Changlin Liu

Supersnowflakes: Stepwise Self-Assembly and Dynamic Exchange of Rhombus Star-Shaped Supramolecules

Co-reporter:Zhe Zhang, Heng Wang, Xu Wang, Yiming Li, Bo Song, Olapeju Bolarinwa, R. Alexander Reese, Tong Zhang, Xu-Qing Wang, Jianfeng Cai, Bingqian Xu, Ming Wang, Changlin Liu, Hai-Bo Yang, and Xiaopeng Li

Journal of the American Chemical Society June 21, 2017 Volume 139(Issue 24) pp:8174-8174

Publication Date(Web):May 30, 2017

DOI:10.1021/jacs.7b01326

With the goal of increasing the complexity of metallo-supramolecules, two rhombus star-shaped supramolecular architectures, namely, supersnowflakes, were designed and assembled using multiple 2,2′:6′,2″-terpyridine (tpy) ligands in a stepwise manner. In the design of multicomponent self-assembly, ditopic and tritopic ligands were bridged through Ru(II) with strong coordination to form metal–organic ligands for the subsequent self-assembly with a hexatopic ligand and Zn(II). The combination of Ru(II)–organic ligands with high stability and Zn(II) ions with weak coordination played a key role in the self-assembly of giant heteroleptic supersnowflakes, which encompassed three types of tpy-based organic ligands and two metal ions. With such a stepwise strategy, the self-sorting of individual building blocks was prevented from forming the undesired assemblies, e.g., small macrocycles and coordination polymers. Furthermore, the intra- and intermolecular dynamic exchange study of two supersnowflakes by NMR and mass spectrometry revealed the remarkable stability of these giant supramolecular complexes.

The rational design of specific SOD1 inhibitors via copper coordination and their application in ROS signaling research

Co-reporter:Xiongwei Dong, Zhe Zhang, Jidong Zhao, Juan Lei, Yuanyuan Chen, Xiang Li, Huanhuan Chen, Junli Tian, Dan Zhang, Chunrong Liu and Changlin Liu

Chemical Science 2016 vol. 7(Issue 9) pp:6251-6262

Publication Date(Web):16 Jun 2016

DOI:10.1039/C6SC01272H

Efficient methods for the regulation of intracellular O2˙− and H2O2 levels, without altering intracellular processes, are urgently required for the rapidly growing interest in ROS signaling, as ROS signaling has been confirmed to be involved in a series of basic cellular processes including proliferation, differentiation, growth and migration. Intracellular H2O2 is formed mainly via the catalytic dismutation of O2˙− by SODs including SOD1, SOD2 and SOD3. Thus, the intracellular levels of O2˙− and H2O2 can directly be controlled through regulating SOD1 activity. Here, based on the active site structure and catalytic mechanism of SOD1, we developed a new type of efficient and specific SOD1 inhibitors which can directly change the intracellular levels of H2O2 and O2˙−. These inhibitors inactivate intracellular SOD1 via localization into the SOD1 active site, thereby coordinating to the Cu2+ in the active site of SOD1, blocking the access of O2˙− to Cu2+, and breaking the Cu2+/Cu+ catalytic cycle essential for O2˙− dismutation. The reduced ERK1/2 phosphorylation induced by the specific SOD1 inactivation-mediated decrease of intracellular H2O2 levels reveals the potential of these specific SOD1 inhibitors in understanding and regulating ROS signaling. Furthermore, these specific SOD1 inhibitors also lead to selectively elevated cancer cell apoptosis, indicating that these kinds of SOD1 inhibitors might be candidates for lead compounds for cancer treatment.

An ESIPT fluorescent probe sensitive to protein α-helix structures

Co-reporter:Nan Jiang, Chanli Yang, Xiongwei Dong, Xianglang Sun, Dan Zhang and Changlin Liu

