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

被引：27

作者：

Uto, Yoshihiro ^{[1
]}

Nagasawa, Hideko ^{[1
,2
]}

Jin, Cheng-Zhe ^{[1
]}

Nakayama, Shinichi ^{[1
]}

Tanaka, Ayako ^{[1
]}

Kiyoi, Saori ^{[1
]}

Nakashima, Hitomi ^{[1
]}

Shimamura, Mariko ^{[3
]}

Inayama, Seiichi ^{[4
]}

Fujiwara, Tomoya ^{[5
]}

Takeuchi, Yoshio ^{[5
]}

Uehara, Yoshimasa ^{[6
]}

Kirk, Kenneth L. ^{[7
]}

Nakata, Eiji ^{[1
]}

Hori, Hitoshi ^{[1
]}

机构：

[1] Univ Tokushima, Dept Life Syst, Inst Sci & Technol, Grad Sch, Tokushima 7708506, Japan

[2] Gifu Pharmaceut Univ, Lab Pharmaceut Chem, Gifu 5028585, Japan

[3] Tokyo Metropolitan Inst Med Sci, Med Res & Dev Ctr, Bunkyo Ku, Tokyo 1138613, Japan

[4] Inst Oriental Med Sci, Shibuya Ku, Tokyo 1550021, Japan

[5] Toyama Univ, Grad Sch Med & Pharmaceut Sci Res, Toyama 9300194, Japan

[6] Natl Inst Hlth, Dept Bioact Mol, Shinjuku Ku, Tokyo 1628640, Japan

[7] NIDDKD, Bioorgan Chem Lab, Natl Inst Hlth, DHHS, Bethesda, MD 20892 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2008年 / 16卷 / 11期

关键词：

hypoxic cell radiosensitizers; antiangiogenic agents; 2-aminomethylene-4-cyclopentene-1,3-dione; protein tyrosine kinase;

D O I：

10.1016/j.bmc.2008.04.041

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

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-cyclopentene1,3-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 mu M. This compound also was an Flt-1 kinase inhibitor having an IC50 value of lower than 20 mu M. Our results show that these chiral 2- nitroimidazole derivatives that contain the 2- aminomethylene-4- cyclopentene1,3-dione moiety as a potent antiangiogenic pharmacophoric descriptor are promising lead candidates for the development of antiangiogenic hypoxic cell radiosensitizers. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：6042 / 6053

页数：12

共 18 条

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