Design of antiangiogenic hypoxic cell radiosensitizers: 2-Nitroimidazoles containing a 2-aminomethylene-4-cyclopentene-1,3-dione moiety

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• 作者：Yoshihiro Uto ; Hideko Nagasawa ; Cheng-Zhe Jin ; Shinichi Nakayama ; Ayako Tanaka ; Saori Kiyoi ; Hitomi Nakashima ; Mariko Shimamura ; Seiichi Inayama ; Tomoya Fujiwara ; Yoshio Takeuchi ; Yoshimasa Uehara ; Ke
• 关键词：Hypoxic cell radiosensitizers ; Antiangiogenic agents ; 2-Aminomethylene-4-cyclopentene-1 ; 3-dione ; Protein tyrosine kinase
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2008
• 期刊代码：9_09680896
• 类别：ch
• 出版时间：1 June 2008
• 卷：16
• 期：11
• 页码：6042-6053
• 文件大小：619 K

摘要

We designed chiral 2-nitroimidazole derivatives containing a 2-aminomethylene-4-cyclopentene-1,3-dione moiety as antiangiogenic hypoxic cell radiosensitizers. Based on results of molecular orbital calculations, the 2-aminomethylene-4-cyclopentene-1,3-dione moiety is expected to show high electrophilicity comparable to that of the 2-methylene-4-cyclopentene-1,3-dione moiety included in TX-1123 and tyrphostin AG17. We evaluated the antiangiogenic and radiosensitizing effects of the new compounds, along with other biological properties including their activities as hypoxic cytotoxicities and protein tyrosine kinase (PTK) inhibitory activities. Among the compounds tested, 5 (TX-2036) proved to be the strongest antiangiogenic hypoxic cell radiosensitizer. All the other chiral 2-nitroimidazole derivatives having 2-aminomethylene-4-cyclopentene-1,3-dione moiety tested were also antiangiogenic hypoxic cell radiosensitizers. The PTK inhibitory activity of 5 (TX-2036) showed this to be a promising and potent EGFR kinase inhibitor, having an IC₅₀ value of lower than 2 μM. This compound also was an Flt-1 kinase inhibitor having an IC₅₀ value of lower than 20 μM. Our results show that these chiral 2-nitroimidazole derivatives that contain the 2-aminomethylene-4-cyclopentene-1,3-dione moiety as a potent antiangiogenic pharmacophoric descriptor are promising lead candidates for the development of antiangiogenic hypoxic cell radiosensitizers.