Design of Dioxygen Activating Agents and Active Oxygen Deactivating Agents and Their Medicinal Application

双氧活化剂和活性氧钝化剂的设计及其医药应用

• 批准号: 63470128
• 负责人: KIMURA Eiichi
• 金额: $ 4.1万
• 依托单位: Coordination Chemistry Laboratories, Institute for Molecular Science
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1988
• 资助国家: 日本
• 起止时间: 1988 至 1989
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-63470128/
• 关键词: activation of O_2; active oxygen species; superoxide dismutase; macrocyclic polyamine; heme-like function; bleomycine; model ligands; catalysis; 大環状テトラアミン; コバルト(II)錯体; 1:1酸素付加体; 大環状トリアミン; 銅(II)錯体; SOD様活性

New series of macrocyclic polyamine ligands have been synthesized, which were designed to activate O_2 or deactivate active oxygen species. Among these, a macrocyclic tetraamine and a triamine with an imidazole-pendant are of interest, which mimic a heme-like O_2 uptake function and a superoxide dismutase function, respectively.Our original nickel(II) complex of a macrocyclic dioxopentaamine has been shown to form a 1:1 O_2 adduct and thereby activate O_2 in aqueous solution at room temperature. We have long met an extreme difficulty in studying these novel reaction mechanisms due to instability of the Ni(II) complex and its O_2 adduct. However, we have now succeeded in isolation of a stable complex precursor that brings a bright breakthrough for the mechanistic study.Bleomycin is an antibiotic that kills cancer cells via an O_2 activation mechanism. It has been long disputed whether copper(I) can be the central metal ion. To settle this debate, we have synthesized two model compounds. Through this model study, we could demonstrate that there are two isomeric Cu(I) complexes formed by the bleomycin-like ligands, of which only one species can activate O_2 as much as the Fe(II)complex. The solution of such a question with our present can activate O_2 as much as the Fe(II)complex. The solution of such a question with our present study will lead to development of new O_2 activating agents, catalysis and medicines.

合成了一系列新的大环多胺配体，设计了它们对O_2的活化或对活性氧的钝化作用。其中，大环四胺和咪唑基三胺分别具有类似血红素的O_2吸收功能和超氧化物歧化酶的活性，并在室温下与大环二氧五胺形成1：1的O_2加合物，从而激活O_2。由于Ni（II）配合物及其O_2加合物的不稳定性，一直是研究这些反应机理的难点。然而，我们已经成功地分离出了一种稳定的复合物前体，这为机理研究带来了一个光明的突破。铜（I）是否可以作为中心金属离子一直存在争议。为了解决这一争论，我们合成了两种模型化合物。通过该模型的研究，我们可以证明博来霉素类配体形成了两种异构的Cu（I）配合物，其中只有一种配合物可以像Fe（II）配合物一样激活O_2。用我们的方法解决了这个问题，可以使O_2的活化程度与Fe（II）配合物相当。这一问题的解决将有助于开发新的氧活化剂、催化剂和药物。

项目成果

E.Kiumra,M.Shionoya,M.Okamoto,H.Nada: "The First Fluorinated Cyclams." J.Am.Chem.Soc.110. 3679-3680 (1988)

E.Kiumra、M.Shionoya、M.Okamoto、H.Nada：“第一个氟化仙客来”。

I.Kimura,T.Koike,H.Nada,Y.Iitaka,: "The First X-Ray Crystal Structure of Ni^<II>-Monooxocyclam Complexes.The Effects of the Deprotonated Amide and of Intramolecular Pendant Pyridine on Cyclam Ligand Field." Inorg.Chem.27. 1036-1040 (1988)

I.Kimura,T.Koike,H.Nada,Y.Iitaka,：“Ni^<II>-Monooxocyclam 配合物的第一个 X 射线晶体结构。去质子化酰胺和分子内悬垂吡啶对 Cyclam 配体场的影响

E.Kimura,H.Anan,T.Koike,and M.Shiro,: "A Conenient Synthesis of a Macrocyclic Dioxo Pentaamine and X-ray Crystal Structure of Its Monohydrazoic Acid Salt," J.Org.Chem.54. 3998-4000 (1989)

E.Kimura、H.Anan、T.Koike 和 M.Shiro，“大环二氧代五胺的简便合成及其单肼酸盐的 X 射线晶体结构”，J.Org.Chem.54。

E. Kimura, T. Koike, M. Kodama, and Dan Meyerstein,: "A Copper(I)-N, N, N' , N" , N" -Pentamethylenetriamine Complex and Its Carbon Monoxide Addult in Aqueous Solutions" Inorg.Chem., 28, 2998-3001, 1989.

E. Kimura、T. Koike、M. Kodama 和 Dan Meyerstein，“铜 (I)-N、N、N、N”、N”-五亚甲基三胺络合物及其在水溶液中的一氧化碳加成物”Inorg。

E.Kimura;T.Koike;M.Kodama;Y.Iitaka, et al: Inorg.Chem.26. 2975-2983 (1987)

E.Kimura；T.Koike；M.Kodama；Y.Iitaka 等人：Inorg.Chem.26。