Organic & Biomolecular Chemistry 2014 vol. 12(Issue 28) pp:5250-5259

Publication Date(Web):01 May 2014

DOI:10.1039/C4OB00405A

A large majority of membrane proteins have one or more transmembrane regions consisting of α-helices. Membrane protein levels differ from one type of cell to another, and the expression of membrane proteins also changes from normal to diseased cells. For example, prostate cancer cells have been reported to have downregulated expression of membrane proteins, including zinc transporters, compared with normal prostate cells. These reports inspired us to design a fluorescence probe sensitive to protein α-helical structures to discriminate individual prostate cancer cells from normal ones. A benzazole derivative (1 in this study) was observed to emit strong fluorescence resulting from an excited-state intramolecular proton transfer (ESIPT) in protein α-helical environments. The intensity of ESIPT fluorescence of 1 was observed to be positively correlated with the α-helix content of proteins. The molecular docking simulation suggested that it had low energy for the binding of 1 to proteins when the binding sites were localized within the α-helical regions of protein via H-bonds. Furthermore, 1 was found to be localized in cell membranes through binding to transmembrane α-helical regions of membrane proteins, and was capable of probing differences in the α-helix contents of membrane proteins between normal and cancerous prostate cells through changes in the ESIPT emission intensity. These results indicated that 1 could distinguish individual prostate cancer cells from normal ones, as the changes in the ESIPT fluorescence intensity of 1 could reflect the regulation in expression of the membrane proteins including zinc transporters. This recognition strategy of individual prostate cancer cells might contribute to early diagnosis techniques for prostate cancer.

Metal–polybenzimidazole complexes as a nonviral gene carrier: Effects of the DNA affinity on gene delivery

Co-reporter:Xueying Huang, Xiongwei Dong, Xue Li, Xianggao Meng, Dan Zhang, Changlin Liu

Journal of Inorganic Biochemistry 2013 Volume 129() pp:102-111

Publication Date(Web):December 2013

DOI:10.1016/j.jinorgbio.2013.09.009

•The correlations between the DNA affinity and transfection efficacy were examined by characterizing gene-delivering ability of a series of Co2 +- and Ca2 +-polybenzimidazole complexes.•The properties, cell transfection and toxicity of DNA condensates were shown to be altered with binding equilibrium constants of the divalent metal complexes to DNA.The metal complex-based carriers are emerging likely as a new type of gene-delivery systems prone to systematic structural alteration and chemical tailoring. In our work, the DNA affinity of metal complexes with polybenzimidazoles was found to be one of the determinants that can regulate expression of the transgenes. Here, the correlations between the DNA affinity and transfection efficacy were explored by characterizing gene-delivering properties of a series of Co2 +- and Ca2 +–polybenzimidazole complexes. The binding equilibrium constants (Kobs) of the divalent metal complexes to DNA, which is considered as a measure of the DNA affinity of metal complexes, were evaluated by isothermal titration calorimetry (ITC) and UV–visible absorption titration. The properties of DNA condensates formed with the metal complexes including sizes, ζ potential and morphology were observed to be altered with Kobs values. The monodispersed spherical condensates were found only for the Ca2 + complexes whose DNA affinity is weaker than that of the Co2 + complexes. However, the cell internalization examination indicated that cell uptake of the DNA condensates is independent of homogeneity in their sizes and morphology. The comparison of transgene expression showed that that the Ca2 + complex-mediated transfection has higher efficiency than the Co2 + complexes under the conditions tested, and the transfection efficacy cannot be correlated with the cell uptake of DNA condensates. Moreover, the Ca2 + complexes and their DNA condensates had lower cytotoxicity than the Co2 + complexes. Thus, the DNA affinity should be one of the factors to be capable of regulating the gene-delivering property of metal complexes.The correlations between the DNA affinity and transfection efficacy were examined by characterizing gene-delivering ability of a series of Co2 +- and Ca2 +–polybenzimidazole complexes. The properties, cell transfection and toxicity of DNA condensates were shown to be altered with binding equilibrium constants of the divalent metal complexes to DNA.

Regulation of Both the Reactive Oxygen Species Level and Antioxidant Enzyme Activity in Drought-Stressed Rice Organs by Benzimidazolate-Based SOD1 Mimics

Co-reporter:Xianggao Meng, Min Wang, Nuowei Jiang, Dan Zhang, Li Wang, and Changlin Liu

Journal of Agricultural and Food Chemistry 2012 Volume 60(Issue 45) pp:11211-11221

Publication Date(Web):October 23, 2012

DOI:10.1021/jf301942s

In the study, three benzimidazolate-based Cu2+ complexes were identified as SOD1 mimics to explore their effects on the levels of reactive oxygen species (ROS) and activities of antioxidant enzymes in drought-stressed rice organs. Superoxide dismutase (SOD) activity of the mimics was found to be controlled by unsaturated coordination, auxiliary ligands, and counter-anions. In comparison to the control, SOD1 mimic treatment for rice seeds significantly reduced ROS (O2• –, H2O2, and •OH) levels in the rice leaf and root while notably increased activities of antioxidant enzymes, including SOD1 and catalase. It can enhance the tolerance of plant organs to drought stress and, thus, has a practical potency of application in rice production on arid land.

