RUTHENIUM CONTAINING METALLOPHARMACEUTICALS

含钌金属药品

• 批准号: 2402885
• 负责人: MICHAEL CLARKE
• 金额: $ 20.48万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-08-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2402885
• 关键词: antineoplastics; chemical structure function; electron spin resonance spectroscopy; electron transport; glutathione; hippocampus; histidine; immunosuppressive; laboratory mouse; long term potentiation; magnetic resonance imaging; nitric oxide; nitroso compounds; nuclear magnetic resonance spectroscopy; psychopharmacologic agent; psychopharmacology; radiosensitizer; ruthenium; thermodynamics; transferrin

Classical ruthenium coordination chemistry has recently yielded extraordinary potential health care dividends involving: 1) The rational design of ruthenium complexes as anticancer agents with overall mechanisms of action distinct from other metallo- anticancer drugs. 2) simple Ru complexes that are superbly efficient immunosuppressive agents by inhibiting T-cell proliferation at nanormolar levels. 3) The design of a ruthenium complex that enhances the electrochemical long-term-potentiation response in brain tissue. Work in this laboratory has helped to stimulate research into the development of Ru-containing pharmaceuticals in several laboratories worldwide. We have recently shown that two suggested mechanisms, which were often thought to be competing for the action of ruthenium antitumor agents, probably work in concert to promote selective Ru binding to tumor cell DNA. This points the way to a possible new class of hybrid, metalloprotein complexes as active antitumor agents. A recently disclosed discovery by Procept, Inc., a local biotechnology company, suggests an entirely new approach to drugs that could facilitate the survival of transplanted organs and combat some immune-system based diseases such as psoriasis. While contributory, complexes we provided paved the away to the discovery of the most active agents. Our results with nitrosyl complexes of technetium suggested a means of manipulating the release of coordinating nitrosyls both thermally and following reduction. A collaborative effort has shown that this is possible and has yielded an active Ru agent that promotes LTP in hippocampal slices. Consequently, an investigation of a series of metallonitrosyl complexes involving strongpi-acceptor ligands, particularly those which can act as trans labilizers, will be undertaken to determine how NO release is affected. The ability to control NO loss should yield a new class of agents capable of crossing membrane barriers and releasing NO within the brain and at other strategic locations.

经典的钌配位化学最近产生了 非凡的潜在医疗保健红利涉及： 1) 合理设计钌配合物作为抗癌剂 与其他金属不同的总体作用机制 抗癌药物。 2) 简单的 Ru 配合物，效果非常好 通过抑制 T 细胞的有效免疫抑制剂 纳米摩尔水平的增殖。 3）钌的设计 增强电化学长时程增强的复合物 脑组织的反应。 该实验室的工作有助于促进对这一问题的研究 含钌药物的开发 世界各地的实验室。 我们最近证明了两个 建议的机制，通常被认为是相互竞争的 对于钌抗肿瘤剂的作用，可能在 协同促进Ru与肿瘤细胞DNA的选择性结合。 这 为可能的新型杂合金属蛋白指明了道路 复合物作为活性抗肿瘤剂。 当地一家公司 Procept, Inc. 最近披露的一项发现 生物技术公司提出了一种全新的方法 可以促进移植器官存活的药物 对抗一些基于免疫系统的疾病，例如牛皮癣。 在做出贡献的同时，我们提供的综合体为 发现最活跃的药剂。 我们对锝的亚硝酰基配合物的研究结果表明 操纵协调亚硝酰基释放的方法 热和随后的还原。 经过共同努力， 表明这是可能的，并产生了一种活性 Ru 剂， 促进海马切片中的 LTP。 因此，一个 一系列金属亚硝基配合物的研究 强π受体配体，特别是那些可以充当反式的配体 稳定剂，将被用来确定 NO 的释放情况 做作的。 控制一氧化氮损失的能力应该会产生一个新的类别 能够穿过膜屏障并释放 NO 的药物 在大脑和其他战略位置。