Uto Yoshihiro, Nagasawa Hideko, Jin Cheng-Zhe, Nakayama Shinichi, Tanaka Ayako, Kiyoi Saori, Nakashima Hitomi, Shimamura Mariko, Inayama Seiichi, Fujiwara Tomoya, Takeuchi Yoshio, Uehara Yoshimasa, Kirk Kenneth L, Nakata Eiji, Hori Hitoshi
Department of Life System, Institute of Technology and Science, Graduate School, The University of Tokushima, Minamijasanjimacho-2, Tokushima 770-8506, Japan.
Bioorg Med Chem. 2008 Jun 1;16(11):6042-53. doi: 10.1016/j.bmc.2008.04.041. Epub 2008 Apr 24.
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 IC(50) value of lower than 2microM. This compound also was an Flt-1 kinase inhibitor having an IC(50) value of lower than 20microM. 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.
我们设计了含有2-氨基亚甲基-4-环戊烯-1,3-二酮部分的手性2-硝基咪唑衍生物，作为抗血管生成的低氧细胞放射增敏剂。基于分子轨道计算结果，预计2-氨基亚甲基-4-环戊烯-1,3-二酮部分具有与TX-1123和 tyrphostin AG17中所含的2-亚甲基-4-环戊烯-1,3-二酮部分相当的高亲电性。我们评估了这些新化合物的抗血管生成和放射增敏作用，以及其他生物学特性，包括它们作为低氧细胞毒性和蛋白酪氨酸激酶（PTK）抑制活性的作用。在所测试的化合物中，5（TX-2036）被证明是最强的抗血管生成低氧细胞放射增敏剂。所有测试的具有2-氨基亚甲基-4-环戊烯-1,3-二酮部分的其他手性2-硝基咪唑衍生物也都是抗血管生成低氧细胞放射增敏剂。5（TX-2036）的PTK抑制活性表明它是一种有前途的强效表皮生长因子受体（EGFR）激酶抑制剂，其半数抑制浓度（IC50）值低于2μM。该化合物也是一种Flt-1激酶抑制剂，IC50值低于20μM。我们的结果表明，这些含有2-氨基亚甲基-4-环戊烯-1,3-二酮部分作为有效的抗血管生成药效基团描述符的手性2-硝基咪唑衍生物，是开发抗血管生成低氧细胞放射增敏剂的有前途的先导候选物。