The effect of a nuclear localization sequence on transfection efficacy of genes delivered by cobalt(II)–polybenzimidazole complexes

Co-reporter:Jun Yin, Xianggao Meng, Shibing Zhang, Dan Zhang, Li Wang, Changlin Liu

Biomaterials 2012 33(31) pp: 7884-7894

Publication Date(Web):

DOI:10.1016/j.biomaterials.2012.07.017

Tris(benzimidazolyl)amine-Cu(II) coordination units bridged by carboxylates: structures and DNA-condensing property

Co-reporter:Xianggao Meng, Liang Liu, Hang Zhang, Yuanyuan Luo and Changlin Liu

Dalton Transactions 2011 vol. 40(Issue 48) pp:12846-12855

Publication Date(Web):20 Oct 2011

DOI:10.1039/C1DT10695C

Multinuclear multibenzimidazole metal complexes frequently exhibit novel structures and properties, and are an example of versatile compounds in bioinorganic chemistry. In this work, first, we synthesized the mononuclear complex [Cu(ntb)(H2O)]2+, 1, by using tris[(benzimidazol-2-yl)methyl]amine (ntb). Then, a library of multicationic ntb-Cu(II) complexes, 2–9, was prepared by replacing the labile water molecule in 1 with multifunctional carboxylates acting as a bridge linker between two or four ntb-Cu(II) units under slightly acidic or alkaline conditions. Their X-ray crystal structures reveal that these complexes contain one, two or four [Cu(ntb)]2+ units. The pH media used in preparation can control the coordination patterns of the carboxylates and the overall architecture of the complexes, although the Cu(II) centers in the complexes always maintain a five-coordinated structure regardless of the preparation conditions used. Both intra- and inter-molecular π⋯π interactions involved in the benzimidazoles, as well as extensive hydrogen bonding networks in the complexes were observed to occur in the crystal packing. We selected complexes 1 and the dicarboxylate-bridged 4–7 as potential DNA condensers, as they can be dissolved to the required levels for examining their DNA-binding and -condensing properties in the buffer solutions tested (pH 7.4). For these complexes, the effects of the structural variations, including the number of Cu(II) ions and positive charges, length of linkers, and overall architecture, on the DNA-binding and -condensing properties and cytotoxicity were assessed and compared by biophysical measurements. The results from absorption titration showed that the affinities of the complexes for DNA are dominated by both the electrostatic interaction between them and the π⋯π interactions through the intercalation of the benzimidazolyl groups in the complexes into DNA base pairs. The DNA-condensing ability was observed to be mainly controlled by the numbers of positive charges on the complexes, and less correlated with the carboxylate linkers. Moreover, no direct relationships have been found between the apparent DNA-binding affinity and DNA-condensing ability of the complexes. The ability of DNA condensation triggered by 7b that carries four ntb-Cu(II) units and six positive charges is much stronger than those by the other complexes, but it also exhibits the largest cytotoxicity. This work aids in understanding the structure–activity relationships for metal complexes likely acting as a new type of gene-delivery systems.

The chelation targeting metal–Aβ40 aggregates may lead to formation of Aβ40 oligomers

Co-reporter:Yong Zhang, Li-Yuan Chen, Wen-Xing Yin, Jun Yin, Shi-Bing Zhang and Chang-Lin Liu

Dalton Transactions 2011 vol. 40(Issue 18) pp:4830-4833

Publication Date(Web):24 Mar 2011

DOI:10.1039/C1DT00020A

The fluorescent chelator (FC-1) was designed by combining a metal-chelating unit and a ThT-based Aβ aggregate-binding fluorescent unit. FC-1 is a cell membrane-penetrable chelator with a moderate chelation ability to Cu2+ and Zn2+ and can target metal–Aβ40 aggregates. Treatment with FC-1 led to enhanced cytotoxicity of the aggregates, because the aggregates were converted into a pool of oligomers.

