POTENT INHIBITION OF ANGIOGENESIS BY HYPOXIA-DEPENDENT NOVEL NITROIMIDAZOLE

在实体瘤中，血管生成对其持续生长和转移是必不可少的。有效的血管生成抑制剂抑制肿瘤血管生成可能是预防肿瘤生长和转移的有效治疗方法。为了寻找一种新的有效的血管生成抑制剂，我们着眼于肿瘤中缺氧细胞大量产生血管内皮生长因子等促血管生成的血管生成因子这一现象，寻找有效的化合物来攻击缺氧细胞，抑制血管生成因子的产生。由于2-硝基咪唑类化合物侧链上含有异羟肟酸基团，因此我们设计合成了2-硝基咪唑类化合物KIN。我们利用鸡胚绒毛尿囊膜(CAM)检测了它们的抗血管生成活性。其中，KIN-841具有明显的血管生成抑制作用，且呈剂量依赖性。该化合物抑制常氧和低氧条件下内皮细胞的增殖，并抑制缺氧肿瘤细胞产生血管生成因子(S)。KIN-841抑制肿瘤诱导的DAS实验中的血管生成。为了寻找更有效的抑制剂，我们开发了许多KIN-841衍生物，并用CAM法检测了它们的抗血管生成活性。KIN-861被发现是一种最有效的抑制剂。KIN-861对荷瘤小鼠的自发性肺转移有抑制作用。这些结果提示，KIN-841和KIN-861类化合物在常氧和低氧条件下都能抑制血管生成，可能是一种有效的血管生成抑制和抗癌药物。

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.