8-Benzenesulfonyloxy-5- N,N-dimethylaminosulfonylquinolin-2-ylmethyl-pendant cyclen (BS-caged-L(4... more 8-Benzenesulfonyloxy-5- N,N-dimethylaminosulfonylquinolin-2-ylmethyl-pendant cyclen (BS-caged-L(4), BS = benzenesulfonyl) was designed and synthesized as a "caged" derivative of a previously described Zn(2+) fluorophore, 8-hydroxy-5- N,N-dimethylaminosulfonylquinolin-2-ylmethyl-pendant cyclen (L(4)) (cyclen = 1,4,7,10-tetraazacyclododecane). In the absence of metal ions and in the dark, BS-caged-L(4) (10 microM) showed negligible fluorescence emission at pH 7.4 (10 mM HEPES with I = 0.1 (NaNO3)) and 25 degrees C (excitation at 328 nm). Addition of Zn(2+) induced an increase in the UV/vis absorption of BS-caged-L(4) (10 microM) at 258 nm and a significant increase in fluorescence emission at 512 nm. These responses are results from the formation of Zn(H-1L(4)) by the hydrolysis of the sulfonyl ester at the 8-position of the quinoline unit promoted by the Zn(2+)-bound HO(-). Improvement of cell membrane permeation in comparison with L(4) is also described.
In this article we report on the successful synthesis and isolation of cyclometalated Ir complexe... more In this article we report on the successful synthesis and isolation of cyclometalated Ir complexes having three different nonsymmetric ligands based on ligand-selective electrophilic reactions via interligand HOMO (highest occupied molecular orbital) hopping phenomena. It was hypothesized that the electrophilic substitution reactions of bis-heteroleptic Ir complexes having 8-benzenesulfonamidoquinoline as an ancillary ligand, 5a and 7, would proceed at the 5 position of the quinoline ring of these Ir complexes to afford 18 and 19, because their HOMOs are localized on the quinoline rings, as predicted by density functional theory (DFT) calculations. In these products, the HOMO is transferred to one of two ppy ligands, in which the phenyl group is trans to the Ir-N (1 position of quinoline) bond, and hence, the iodination or formylation of 18 and 19 occurs at the 5' position of the ppy ligand to provide 20a, 23, and 24. Furthermore, we carried out the functionalization of 20a usin...
Photodynamic therapy (PDT), a noninvasive method for cancer therapy, involves the generation of r... more Photodynamic therapy (PDT), a noninvasive method for cancer therapy, involves the generation of reactive oxygen species (ROS) by the photochemical excitation of photosensitizers (PSs) to induce cell death in cancer cells. A variety of PS including porphyrin derivatives and metal complexes such as iridium (Ir) complexes have been reported. In clinical trials, red-near infrared (NIR) light (650–900 nm) is preferred for the excitation of PSs due to its deeper penetration into tissues compared with visible light (400–500 nm). To overcome this limitation, we established a PDT system that uses cyclometalated iridium(III) (Ir(III)) complexes that are excited with blue light in the wireless power transmission (WPT) system. To achieve this, we developed a light-emitting diode (LED) light device equipped with a receiver coil that receives electricity from the transmitter coil through magnetic resonance coupling. The LEDs in the receiving device use blue light (470 nm) to irradiate a given Ir(...
Luminescence chemosensors are one of the most useful tools for the determination and imaging of s... more Luminescence chemosensors are one of the most useful tools for the determination and imaging of small biomolecules and ions in situ in real time. Based on the unique photo-physical/-chemical properties of ruthenium(II) (Ru(II)) complexes, the development of Ru(II) complex-based chemosensors has attracted increasing attention in recent years, and thus many Ru(II) complexes have been designed and synthesized for the detection of ions and small biomolecules in biological and environmental samples. In this work, we summarize the research advances in the development of Ru(II) complex-based chemosensors for the determination of ions and small biomolecules, including anions, metal ions, reactive biomolecules and amino acids, with a particular focus on binding/reaction-based chemosensors for the investigation of intracellular analytes’ evolution through luminescence analysis and imaging. The advances, challenges and future research directions in the development of Ru(II) complex-based chemo...