Dinuclear metal(II) complexes of polybenzimidazole ligands as carriers for DNA delivery

Co-reporter:Liang Liu, Hang Zhang, Xianggao Meng, Jun Yin, Dongfeng Li, Changlin Liu

Biomaterials 2010 31(6) pp: 1380-1391

Publication Date(Web):

DOI:10.1016/j.biomaterials.2009.10.056

DNA hydrolytic cleavage catalyzed by synthetic multinuclear metallonucleases

Co-reporter:Changlin Liu and Li Wang

Dalton Transactions 2009 (Issue 2) pp:227-239

Publication Date(Web):28 Oct 2008

DOI:10.1039/B811616D

Much effort has been directed at understanding the roles of metal ions in catalyzing the hydrolysis of phosphodiester bonds of nucleic acids. Nucleases are metalloenzymes that have a wide variety of active site motifs and that contain a variety of different metal ions. This property has made it difficult to propose a simple mechanism for these enzymes. Therefore, design and synthesis of metal complexes, which can mediate phosphodiester bond cleavage via hydrolytic pathways, are of important significance in elucidation of the catalytic mechanisms for the natural nucleases and in development of the biomacromolecule-targeted drugs. Recent progress has extended to the design of synthetic multinuclear metallonucleases containing two or more Fe(III), Zn(II), Cu(II), Co(II/III), or Ln(III/IV) ions. The ligands in these complexes include natural and nonnatural organic molecules, i.e., mainly benzimidazolyl- and pyridyl-based organic molecules, azamacrocyclic and aminocarboxylic derivatives, and their conjugates to polypeptides or oligonucleotides. The purpose of this perspective is to highlight: (1) the differences in structure and composition between natural and synthetic multinuclear metallonucleases; (2) the design strategies of synthetic multinuclear metallonucleases; (3) the relationship between the structures and nucleolytic activities of synthetic multinuclear metallonucleases; and (4) the cooperativities between metal sites, and between metal sites and ligands in the courses of phospodiester linkage hydrolysis. A comparison illustrates unifying themes in the catalysis of phosphodiester linkage hydrolysis by natural and synthetic multinuclear metallonucleases. Indeed, there are features that converge about the chemistry that provides insight into how changes in metal ions and ligands of both natural and synthetic metallonucleases may lead to the same overall outcome of phosphodiester backbone cleavage. In addition, we will also discuss the solvation effect of synthetic multinuclear metallonucleases and the challenges that should be faced toward the development of synthetic multinuclear metallonucleases with DNA sequence or structure selectivity by applying the principles of coordination and enzymatic chemistry.

Dinuclear Copper(II) Complexes of a Polybenzimidazole Ligand: Their Structures and Inductive Roles in DNA Condensation

Co-reporter:Xianggao Meng ; Liang Liu ; Chunshan Zhou ; Li Wang

Inorganic Chemistry 2008 Volume 47(Issue 15) pp:6572-6574

Publication Date(Web):July 2, 2008

DOI:10.1021/ic800532q

The structures of two dinuclear Cu(II) complexes of dtpb were determined. They are shown to be capable of inducing DNA condensation into nanometer- and micrometer-scale particles under neutral conditions.

Extra Copper-mediated Enhancement of the DNA Cleavage Activity Supported with Wild-type Cu, Zn Superoxide Dismutase

Co-reporter:Ruo-Yu ZHOU;Wei JIANG;Li-Na ZHANG;Li WANG ;Chang-Lin LIU

Chinese Journal of Chemistry 2008 Volume 26( Issue 3) pp:564-570

Publication Date(Web):

DOI:10.1002/cjoc.200890106

Abstract

It is well known that the primary function of wild type Cu, Zn superoxide dismutase (holo SOD) is to catalyze the conversion of the superoxide anion to H₂O₂ and O₂ as an antioxidant enzyme. However, the aberrant copper-mediated oxidation chemistry in the enzyme (including its mutation forms) that damages nucleic acids, proteins including itself and cell membrane has attracted extensive attention in the past decade. The present study examined the hydrogen peroxide-dependent DNA cleavage activity supported with the combinations between holo SOD and extra copper (holo SOD+nCu(II)). The results indicate that the presence of extra copper can enhance the DNA cleavage activity and a cooperative effect between holo SOD and the extra Cu(II) occurs in DNA cleavage. The relative activity and kinetic assay showed that the DNA cleavage activity of holo SOD+nCu(II) was enhanced upon addition of extra Cu(II). The favorable pH regions for the DNA cleavage were observed to be 3.6–5.6 and 9.0–10, suggesting the species responsible for the DNA cleavage are different in different pH regions. In addition, to obtain an insight into DNA cleavage pathways, the effect of free radical scavengers and inhibitors on the DNA cleavage activity was probed.

