Design and Synthesis of Amphiphilic and Luminescent Tris-Cyclometalated Iridium(III) Complexes Containing Cationic Peptides as Inducers and Detectors of Cell Death via a Calcium-Dependent Pathway
Design and Synthesis of Amphiphilic and Luminescent Tris-Cyclometalated Iridium(III) Complexes Containing Cationic Peptides as Inducers and Detectors of Cell Death via a Calcium-Dependent Pathway
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DOI：
10.1021/acs.bioconjchem.5b00095
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发表时间：
2015-05-01
影响因子：
4.7
通讯作者：
Aoki, Shin
中科院分区：
文献类型：
--
作者：
Hisamatsu, Yosuke;Shibuya, Ai;Aoki, Shin
阳离子两亲性多肽有可能作为治疗微生物感染和癌症治疗的试剂。这些分子的阳离子和疏水部分使它们能够与带负电荷的细菌或癌细胞膜强烈结合，从而通过破坏膜发挥抗菌和抗癌活性。同时，环金属化的Ir(III)配合物如fac-ir(Ppy)(3)(ppy=2-苯基吡啶)和fac-ir(Tpy)(3)(tpy=2-(4‘-tolyopyridine))具有C-3对称结构和优异的光物理性能作为磷光材料，这使得它们在化学传感器、生物标记、活细胞染色、体内肿瘤成像和抗癌药物等生物应用中具有重要的应用前景。我们最近报道了2-苯基吡啶配体上Ir(Tpy)(3)和Ir(Ppy)(3)在5‘位(相对于C-Ir键的p位)的区域选择性取代反应，以及它们随后转化为各种官能团的反应。本文报道了两亲性和发光三环金属Ir配合物的设计和合成，其中阳离子多肽通过烷基链键连接，作为细胞死亡的诱导剂和检测器。含有KKGG序列等阳离子多肽和适当长度的烷基链连接基(C6和C8)的IR络合物对Jurkat、Molt-4、HeLa-S3和A549等癌细胞表现出较强的细胞毒性，并且死亡细胞与这些Ir络合物染色良好。此外，KKGG多肽通过C6接头连接的Ir复合体对正常小鼠淋巴细胞显示出较低的细胞毒性。机制研究表明，含有KKGG多肽的Ir络合物与细胞表面和/或膜受体上的阴离子分子相互作用，触发钙依赖途径和细胞内钙反应，导致坏死并伴有膜破裂。
Cationic amphiphilic peptides have the potential to function as agents for the treatment of microbial infections and cancer therapy. The cationic and hydrophobic parts of these molecules allow them to associate strongly with negatively charged bacterial or cancer cell membranes, thus exerting antimicrobial and anticancer activities through membrane disruption. Meanwhile, cydometalated iridium(III) complexes such as fac-Ir(ppy)(3) (ppy = 2-phenylpyridine) and fac-Ir(tpy)(3) (tpy = 2-(4'-tolyOpyridine) possess C-3-symmetric structures and excellent photophysical properties as phosphorescence materials, which make them important candidates for use in biological applications such as chemosensors, biolabeling, living cell staining, in vivo tumor imaging, and anticancer agents. We recently reported on some regioselective substitution reactions of Ir(tpy)(3) and Ir(ppy)(3) at the 5'-position (p-position with respect to the C-Ir bond) on the 2-phenylpyridine ligands and their subsequent conversions to a variety of functional groups. We report here on the design and synthesis of amphiphilic and luminescent tris-cydometalated Ir complexes in which cationic peptides are attached through alkyl chain linkers that work as inducers and detectors of cell death. Ir complexes containing cationic peptides such as a KKGG sequence and alkyl chain linkers of adequate length (C6 and C8) exhibit considerable cytotoxicity against cancer cells such as Jurkat, Molt-4, HeLa-S3, and A549 cells, and that dead cells are well stained with these Ir complexes. Furthermore, an Ir complex in which the KKGG peptide is attached through a C6 linker displayed lower cytotoxicity against normal mouse lymphocytes. Mechanistic studies suggest that Ir complexes containing the KKGG peptide interact with anionic molecules on the cell surface and/or membrane receptors to trigger the Ca2+ dependent pathway and intracellular Ca2+ response, resulting in necrosis accompanied by membrane disruption.