title: 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.
abstract: 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, cyclometalated iridium(III) complexes such as fac-Ir(ppy)3 (ppy = 2-phenylpyridine) and fac-Ir(tpy)3 (tpy = 2-(4'-tolyl)pyridine) possess C3-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-cyclometalated 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 Ca(2+) dependent pathway and intracellular Ca(2+) response, resulting in necrosis accompanied by membrane disruption.
authors: †Faculty of Pharmaceutical Sciences, ‡Research Institute for Biomedical Sciences, and §Division of Medical Science-Engineering Corporation, Research Institute of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors: Yosuke
authors: Y
authors: Hisamatsu
authors: †Faculty of Pharmaceutical Sciences, ‡Research Institute for Biomedical Sciences, and §Division of Medical Science-Engineering Corporation, Research Institute of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors: Ai
authors: A
authors: Shibuya
authors: †Faculty of Pharmaceutical Sciences, ‡Research Institute for Biomedical Sciences, and §Division of Medical Science-Engineering Corporation, Research Institute of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors: Nozomi
authors: N
authors: Suzuki
authors: †Faculty of Pharmaceutical Sciences, ‡Research Institute for Biomedical Sciences, and §Division of Medical Science-Engineering Corporation, Research Institute of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors: Toshihiro
authors: T
authors: Suzuki
authors: †Faculty of Pharmaceutical Sciences, ‡Research Institute for Biomedical Sciences, and §Division of Medical Science-Engineering Corporation, Research Institute of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors: Ryo
authors: R
authors: Abe
authors: †Faculty of Pharmaceutical Sciences, ‡Research Institute for Biomedical Sciences, and §Division of Medical Science-Engineering Corporation, Research Institute of Science and Technology, Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.
authors: Shin
authors: S
authors: Aoki
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007495:Iridium / Q000737:chemistry*; D008024:Ligands; D008081:Liposomes / Q000378:metabolism; D049408:Luminescent Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D057054:Molecular Imaging; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D008081:Liposomes; D049408:Luminescent Agents; D009942:Organometallic Compounds; D010455:Peptides; D011725:Pyridines; D007495:Iridium; C023666:pyridine; D002118:Calcium