Polymorphism of the SOD1-DNA aggregation species can be modulated by DNA

Co-reporter:Wei Jiang;Bo Zhang;Jun Yin;Liang Liu;Li Wang

Biopolymers 2008 Volume 89( Issue 12) pp:1154-1169

Publication Date(Web):

DOI:10.1002/bip.21067

Abstract

Proteinaceous aggregates rich in copper, zinc superoxide dismutase (SOD1) have been found in both in vivo and in vitro models. We have shown that double-stranded DNA that acts as a template accelerates the in vitro formation of wild-type SOD1 aggregates. Here, we examined the polymorphism of templated-SOD1 aggregates generated in vitro upon association with DNA under different conditions. Electron microscopy imaging indicates that this polymorphism is capable of being manipulated by the shapes, structures, and doses of the DNAs tested. The nanometer- and micrometer-scale aggregates formed under acidic conditions and under neutral conditions containing ascorbate fall into three classes: aggregate monomers, oligomeric aggregates, and macroaggregates. The aggregate monomers observed at given DNA doses exhibit a polymorphism that is markedly corresponded to the coiled shapes of linear DNA and structures of plasmid DNA. On the other hand, the regularly branched structures observed under both atomic force microscopy and optical microscope indicate that the DNAs tested are simultaneously condensed into a nanoparticle with a specific morphology during SOD1 aggregation, revealing that SOD1 aggregation and DNA condensation are two concurrent phenomena. The results might provide the basis of therapeutic approaches to suppress the formation of toxic protein oligomers or aggregates by screening the toxicity of the protein aggregates with various sizes and morphologies. © 2008 Wiley Periodicals, Inc. Biopolymers 89: 1154–1169, 2008.

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com

A novel 3-Hydroxychromone fluorescence sensor for intracellular Zn2+ and its application in the recognition of prostate cancer cells

Co-reporter:Xiang Li, Jie Li, Xiongwei Dong, Xiang Gao, Dan Zhang, Changlin Liu

Sensors and Actuators B: Chemical (June 2017) Volume 245() pp:

Publication Date(Web):1 June 2017

DOI:10.1016/j.snb.2017.01.170

•3HC-DPA can chelate Zn2+ in a dimeric form (2:2), emitting strong fluorescence sensitively and selectively.•3HC-DPA was a novel fluorescent ESIPT-blocking zinc sensor.•3HC-DPA provided an opportunity to further development of ESIPT-based metal sensors in bio-imaging.•3HC-DPA possessed the ability to monitor intracellular free zinc ions, and had an excellent mean cell retention time.•3HC-DPA has a promising application in the recognition of cancerous prostate cells from normal prostate cells.A novel fluorescent zinc sensor 3HC−DPA, containing a 3-hydroxychromone (3HC) chromophore and a zinc-selective metal chelator di(2-picolyl)amine (DPA), was prepared and found to chelate Zn2+ in a dimeric form. Due to the deprotonation of 3HC and occupation of the lone electron pairs on the nitrogen atoms of DPA, the complex [Zn2(3HC-DPA)2]2+ emitted sensitively and selectively strong fluorescence in solution. Moreover, cell experiments, including flow cytometry and two-photo excitation fluorescence microscopy, as well as inductively coupled plasma-atomic emission spectrometry (ICP-AES), demonstrated that 3HC-DPA possessed the ability to monitor intracellular free zinc ions in live cells. A promising use was developed for the ability of 3HC-DPA in the recognition of cancerous prostate cells from normal prostate cells, based on the added Zn2+ detection by flow cytometry and cell imaging.Download high-res image (133KB)Download full-size image

The rational design of specific SOD1 inhibitors via copper coordination and their application in ROS signaling research

Co-reporter:Xiongwei Dong, Zhe Zhang, Jidong Zhao, Juan Lei, Yuanyuan Chen, Xiang Li, Huanhuan Chen, Junli Tian, Dan Zhang, Chunrong Liu and Changlin Liu

