POTENT INHIBITION OF ANGIOGENESIS BY HYPOXIA-DEPENDENT NOVEL NITROIMIDAZOLE

点击翻译按钮获取中文摘要

In solid tumors, angiogenesis is essential for their continuous growth and metastasis. The inhibition of tumor angiogenesis by potent angiogenic inhibitors may be a useful therapeutic approach for preventing tumor growth and metastasis. To find a new potent angiogenic inhibitor, we focused the phenomenon of the initiation of angiogenesis that the hypoxic cells in tumor greatly produce the angiogenic factor such as vascular endothelial growth factor which stimulates the angiogenesis and thought to search for the compound available to attack hypoxic cells and to stop the production of angiogenic factors.We designed and synthesized 2-nitroimidazole derivatives named KIN compound, containing hydroxamic acid group in their side chain, because 2-nitroimidazole moiety easily incorporated into the hypoxic cells. We examined their antiangiogenic activities, using chick embryo chorioallantoic membrane (CAM). Among them tested, KIN-841 potently showed the angiogenic inhibition in dose-dependent manner. This compound inhibited the proliferation of endothelial cells under normoxia and hypoxia and prevented the production of angiogenic factor(s) by hypoxic tumor cells. KIN-841 suppressed tumor-induced angiogenesis in dorsal air sac (DAS) assay. For search for more potent inhibitor, we developed many KIN-841 derivatives and examined their antiangiogenic activities by CAM assay. KIN-861 was found to be a most potent inhibitor. KIN-861 inhibited the spontaneous lung metastasis of tumor-bearing mouse. These results suggested the compound like KIN-841 and KIN-861 that can inhibit angiogenesis in both normoxia and hypoxia may be a potent angiogenic inhibitor and anticancer agent.