Design of antiangiogenic hypoxic cell radiosensitizers: 2-nitroimidazoles containing a 2-aminomethylene-4-cyclopentene-1,3-dione moiety.
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.
Uto
Yoshihiro
Y
Department of Life System, Institute of Technology and Science, Graduate School, The University of Tokushima, Minamijasanjimacho-2, Tokushima 770-8506, Japan.
Nagasawa
Hideko
H
Jin
Cheng-Zhe
CZ
Nakayama
Shinichi
S
Tanaka
Ayako
A
Kiyoi
Saori
S
Nakashima
Hitomi
H
Shimamura
Mariko
M
Inayama
Seiichi
S
Fujiwara
Tomoya
T
Takeuchi
Yoshio
Y
Uehara
Yoshimasa
Y
Kirk
Kenneth L
KL
Nakata
Eiji
E
Hori
Hitoshi
H
D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000633:toxicity; D015687:Cell Hypoxia / Q000187:drug effects*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002642:Chick Embryo; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000633:toxicity; D015195:Drug Design; D051379:Mice; D008958:Models, Molecular; D009593:Nitroimidazoles / Q000737:chemistry* / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000633:toxicity; D051381:Rats; D013237:Stereoisomerism
C531103:2-aminomethylene-4-cyclopentene-1,3-dione; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D003517:Cyclopentanes; D009593:Nitroimidazoles; D047428:Protein Kinase Inhibitors; D011838:Radiation-Sensitizing Agents