Diverse functions of cationic Mn(III) N-substituted pyridylporphyrins, recognized as SOD mimics.
Diverse functions of cationic Mn(III) N-substituted pyridylporphyrins, recognized as SOD mimics.
复制标题
阳离子Mn（III）N-取代的吡啶基卟啉的各种功能，被识别为SOD模拟物。
DOI：
10.1016/j.freeradbiomed.2011.04.046
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发表时间：
2011-09-01
影响因子：
7.4
通讯作者：
Spasojevic I
中科院分区：
文献类型：
--
作者：
Batinic-Haberle I;Rajic Z;Tovmasyan A;Reboucas JS;Ye X;Leong KW;Dewhirst MW;Vujaskovic Z;Benov L;Spasojevic I
氧化应激是内源性活性物质和抗氧化系统之间的氧化还原失衡，在许多病理条件如癌症、中枢神经系统损伤、辐射损伤、糖尿病等中是常见的。因此，30多年来一直在积极寻找能够降低氧化应激的化合物。超氧化物是参与氧化应激的主要物质，无论是自身还是通过其后代，如ONOO−、H2 O2、·OH、CO 3·−和·NO2。因此，在20世纪70年代后期开发的第一批化合物是超氧化物歧化酶（SOD）模拟物。到目前为止，最有效的模拟物是阳离子meso Mn（III）N-取代吡啶基卟啉和N，N′-二取代咪唑基卟啉（MNP），其中一些具有与SOD酶的kcat相似的kcat（O2·−）。最常研究的是邻位异构体MnTE-2-PyP 5+、MnTnHex-2-PyP 5+和MnTDE-2-ImP 5+。使O2·−不成比例的能力与它们去除其他主要氧化物质过氧亚硝酸盐（ONOO−）的能力相似。与产生高kcat（O2·−）和kred（ONOO−）的结构特征相同，MNP能够强烈影响氧化还原敏感性转录因子HIF-1α、NF-κB、AP-1和SP-1的活化，从而改变过度的炎症和免疫反应。与细胞还原剂和其他氧化还原活性的内源性蛋白质的耦合似乎参与锰卟啉的行动。虽然亲水性类似物，如MnTE-2-PyP 5+和MnTDE-2-ImP 5+在许多疾病的动物模型中是有效的，但亲脂性类似物被开发为穿过血脑屏障并靶向中枢神经系统和关键细胞区室线粒体。其结构的修饰，旨在保持SOD样的效力和亲脂性，并减少毒性，目前已经被追求。MnTnHex-2-PyP 5+的肺放射保护是第一个在非人灵长类动物中成功进行的有效性研究。对N，N′-二乙基咪唑类似物MnTDE-2-ImP 5+（AEOL 10150）治疗肌萎缩侧索硬化症患者进行I期毒性临床试验。风神药业积极开发广谱抗辐射剂，得到美国联邦政府的支持。在吡啶基取代基中带有氧的最新一代化合物目前正在杜克大学积极开发用于癌症和CNS损伤，并得到杜克转化研究所、华莱士H.库尔特翻译合作伙伴赠款计划，普雷斯顿罗伯特蒂施脑肿瘤中心在杜克，和国家过敏和传染病研究所。阳离子锰卟啉的金属中心很容易接受和提供电子，例如催化O2·−歧化。因此，这些化合物可以是同样好的抗氧化剂和促氧化剂;在任一情况下，可以观察到有益的治疗效果。此外，虽然体内作用可能表现为抗氧化，但产生这种作用的MNP的作用机制可能是促氧化;最明显的例子是抑制NF-κB。因此，实验数据告诉我们，我们需要区分MNP的作用机制和我们观察到的效果。许多因素影响MNP的作用类型，导致有利的治疗效果：活性物质和氧的水平，内源性抗氧化剂（酶和低分子化合物）的水平，MNP的水平，它们的积累部位，以及所有这些物质的相互接触。体内氧化还原系统的复杂性和MNP的复杂氧化还原化学挑战并激励我们进一步理解正常和患病细胞的生理学，最终目标是成功治疗人类疾病。
Oxidative stress, a redox imbalance between the endogenous reactive species and antioxidant systems, is common to numerous pathological conditions such as cancer, central nervous system injuries, radiation injury, diabetes etc. Therefore, compounds able to reduce oxidative stress have been actively sought for over 3 decades. Superoxide is the major species involved in oxidative stress either in its own right or through its progeny, such as ONOO−, H2O2, ·OH, CO3·−, and ·NO2. Therefore, the very first compounds developed in the late 1970-ies were the superoxide dismutase (SOD) mimics. Thus far the most potent mimics have been the cationic meso Mn(III) N-substituted pyridylporphyrins and N,N′-disubstituted imidazolylporphyrins (MnPs), some of them with kcat(O2·−) similar to the kcat of SOD enzymes. Most frequently studied are ortho isomers MnTE-2-PyP5+, MnTnHex-2-PyP5+, and MnTDE-2-ImP5+. The ability to disproportionate O2·− parallels their ability to remove the other major oxidizing species, peroxynitrite, ONOO−. The same structural feature that gives rise to the high kcat (O2·−) and kred (ONOO−), allows MnPs to strongly impact the activation of the redox-sensitive transcription factors, HIF-1α, NF-κB, AP-1, and SP-1, and therefore modify the excessive inflammatory and immune responses. Coupling with cellular reductants and other redox-active endogenous proteins seems to be involved in the actions of Mn porphyrins. While hydrophilic analogues, such as MnTE-2-PyP5+ and MnTDE-2-ImP5+ are potent in numerous animal models of diseases, the lipophilic analogues were developed to cross blood brain barrier and target central nervous system and critical cellular compartment, mitochondria. The modification of its structure, aimed to preserve the SOD-like potency and lipophilicity, and diminish the toxicity, has presently been pursued. The pulmonary radioprotection by MnTnHex-2-PyP5+ was the first efficacy study performed successfully with non-human primates. The Phase I toxicity clinical trials were done on amyotrophic lateral sclerosis patients with N,N′-diethylimidazolium analogue, MnTDE-2-ImP5+ (AEOL10150). Its aggressive development as a wide spectrum radioprotector by Aeolus Pharmaceuticals has been supported by USA Federal government. The latest generation of compounds, bearing oxygens in pyridyl substituents is presently under aggressive development for cancer and CNS injuries at Duke University and is supported by Duke Translational Research Institute, The Wallace H. Coulter Translational Partners Grant Program, Preston Robert Tisch Brain Tumor Center at Duke, and National Institute of Allergy and Infectious Diseases. Metal center of cationic manganese porphyrins easily accepts and donates electrons as exemplified in the catalysis of O2·− dismutation. Thus such compounds may be equally good anti- and pro-oxidants; in either case the beneficial therapeutic effects may be observed. Moreover, while the in vivo effects may appear antioxidative, the mechanism of action of MnPs that produced such effects may be pro-oxidative; the most obvious example being the inhibition of NF-κB. The experimental data therefore teach us that we need to distinguish between the mechanism/s of action/s of MnPs and the effects we observe. A number of factors impact the type of action of MnPs leading to favorable therapeutic effects: levels of reactive species and oxygen, levels of endogenous antioxidants (enzymes and low-molecular compounds), levels of MnPs, their site of accumulation, and the mutual encounters of all of those species. The complexity of in vivo redox systems and the complex redox chemistry of MnPs challenge and motivate us to further our understanding of the physiology of the normal and diseased cell with ultimate goal to successfully treat human diseases.