DEVELOPMENT OF SUPEROXIDE DISMUTASE MIMICS

我们的实验室已经表明，氮氧化物，这已被用作EPR 自旋标记物表现出超氧化物歧化酶（SOD）活性， 保护细胞免受多种氧化损伤的有效药物 压力 我们的先导化合物Tempol是一种水溶性氮氧化物， 保护哺乳动物细胞免受超氧化物的侵害， 黄嘌呤/黄嘌呤氧化酶和直接过氧化氢细胞毒性。 我们已经证明Tempol在体外和小鼠中保护细胞 对抗电离辐射 因此，氮氧自由基代表了一个新的类别 辐射防护器，可广泛用于保护人类 对抗辐射 使用啮齿动物肿瘤模型的初步研究 表明Tempol不能保护肿瘤组织。 进一步化学 对氮氧自由基的SOD模拟活性的表征揭示了 氧代铵阳离子中间体的存在。 这些信息将 用于确定最大保护能力， 氧化电位和电荷。 Tempol已被证明可以保护细胞 抗由超氧化物、过氧化氢和 辐射 Tempol也被证明可以保护暴露于 包括丝裂霉素C和SR-4233在内的各种化疗药物。 不仅 这些药物是否能有效地预防某些化疗 代理人，但应在确定行动机制的指导。 局部应用，Tempol已被证明可以防止辐射- 诱发豚鼠脱发。它也被证明是一部小说 一类抗溃疡化合物。 由于这些代理人很容易 穿透细胞膜，它们可以用于其他医学领域。 例如缺血/再灌注损伤研究。 而且这些 研究开启了将生物化学 和氮氧化物代谢到内源性产生的内皮细胞 松弛因子一氧化氮

Our laboratory has shown that nitroxides, which have been used as EPR spin labels exhibit superoxide dismutase (SOD) activity and are quite effective agents in protecting cells against a wide variety of oxidative stresses. Our lead compound, Tempol, a water soluble nitroxide has been shown to protect mammalian cells against superoxide generated from xanthine/xanthine oxidase, and direct hydrogen peroxide cytotoxicity. We have demonstrated that Tempol protects both cells in vitro and mice against ionizing radiation. Thus, the nitroxides represent a new class of radiation protectors that may have widespread use in protecting humans against radiation. Preliminary studies using a rodent tumor model have shown that Tempol does not protect tumor tissue. Further chemical characterization of the SOD mimic activity of nitroxides has revealed the presence of an oxoammonium cation intermediate. This information will be used to identify for maximal protective capacity based on their oxidation potential and charge. Tempol has been shown to protect cells against mutation induction mediated by superoxide, hydrogen peroxide, and radiation. Tempol has also been shown to protect cells exposed to various chemotherapy drugs including mitomycin C and SR-4233. Not only might these agents be useful in protecting against certain chemotherapy agents but should be instructive in determining mechanisms of action. Topically applied, Tempol has been shown to protect against radiation- induced alopecia in guinea pigs. It has also been shown to be a novel class of anti-ulcerogenic compounds. Since these agents readily penetrate cell membranes, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies. Furthermore, these studies have opened the possibility of inter-relating the biochemistry and metabolism of nitroxides to endogenously produced endothelial relaxation factor, nitric oxide.