Recently, our research group turned its attention to the identification of structurally new vascular disrupting agents (VDAs) which are water soluble or may be easily converted into water soluble derivatives, possess vascular disrupting activity, and exhibit antitumor activity at non-toxic doses. In particular, 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 the basicity of its N-3 atom might be exploited to prepare water soluble salts having improved physico-chemical properties. On the other hand, since the 3,4,5-trimethoxyphenyl substituted A ring of the CA-4 seems to be essential for the bioactivity 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. Imidazoles 1 and 2 were prepared using the innovative synthetic protocols we recently developed. These protocols let us to prepare selectively compounds 1 and 2 starting from common and cheap precursors on a multigram scale. We then evaluated the vascular disrupting activity of some selected imidazole derivatives in vitro on HUVECs, and in vivo on experimental tumors. In particular, we observed that imidazoles 1a–c caused profound changes in the morphology of endothelial cells (ECs) (IC50 = 6.5, 27.1 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 selected compounds to induce necrosis of experimental tumors in vivo, the hallmark of vascular disrupting activity. Following a single treatment, imidazoles 1a–c caused massive central necrosis of tumors. They were also subjected to primary cytotoxicity screening against the NCI 60 tumor cell line panel. On the analogy of CA-4, imidazole 1a–c had a definite cytotoxic activity, displaying MG_MID LogGI50 values of -6.59, -7.40 and -7.14, 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 main biological target for combretastatins, is similar to that of the in vitro LogGI50 values of these compounds. In conclusion, the combretastatin-like imidazole derivatives 1 and 2 possess vascular disrupting activity and represent promising chemical entities for the design of novel VDAs.

New vicinal diaryl-substituted imidazole derivatives with vascular disrupting activity

BELLINA, FABIO;ROSSI, RENZO
2007

Abstract

Recently, our research group turned its attention to the identification of structurally new vascular disrupting agents (VDAs) which are water soluble or may be easily converted into water soluble derivatives, possess vascular disrupting activity, and exhibit antitumor activity at non-toxic doses. In particular, 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 the basicity of its N-3 atom might be exploited to prepare water soluble salts having improved physico-chemical properties. On the other hand, since the 3,4,5-trimethoxyphenyl substituted A ring of the CA-4 seems to be essential for the bioactivity 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. Imidazoles 1 and 2 were prepared using the innovative synthetic protocols we recently developed. These protocols let us to prepare selectively compounds 1 and 2 starting from common and cheap precursors on a multigram scale. We then evaluated the vascular disrupting activity of some selected imidazole derivatives in vitro on HUVECs, and in vivo on experimental tumors. In particular, we observed that imidazoles 1a–c caused profound changes in the morphology of endothelial cells (ECs) (IC50 = 6.5, 27.1 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 selected compounds to induce necrosis of experimental tumors in vivo, the hallmark of vascular disrupting activity. Following a single treatment, imidazoles 1a–c caused massive central necrosis of tumors. They were also subjected to primary cytotoxicity screening against the NCI 60 tumor cell line panel. On the analogy of CA-4, imidazole 1a–c had a definite cytotoxic activity, displaying MG_MID LogGI50 values of -6.59, -7.40 and -7.14, 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 main biological target for combretastatins, is similar to that of the in vitro LogGI50 values of these compounds. In conclusion, the combretastatin-like imidazole derivatives 1 and 2 possess vascular disrupting activity and represent promising chemical entities for the design of novel VDAs.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/200440
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