Chemical Science (2010-Present) 2016 - vol. 7(Issue 9) pp:NaN6262-6262

Publication Date(Web):2016/06/16

DOI:10.1039/C6SC01272H

Efficient methods for the regulation of intracellular O2˙− and H2O2 levels, without altering intracellular processes, are urgently required for the rapidly growing interest in ROS signaling, as ROS signaling has been confirmed to be involved in a series of basic cellular processes including proliferation, differentiation, growth and migration. Intracellular H2O2 is formed mainly via the catalytic dismutation of O2˙− by SODs including SOD1, SOD2 and SOD3. Thus, the intracellular levels of O2˙− and H2O2 can directly be controlled through regulating SOD1 activity. Here, based on the active site structure and catalytic mechanism of SOD1, we developed a new type of efficient and specific SOD1 inhibitors which can directly change the intracellular levels of H2O2 and O2˙−. These inhibitors inactivate intracellular SOD1 via localization into the SOD1 active site, thereby coordinating to the Cu2+ in the active site of SOD1, blocking the access of O2˙− to Cu2+, and breaking the Cu2+/Cu+ catalytic cycle essential for O2˙− dismutation. The reduced ERK1/2 phosphorylation induced by the specific SOD1 inactivation-mediated decrease of intracellular H2O2 levels reveals the potential of these specific SOD1 inhibitors in understanding and regulating ROS signaling. Furthermore, these specific SOD1 inhibitors also lead to selectively elevated cancer cell apoptosis, indicating that these kinds of SOD1 inhibitors might be candidates for lead compounds for cancer treatment.

DNA hydrolytic cleavage catalyzed by synthetic multinuclear metallonucleases

Co-reporter:Changlin Liu and Li Wang

Dalton Transactions 2009(Issue 2) pp:NaN239-239

Publication Date(Web):2008/10/28

DOI:10.1039/B811616D

Much effort has been directed at understanding the roles of metal ions in catalyzing the hydrolysis of phosphodiester bonds of nucleic acids. Nucleases are metalloenzymes that have a wide variety of active site motifs and that contain a variety of different metal ions. This property has made it difficult to propose a simple mechanism for these enzymes. Therefore, design and synthesis of metal complexes, which can mediate phosphodiester bond cleavage via hydrolytic pathways, are of important significance in elucidation of the catalytic mechanisms for the natural nucleases and in development of the biomacromolecule-targeted drugs. Recent progress has extended to the design of synthetic multinuclear metallonucleases containing two or more Fe(III), Zn(II), Cu(II), Co(II/III), or Ln(III/IV) ions. The ligands in these complexes include natural and nonnatural organic molecules, i.e., mainly benzimidazolyl- and pyridyl-based organic molecules, azamacrocyclic and aminocarboxylic derivatives, and their conjugates to polypeptides or oligonucleotides. The purpose of this perspective is to highlight: (1) the differences in structure and composition between natural and synthetic multinuclear metallonucleases; (2) the design strategies of synthetic multinuclear metallonucleases; (3) the relationship between the structures and nucleolytic activities of synthetic multinuclear metallonucleases; and (4) the cooperativities between metal sites, and between metal sites and ligands in the courses of phospodiester linkage hydrolysis. A comparison illustrates unifying themes in the catalysis of phosphodiester linkage hydrolysis by natural and synthetic multinuclear metallonucleases. Indeed, there are features that converge about the chemistry that provides insight into how changes in metal ions and ligands of both natural and synthetic metallonucleases may lead to the same overall outcome of phosphodiester backbone cleavage. In addition, we will also discuss the solvation effect of synthetic multinuclear metallonucleases and the challenges that should be faced toward the development of synthetic multinuclear metallonucleases with DNA sequence or structure selectivity by applying the principles of coordination and enzymatic chemistry.

An ESIPT fluorescent probe sensitive to protein α-helix structures

Co-reporter:Nan Jiang, Chanli Yang, Xiongwei Dong, Xianglang Sun, Dan Zhang and Changlin Liu

