work should make a difference in the field of new anticancer drug discovery. Indeed, the results obtained by us so far, open a new window for developing new, potent and selective CBSIs with improved water solubility as potential drug candidate for treatment of human cancer.
References. [1] La Regina, G. et al. ACS Med. Chem. Lett. 2017, 8, 521-526.