Imidazole derivatives with vascular disrupting activity

Introduction Our research group has directed its attention to the identification of structurally new vascular disrupting agents (VDAs) which are water soluble or may be converted into water soluble derivatives, possess vascular disrupting activity, and show antitumor activity at non-toxic doses. We prepared 1,5- and 1,2-diaryl-1H-imidazoles of general formula 1 and 2, respectively, which can be considered as cis-locked analogues of combretastatin A-4 (CA-4), a natural tubulin-binding VDA. We became interested in the imidazole core since its basic nitrogen atom may lead to compounds which can easily be formulated as water-soluble salts. Moreover, since the 3,4,5-trimethoxyphenyl substituted A ring of the CA-4 seems to be essential for the activity of this natural product, we maintained this moiety in compounds 1 and 2 and evaluated the effect due to the replacement of the B-ring of CA-4 with a variety of aryl substituents. Material and methods Imidazoles 1 and 2 were prepared using the innovative synthetic protocols we recently developed. The vascular disrupting activity of some selected compounds was evaluated in vitro on HUVEC, and in vivo on experimental tumors. Results Compounds 1a–c caused profound changes in the morphology of endothelial cells (ECs) (IC50 = 6.5, 30.9 and 38.8 µM, respectively). Interestingly, in comparable experimental conditions, 1a - but not 1b and 1c - induced changes in the shape of ECs at concentrations that did not affect their proliferation. By immunohistochemistry we confirmed the ability of 1a to cause depolymerization of microtubules in ECs. We next analyzed the ability of the compounds to induce necrosis of experimental tumors in vivo, the hallmark of vascular disrupting activity. Following a single treatment, compounds 1a–c caused massive central necrosis of tumors. They were also subjected to primary cytotoxicity screening against the NCI 60 tumor cell line panel. Similar to CA-4, compounds 1a–c had a definite cytotoxic activity, displaying MG_MID LogGI50 values of -6.59, -7.50 and -7.17, respectively. Docking experiments also showed that the trend of the calculated interaction energies of 1 and 2 with the colchicine binding site on tubulin, which is the target for combretastatins, is similar to that of the in vitro LogGI50 values of these compounds. Conclusions Combretastatin-like imidazole derivatives possess vascular disrupting activity, hence representing promising chemical entities for the design of novel VDA.