Organic & Biomolecular Chemistry 2014 - vol. 12(Issue 28) pp:NaN5259-5259

Publication Date(Web):2014/05/01

DOI:10.1039/C4OB00405A

A large majority of membrane proteins have one or more transmembrane regions consisting of α-helices. Membrane protein levels differ from one type of cell to another, and the expression of membrane proteins also changes from normal to diseased cells. For example, prostate cancer cells have been reported to have downregulated expression of membrane proteins, including zinc transporters, compared with normal prostate cells. These reports inspired us to design a fluorescence probe sensitive to protein α-helical structures to discriminate individual prostate cancer cells from normal ones. A benzazole derivative (1 in this study) was observed to emit strong fluorescence resulting from an excited-state intramolecular proton transfer (ESIPT) in protein α-helical environments. The intensity of ESIPT fluorescence of 1 was observed to be positively correlated with the α-helix content of proteins. The molecular docking simulation suggested that it had low energy for the binding of 1 to proteins when the binding sites were localized within the α-helical regions of protein via H-bonds. Furthermore, 1 was found to be localized in cell membranes through binding to transmembrane α-helical regions of membrane proteins, and was capable of probing differences in the α-helix contents of membrane proteins between normal and cancerous prostate cells through changes in the ESIPT emission intensity. These results indicated that 1 could distinguish individual prostate cancer cells from normal ones, as the changes in the ESIPT fluorescence intensity of 1 could reflect the regulation in expression of the membrane proteins including zinc transporters. This recognition strategy of individual prostate cancer cells might contribute to early diagnosis techniques for prostate cancer.

Tris(benzimidazolyl)amine-Cu(II) coordination units bridged by carboxylates: structures and DNA-condensing property

Co-reporter:Xianggao Meng, Liang Liu, Hang Zhang, Yuanyuan Luo and Changlin Liu

Dalton Transactions 2011 - vol. 40(Issue 48) pp:NaN12855-12855

Publication Date(Web):2011/10/20

DOI:10.1039/C1DT10695C

Multinuclear multibenzimidazole metal complexes frequently exhibit novel structures and properties, and are an example of versatile compounds in bioinorganic chemistry. In this work, first, we synthesized the mononuclear complex [Cu(ntb)(H2O)]2+, 1, by using tris[(benzimidazol-2-yl)methyl]amine (ntb). Then, a library of multicationic ntb-Cu(II) complexes, 2–9, was prepared by replacing the labile water molecule in 1 with multifunctional carboxylates acting as a bridge linker between two or four ntb-Cu(II) units under slightly acidic or alkaline conditions. Their X-ray crystal structures reveal that these complexes contain one, two or four [Cu(ntb)]2+ units. The pH media used in preparation can control the coordination patterns of the carboxylates and the overall architecture of the complexes, although the Cu(II) centers in the complexes always maintain a five-coordinated structure regardless of the preparation conditions used. Both intra- and inter-molecular π⋯π interactions involved in the benzimidazoles, as well as extensive hydrogen bonding networks in the complexes were observed to occur in the crystal packing. We selected complexes 1 and the dicarboxylate-bridged 4–7 as potential DNA condensers, as they can be dissolved to the required levels for examining their DNA-binding and -condensing properties in the buffer solutions tested (pH 7.4). For these complexes, the effects of the structural variations, including the number of Cu(II) ions and positive charges, length of linkers, and overall architecture, on the DNA-binding and -condensing properties and cytotoxicity were assessed and compared by biophysical measurements. The results from absorption titration showed that the affinities of the complexes for DNA are dominated by both the electrostatic interaction between them and the π⋯π interactions through the intercalation of the benzimidazolyl groups in the complexes into DNA base pairs. The DNA-condensing ability was observed to be mainly controlled by the numbers of positive charges on the complexes, and less correlated with the carboxylate linkers. Moreover, no direct relationships have been found between the apparent DNA-binding affinity and DNA-condensing ability of the complexes. The ability of DNA condensation triggered by 7b that carries four ntb-Cu(II) units and six positive charges is much stronger than those by the other complexes, but it also exhibits the largest cytotoxicity. This work aids in understanding the structure–activity relationships for metal complexes likely acting as a new type of gene-delivery systems.

The chelation targeting metal–Aβ40 aggregates may lead to formation of Aβ40 oligomers

Co-reporter:Yong Zhang, Li-Yuan Chen, Wen-Xing Yin, Jun Yin, Shi-Bing Zhang and Chang-Lin Liu

Dalton Transactions 2011 - vol. 40(Issue 18) pp:NaN4833-4833

Publication Date(Web):2011/03/24

DOI:10.1039/C1DT00020A

The fluorescent chelator (FC-1) was designed by combining a metal-chelating unit and a ThT-based Aβ aggregate-binding fluorescent unit. FC-1 is a cell membrane-penetrable chelator with a moderate chelation ability to Cu2+ and Zn2+ and can target metal–Aβ40 aggregates. Treatment with FC-1 led to enhanced cytotoxicity of the aggregates, because the aggregates were converted into a pool of oligomers.

TOPICS

Abstract

Abstract