We report on the efficient synthesis of tris-heteroleptic iridium (Ir) complexes based on the deg... more We report on the efficient synthesis of tris-heteroleptic iridium (Ir) complexes based on the degradation of tris-cyclometalated Ir complexes (IrL3, L: cyclometalating ligand) in the presence of Brønsted and Lewis acids such as HCl (in 1,4-dioxane), AlCl3, TMSCl, and ZnX2 (X = Br or Cl), which affords the corresponding halogen-bridged Ir dimers (μ-complexes). Tris-cyclometalated Ir complexes containing electron-withdrawing groups such as fluorine, nitro, or CF3 moieties on the ligands were less reactive. This different reactivity was applied to the selective degradation of heteroleptic Ir complexes such as fac-Ir(tpy)2(F2ppy) (fac-12) (tpy: 2-(4'-tolyl)pyridine and F2ppy: 2-(4',6'-difluorophenyl)pyridine), mer-Ir(tpy)2(F2ppy) (mer-12), and mer-Ir(mpiq)2(F2ppy) (mer-15) (mpiq: 1-(4'-methylphenyl)isoquinoline). For example, the reaction of mer-12 with ZnBr2 gave the heteroleptic μ-complex [{Ir(tpy)(F2ppy)(μ-Br)}2] 27b as a major product, resulting from the selective el...
In silico screening is a powerful drug-discovery tool. However, the application of traditional st... more In silico screening is a powerful drug-discovery tool. However, the application of traditional structure-based and mechanism-based drug design is hampered by the limited availability of three-dimensional structures of target enzymes or proteins. Thus, we propose a new method of screening good inhibitors of target enzymes without using their precise structures, based on machine learning. With this method, the data of ligands and decoys are collected from the inhibitor’s Database of Useful Decoys: Enhanced (DUD-E). We evaluated the accuracy of Inductive-Logic Programing (ILP) by applying a classification model that learned ligands and decoys from DUD-E to ligand candidates that are not included in DUD-E. In the present study, this technique is applied to the screening of inhibitors of carbonic anhydrase. ILP exhibited high classification performance. Furthermore, we visualized the rules from ILP and obtained a clear classification model.
In our previous paper, we reported that amphiphilic Ir complex–peptide hybrids (IPHs) containing ... more In our previous paper, we reported that amphiphilic Ir complex–peptide hybrids (IPHs) containing basic peptides such as KK(K)GG (K: lysine, G: glycine) (e.g., ASb-2) exhibited potent anticancer activity against Jurkat cells, with the dead cells showing a strong green emission. Our initial mechanistic studies of this cell death suggest that IPHs would bind to the calcium (Ca2+)–calmodulin (CaM) complex and induce an overload of intracellular Ca2+, resulting in the induction of non-apoptotic programmed cell death. In this work, we conduct a detailed mechanistic study of cell death induced by ASb-2, a typical example of IPHs, and describe how ASb-2 induces paraptotic programmed cell death in a manner similar to that of celastrol, a naturally occurring triterpenoid that is known to function as a paraptosis inducer in cancer cells. It is suggested that ASb-2 (50 µM) induces ER stress and decreases the mitochondrial membrane potential (ΔΨm), thus triggering intracellular signaling pathway...
Flavonoids are a subclass of polyphenols which are attractive, due to possessing various physiolo... more Flavonoids are a subclass of polyphenols which are attractive, due to possessing various physiological activities, including a radioprotective effect. Tumor suppressor p53 is a primary regulator in the radiation response and is involved in the pathogenesis of radiation injuries. In this study, we revealed that isorhamnetin inhibited radiation cell death, and investigated its action mechanism focusing on DNA damage response. Although isorhamnetin moderated p53 activity, it promoted phosphorylation of ataxia telangiectasia mutated (ATM) and enhanced 53BP1 recruitment in irradiated cells. The radioprotective effect of isorhamnetin was not observed in the presence of ATM inhibitor, indicating that its protective effect was dependent on ATM. Furthermore, isorhamnetin-treated mice survived gastrointestinal death caused by a lethal dose of abdominal irradiation. These findings suggested that isorhamnetin enhances the ATM-dependent DNA repair process, which is presumably associated with the...
