Organoiridium complexes: anticancer agents and catalysts.
Organoiridium complexes: anticancer agents and catalysts.
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DOI：
10.1021/ar400266c
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发表时间：
2014-04-15
影响因子：
18.3
通讯作者：
Sadler, Peter J.
中科院分区：
文献类型：
--
作者：
Liu, Zhe;Sadler, Peter J.
铱是一种相对稀有的贵重重金属，密度仅略低于锇。研究人员早就认识到正方形平面铱配合物的催化性能，例如Crabtree的氢化催化剂，一种具有环辛烷，膦和吡啶配体的有机金属配合物。最近，化学家已经开发了含有二胺配体的半夹心假八面体五甲基铱IrIII络合物，其有效地催化酮和醛在水中使用H2或甲酸盐作为氢源的转移氢化反应。虽然有时被认为是化学惰性的，低自旋5d 6 IrIII中心的反应性是高度依赖于一组配体。具有强的σ-供体C-螯合配体的Cp* 络合物甚至可以稳定IrIV并催化水的氧化。与成熟的Ir催化剂相比，Ir基药物仍处于起步阶段。在这篇文章中，我们综述了有机铱配合物作为催化剂和抗癌剂的最新进展。与有机铱配合物的抗癌活性的初步研究集中在正方形平面铱配合物，因为它们的结构和电子的相似性，如顺铂铂II抗癌配合物。最近，研究人员研究了半夹心IrIII抗癌配合物。这些具有式[（Cpx）Ir（L <$L′）Z]0/n+的配合物（具有Cp* 或扩展的Cp*，且L <$L′ =螯合的C <$N或N <$N配体）对一系列癌细胞（尤其是白血病、结肠癌、乳腺癌、前列腺癌和黑色素瘤）具有比顺铂大得多的效力（纳摩尔）。它们的作用机制可能涉及对DNA的攻击和对细胞氧化还原状态的扰动。这些络合物中的一些可以使用辅酶NAD（P）H作为氢化物源形成Ir III-氢化物络合物以催化H2的产生或醌还原成半醌。有趣的是，含有亚胺作为单齿配体的相对不反应的有机铱络合物具有促氧化活性，这似乎涉及催化氢化物转移到氧气和在细胞中产生过氧化氢。此外，研究人员还设计了惰性IrIII复合物作为有效的激酶抑制剂。八面体环IrIII配合物不仅可以作为细胞显像剂，还可以抑制肿瘤坏死因子α，促进DNA氧化，光活化时产生单线态氧，表现出良好的抗癌活性。虽然相对未被探索，但有机铱化学提供了独特的功能，研究人员可以利用这些功能来产生具有新作用机制的新型诊断剂和药物。
Iridium is a relatively rare precious heavy metal, only slightly less dense than osmium. Researchers have long recognized the catalytic properties of square-planar IrI complexes, such as Crabtree’s hydrogenation catalyst, an organometallic complex with cyclooctadiene, phosphane, and pyridine ligands. More recently, chemists have developed half-sandwich pseudo-octahedral pentamethylcyclopentadienyl IrIII complexes containing diamine ligands that efficiently catalyze transfer hydrogenation reactions of ketones and aldehydes in water using H2 or formate as the hydrogen source. Although sometimes assumed to be chemically inert, the reactivity of low-spin 5d6 IrIII centers is highly dependent on the set of ligands. Cp* complexes with strong σ-donor C∧C-chelating ligands can even stabilize IrIV and catalyze the oxidation of water. In comparison with well developed Ir catalysts, Ir-based pharmaceuticals are still in their infancy. In this Account, we review recent developments in organoiridium complexes as both catalysts and anticancer agents. Initial studies of anticancer activity with organoiridium complexes focused on square-planar IrI complexes because of their structural and electronic similarity to PtII anticancer complexes such as cisplatin. Recently, researchers have studied half-sandwich IrIII anticancer complexes. These complexes with the formula [(Cpx)Ir(L∧L′)Z]0/n+ (with Cp* or extended Cp* and L∧L′ = chelated C∧N or N∧N ligands) have a much greater potency (nanomolar) toward a range of cancer cells (especially leukemia, colon cancer, breast cancer, prostate cancer, and melanoma) than cisplatin. Their mechanism of action may involve both an attack on DNA and a perturbation of the redox status of cells. Some of these complexes can form IrIII-hydride complexes using coenzyme NAD(P)H as a source of hydride to catalyze the generation of H2 or the reduction of quinones to semiquinones. Intriguingly, relatively unreactive organoiridium complexes containing an imine as a monodentate ligand have prooxidant activity, which appears to involve catalytic hydride transfer to oxygen and the generation of hydrogen peroxide in cells. In addition, researchers have designed inert IrIII complexes as potent kinase inhibitors. Octahedral cyclometalated IrIII complexes not only serve as cell imaging agents, but can also inhibit tumor necrosis factor α, promote DNA oxidation, generate singlet oxygen when photoactivated, and exhibit good anticancer activity. Although relatively unexplored, organoiridium chemistry offers unique features that researchers can exploit to generate novel diagnostic agents and drugs with new mechanisms of action.
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影响因子：
2.3
作者：
Canivet, Jerome;Suess-Fink, Georg;Stepnicka, Petr
通讯作者：
Stepnicka, Petr
影响因子：
16.6
作者：
Betanzos-Lara, Soledad;Liu, Zhe;Sadler, Peter J.
通讯作者：
Sadler, Peter J.
影响因子：
4.6
作者：
Johnpeter, Justin P.;Gupta, Gajendra;Therrien, Bruno
通讯作者：
Therrien, Bruno
有机金属抗癌化合物。
影响因子：
7.3
作者：
Gasser G;Ott I;Metzler-Nolte N
通讯作者：
Metzler-Nolte N
影响因子：
2.8
作者：
Brewster, Timothy P.;Blakemore, James D.;Crabtree, Robert H.
通讯作者：
Crabtree, Robert H.