Kubota Riku, Imamura Shinya, Shimizu Takahiko, Asayama Shoichiro, Kawakami Hiroyoshi
Department of Applied Chemistry, Tokyo Metropolitan University , Minami-Osawa 1-1, Hachioji, Tokyo 192-0397, Japan.
Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine , 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
ACS Med Chem Lett. 2014 Mar 27;5(6):639-43. doi: 10.1021/ml400493f. eCollection 2014 Jun 12.
Superoxide dismutase (SOD) and catalase activities of a drug are of great importance for its effective protection against reactive oxygen species (ROS)-induced injury. Achievement of catalase activity of a synthetic compound remains a challenge. Water-soluble Mn-porphyrins have high SOD and peroxynitrite (ONOO(-)) reducing activities, but not catalase-like activity. Herein, we are able to retain the fair SOD-like activity of a mononuclear Mn-5-(N-methylpyridinium-4-yl)-10,15,20-triphenyl porphyrin (MnM4PyP3P), while gaining in catalase-like activity with its dinuclear complex, 1,3-di[5-(N-methylene-pyridinium-4-yl)-10,15,20-triphenyl porphynato manganese] benzene tetrachloride (MnPD). Mechanistic study indicates that catalase-like activity of MnPD is due to synergism of two Mn active sites, where hydroxo-Mn(IV) complex is formed as an intermediate. The in vivo experiments demonstrate that MnPD significantly restores the treadmill-running ability of SOD-deficient mouse and thus indicates the therapeutic potential of MnPD. Furthermore, MnPD may serve as a mechanistic tool and indicate the new directions in the synthesis of catalase-like mimics.
药物的超氧化物歧化酶（SOD）和过氧化氢酶活性对于其有效抵御活性氧（ROS）诱导的损伤至关重要。实现合成化合物的过氧化氢酶活性仍然是一项挑战。水溶性锰卟啉具有较高的SOD和过氧亚硝酸根（ONOO(-)）还原活性，但没有类过氧化氢酶活性。在此，我们能够保留单核锰-5-(N-甲基吡啶-4-基)-10,15,20-三苯基卟啉（MnM4PyP3P）相当的类SOD活性，同时其二核配合物1,3-二[5-(N-亚甲基吡啶-4-基)-10,15,20-三苯基卟啉锰]苯四氯化物（MnPD）获得了类过氧化氢酶活性。机理研究表明，MnPD的类过氧化氢酶活性归因于两个锰活性位点的协同作用，其中羟基锰（IV）配合物作为中间体形成。体内实验表明，MnPD能显著恢复超氧化物歧化酶缺陷小鼠的跑步机跑步能力，从而表明MnPD的治疗潜力。此外，MnPD可作为一种机理工具，并为类过氧化氢酶模拟物的合成指明新方向。