Two novel pyrazole based thiourea palladium(II) complexes, [PdCl(PPh3)(C9H8NO2S-pz)] (1) and [PdC... more Two novel pyrazole based thiourea palladium(II) complexes, [PdCl(PPh3)(C9H8NO2S-pz)] (1) and [PdCl(PPh3)(C14H10NO2S-pz)] (2) [pz = pyrazole (C3H2N2)] have been obtained unexpectedly from chromone thiosemicarbazones (L1 and L2) and [PdCl2(PPh3)2]. The compounds have been fully characterized by physicochemical studies. The single crystal X-ray diffraction and spectral studies revealed square planar geometry for the complexes. The conversion of chromone thiosemicarbazone into pyrazole based thiourea might have happened through coordination to palladium(II) ion after enolization, Michael addition and ring opening followed by cyclization. To the best of our knowledge, this is the first report for the conversion of chromone thiosemicarbazone into pyrazole based thiourea moiety. Plausible mechanism was proposed based on the spectroscopic studies. Calf thymus (CT) DNA binding of the compounds was explored using various spectroscopic and molecular docking methods. DNA cleavage studies suggested that complexes 1 and 2 had the capacity to cleave the supercoiled DNA (pUC19) to its naked form. In vitro cytotoxic property of the ligands and complexes has been evaluated against three human cancer cells such as A549, HepG-2 and U937. Complex 2 exhibited potent cytotoxic activity against HepG-2 cells with the IC50 value of 10.4 μM. In addition, mechanistic studies showed that complex 2 induced apoptosis through mitochondrial signaling pathway in HepG-2 cells. Beneficially, complex 2 showed less toxicity against human lung (IMR90) normal cells and hence it emerges as a potential candidate for further studies.
8-Benzenesulfonyloxy-5- N,N-dimethylaminosulfonylquinolin-2-ylmethyl-pendant cyclen (BS-caged-L(4... more 8-Benzenesulfonyloxy-5- N,N-dimethylaminosulfonylquinolin-2-ylmethyl-pendant cyclen (BS-caged-L(4), BS = benzenesulfonyl) was designed and synthesized as a "caged" derivative of a previously described Zn(2+) fluorophore, 8-hydroxy-5- N,N-dimethylaminosulfonylquinolin-2-ylmethyl-pendant cyclen (L(4)) (cyclen = 1,4,7,10-tetraazacyclododecane). In the absence of metal ions and in the dark, BS-caged-L(4) (10 microM) showed negligible fluorescence emission at pH 7.4 (10 mM HEPES with I = 0.1 (NaNO3)) and 25 degrees C (excitation at 328 nm). Addition of Zn(2+) induced an increase in the UV/vis absorption of BS-caged-L(4) (10 microM) at 258 nm and a significant increase in fluorescence emission at 512 nm. These responses are results from the formation of Zn(H-1L(4)) by the hydrolysis of the sulfonyl ester at the 8-position of the quinoline unit promoted by the Zn(2+)-bound HO(-). Improvement of cell membrane permeation in comparison with L(4) is also described.
In this article we report on the successful synthesis and isolation of cyclometalated Ir complexe... more In this article we report on the successful synthesis and isolation of cyclometalated Ir complexes having three different nonsymmetric ligands based on ligand-selective electrophilic reactions via interligand HOMO (highest occupied molecular orbital) hopping phenomena. It was hypothesized that the electrophilic substitution reactions of bis-heteroleptic Ir complexes having 8-benzenesulfonamidoquinoline as an ancillary ligand, 5a and 7, would proceed at the 5 position of the quinoline ring of these Ir complexes to afford 18 and 19, because their HOMOs are localized on the quinoline rings, as predicted by density functional theory (DFT) calculations. In these products, the HOMO is transferred to one of two ppy ligands, in which the phenyl group is trans to the Ir-N (1 position of quinoline) bond, and hence, the iodination or formylation of 18 and 19 occurs at the 5' position of the ppy ligand to provide 20a, 23, and 24. Furthermore, we carried out the functionalization of 20a usin...
