Potential inhibitors of angiogenesis. Part I: 3-(imidazol-4(5)-ylmethylene)indolin-2-ones |
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Authors: | Braud Emmanuelle Duflos Muriel Nourrisson Marie-Renee Tonnerre Alain Picot Carine Le Baut Guillaume Renard Pierre Pfeiffer Bruno Tucker Gordon |
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Affiliation: | Laboratoire de Chimie Organique et de Chimie Thérapeutique, UPRES EA 1155, Faculté de Pharmacie, 1 rue Gaston Veil, F-44035 Nantes, France. |
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Abstract: | The synthesis and pharmacological evaluation of new 3-(imidazol-4(5)-ylmethylene)indolin-2-ones, analogues of SU-5416, are reported. The final compounds 20-51 were obtained by Knoevenagel coupling between the substituted indolin-2-ones 1-15 and either the formylimidazole derivatives 16-18 or 2-formyl-3,5-dimethylpyrrole 19. Methylation at the nitrogen atom of the indolin-2-one and/or imidazole moities was carried out in the presence of the couple NaH/DMF. A Mannich reaction afforded the 1-dimethylaminomethyl derivatives 43 and 48. The antiangiogenic activity of these compounds was evaluated in a three dimensional in vitro rat aortic ring assay. In this test, compound 20 induced a decrease of angiogenesis comparable to that observed with SU-5416; the vascular density indexes at 1 microM were 30 +/- 18 and 22 +/- 4% of control, respectively. The compounds were also evaluated, in an independent manner, as inhibitors of the human EGF-receptor tyrosine kinase activity. As expected, only minor activities were observed with four compounds, out of thirty-one, exerting inhibitory effects in the range of 40-55% at 10 microM concentration. |
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