Photodynamic therapy (PDT), a noninvasive method for cancer therapy, involves the generation of r... more Photodynamic therapy (PDT), a noninvasive method for cancer therapy, involves the generation of reactive oxygen species (ROS) by the photochemical excitation of photosensitizers (PSs) to induce cell death in cancer cells. A variety of PS including porphyrin derivatives and metal complexes such as iridium (Ir) complexes have been reported. In clinical trials, red-near infrared (NIR) light (650–900 nm) is preferred for the excitation of PSs due to its deeper penetration into tissues compared with visible light (400–500 nm). To overcome this limitation, we established a PDT system that uses cyclometalated iridium(III) (Ir(III)) complexes that are excited with blue light in the wireless power transmission (WPT) system. To achieve this, we developed a light-emitting diode (LED) light device equipped with a receiver coil that receives electricity from the transmitter coil through magnetic resonance coupling. The LEDs in the receiving device use blue light (470 nm) to irradiate a given Ir(...
Luminescence chemosensors are one of the most useful tools for the determination and imaging of s... more Luminescence chemosensors are one of the most useful tools for the determination and imaging of small biomolecules and ions in situ in real time. Based on the unique photo-physical/-chemical properties of ruthenium(II) (Ru(II)) complexes, the development of Ru(II) complex-based chemosensors has attracted increasing attention in recent years, and thus many Ru(II) complexes have been designed and synthesized for the detection of ions and small biomolecules in biological and environmental samples. In this work, we summarize the research advances in the development of Ru(II) complex-based chemosensors for the determination of ions and small biomolecules, including anions, metal ions, reactive biomolecules and amino acids, with a particular focus on binding/reaction-based chemosensors for the investigation of intracellular analytes’ evolution through luminescence analysis and imaging. The advances, challenges and future research directions in the development of Ru(II) complex-based chemo...
We report on the efficient synthesis of tris-heteroleptic iridium (Ir) complexes based on the deg... more We report on the efficient synthesis of tris-heteroleptic iridium (Ir) complexes based on the degradation of tris-cyclometalated Ir complexes (IrL3, L: cyclometalating ligand) in the presence of Brønsted and Lewis acids such as HCl (in 1,4-dioxane), AlCl3, TMSCl, and ZnX2 (X = Br or Cl), which affords the corresponding halogen-bridged Ir dimers (μ-complexes). Tris-cyclometalated Ir complexes containing electron-withdrawing groups such as fluorine, nitro, or CF3 moieties on the ligands were less reactive. This different reactivity was applied to the selective degradation of heteroleptic Ir complexes such as fac-Ir(tpy)2(F2ppy) (fac-12) (tpy: 2-(4'-tolyl)pyridine and F2ppy: 2-(4',6'-difluorophenyl)pyridine), mer-Ir(tpy)2(F2ppy) (mer-12), and mer-Ir(mpiq)2(F2ppy) (mer-15) (mpiq: 1-(4'-methylphenyl)isoquinoline). For example, the reaction of mer-12 with ZnBr2 gave the heteroleptic μ-complex [{Ir(tpy)(F2ppy)(μ-Br)}2] 27b as a major product, resulting from the selective el...
In silico screening is a powerful drug-discovery tool. However, the application of traditional st... more In silico screening is a powerful drug-discovery tool. However, the application of traditional structure-based and mechanism-based drug design is hampered by the limited availability of three-dimensional structures of target enzymes or proteins. Thus, we propose a new method of screening good inhibitors of target enzymes without using their precise structures, based on machine learning. With this method, the data of ligands and decoys are collected from the inhibitor’s Database of Useful Decoys: Enhanced (DUD-E). We evaluated the accuracy of Inductive-Logic Programing (ILP) by applying a classification model that learned ligands and decoys from DUD-E to ligand candidates that are not included in DUD-E. In the present study, this technique is applied to the screening of inhibitors of carbonic anhydrase. ILP exhibited high classification performance. Furthermore, we visualized the rules from ILP and obtained a clear classification model.
In our previous paper, we reported that amphiphilic Ir complex–peptide hybrids (IPHs) containing ... more In our previous paper, we reported that amphiphilic Ir complex–peptide hybrids (IPHs) containing basic peptides such as KK(K)GG (K: lysine, G: glycine) (e.g., ASb-2) exhibited potent anticancer activity against Jurkat cells, with the dead cells showing a strong green emission. Our initial mechanistic studies of this cell death suggest that IPHs would bind to the calcium (Ca2+)–calmodulin (CaM) complex and induce an overload of intracellular Ca2+, resulting in the induction of non-apoptotic programmed cell death. In this work, we conduct a detailed mechanistic study of cell death induced by ASb-2, a typical example of IPHs, and describe how ASb-2 induces paraptotic programmed cell death in a manner similar to that of celastrol, a naturally occurring triterpenoid that is known to function as a paraptosis inducer in cancer cells. It is suggested that ASb-2 (50 µM) induces ER stress and decreases the mitochondrial membrane potential (ΔΨm), thus triggering intracellular signaling pathway...
Flavonoids are a subclass of polyphenols which are attractive, due to possessing various physiolo... more Flavonoids are a subclass of polyphenols which are attractive, due to possessing various physiological activities, including a radioprotective effect. Tumor suppressor p53 is a primary regulator in the radiation response and is involved in the pathogenesis of radiation injuries. In this study, we revealed that isorhamnetin inhibited radiation cell death, and investigated its action mechanism focusing on DNA damage response. Although isorhamnetin moderated p53 activity, it promoted phosphorylation of ataxia telangiectasia mutated (ATM) and enhanced 53BP1 recruitment in irradiated cells. The radioprotective effect of isorhamnetin was not observed in the presence of ATM inhibitor, indicating that its protective effect was dependent on ATM. Furthermore, isorhamnetin-treated mice survived gastrointestinal death caused by a lethal dose of abdominal irradiation. These findings suggested that isorhamnetin enhances the ATM-dependent DNA repair process, which is presumably associated with the...
Two novel pyrazole based thiourea palladium(II) complexes, [PdCl(PPh3)(C9H8NO2S-pz)] (1) and [PdC... more Two novel pyrazole based thiourea palladium(II) complexes, [PdCl(PPh3)(C9H8NO2S-pz)] (1) and [PdCl(PPh3)(C14H10NO2S-pz)] (2) [pz = pyrazole (C3H2N2)] have been obtained unexpectedly from chromone thiosemicarbazones (L1 and L2) and [PdCl2(PPh3)2]. The compounds have been fully characterized by physicochemical studies. The single crystal X-ray diffraction and spectral studies revealed square planar geometry for the complexes. The conversion of chromone thiosemicarbazone into pyrazole based thiourea might have happened through coordination to palladium(II) ion after enolization, Michael addition and ring opening followed by cyclization. To the best of our knowledge, this is the first report for the conversion of chromone thiosemicarbazone into pyrazole based thiourea moiety. Plausible mechanism was proposed based on the spectroscopic studies. Calf thymus (CT) DNA binding of the compounds was explored using various spectroscopic and molecular docking methods. DNA cleavage studies suggested that complexes 1 and 2 had the capacity to cleave the supercoiled DNA (pUC19) to its naked form. In vitro cytotoxic property of the ligands and complexes has been evaluated against three human cancer cells such as A549, HepG-2 and U937. Complex 2 exhibited potent cytotoxic activity against HepG-2 cells with the IC50 value of 10.4 μM. In addition, mechanistic studies showed that complex 2 induced apoptosis through mitochondrial signaling pathway in HepG-2 cells. Beneficially, complex 2 showed less toxicity against human lung (IMR90) normal cells and hence it emerges as a potential candidate for further studies.
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Papers by Shin Aoki