In vitro antitumor activity of novel benzimidazole-based Cu(II) complexes.

Four benzimidazole-based Cu(II) complexes: Cu2(p-2-bmp)2Br4 (1), Cu2(p-2-bmp)2Cl4 (2), Cu2(p-2-bmb)2(DMF)2Br4·(CHCl3) (3), and Cu(p-2-bmb)(NO3)2·(CHCl3) (4) were isolated and characterized, where p-2-bmp is 1-((2-(pyridine-2-yl)-1H-benzoimidazol-1-yl)methyl)-1H-pyridine and p-2-bmb is 1-((2-(pyridin-2-yl)-1-benzoimidazol-1-yl)methyl)-1H-benzotriazole. Complexes 1 and 2 have binuclear configurations, 3 has a mononuclear structure, and 4has a one-dimensional (1-D) chain skeleton. To evaluate their potential anticancer effects on human carcinoma cells, anti-proliferation, DNA binding and cleavage, and apoptosis elicitation were examined. Compared with complexes 2, 3, and 4, complex 1 exhibited potent in vitro cytotoxicity toward four cell lines (MCF7, EC109, SH-SY5Y and QBC939), with SH-SY5Y cells demonstrating the most sensitivity. Therefore, further in-depth investigations were performed using complex 1. Absorption titration experiments, circular dichroism spectroscopic studies, and ethidium bromide displacement assays suggested that complex 1 binds to DNA through intercalation, significantly cleaves supercoiled pBR322 DNA, and inhibits DNA transcription. Cell cycle analysis revealed that SH-SY5Y cells were arrested in the G2/M phase after treatment with complex 1. Membrane permeability analysis and nuclear staining of SH-SY5Y cells showed that complex 1 could induce apoptosis.

Amlexanox-modified platinum(IV) complex triggers apoptotic and autophagic bimodal death of cancer cells.

Platinum(IV) prodrugs c,c,t-[PtCl2(NH3)2(OH)(amlexanox)] (MAP) and c,c,t-[PtCl2(NH3)2(amlexanox)2] (DAP) were synthesized by reacting amlexanox with oxoplatin and characterized by NMR, HR-MS, HPLC, and elemental analysis. The complexes could be reduced to platinum(II) species and amlexanox to exert antitumor activity. Generally, MAP was more potent than DAP and cisplatin towards various human cancer cell lines; particularly, it was active in cisplatin-resistant Caov-3 ovarian cancer and A549/DDP lung cancer cells. MAP induced serious damage to DNA, remarkable change in mitochondrial morphology, decrease in mitochondrial membrane potential, release of cytochrome c from mitochondria, and up-regulation of pro-apoptotic protein Bax in Caov-3 cells, thereby leading to evident apoptosis. Meanwhile, MAP markedly promoted the autophagic flux, including affecting the expression of microtubule-associated protein light chain 3 (LC3) and autophagy adaptor protein p62 in Caov-3 cells, with an increase in the ratio of LC3-II/LC3-I and a decrease in p62, thus trigging the occurrence of autophagy. The MAP-induced bimodal cell death mode is uncommon for platinum complexes, which presents a new possibility to invent anticancer drugs with unique mechanism of action.

Thiosemicarbazone N-Heterocyclic Cu(II) complexes inducing nuclei DNA and mitochondria damage in hepatocellular carcinoma cells.

The α-N-Heterocyclic thiosemicarbazones and their metal complexes have been widely investigated as anticancer and antibacterial agents for their broad spectrum of pharmacological properties. Thus, two thiosemicarbazone-based Cu(II) complexes, [Cu2(ptpc)I2] (1) and [Cu(qtpc)I] (2) with thiosemicarbazone ligand (ptpc = 2-(di(pyridin-2-yl)methylene)-N-(2-(trifluoromethyl)phenyl)-hydrazine-1-carbothioamide, qtpc = 2-(quinolin-8-ylmethylene)-N-(2-(trifluoromethyl)phenyl)hydrazine-1-carbothioamide) were synthesized and evaluated for their biological activities. Complexes 1 and 2 are superior to cisplatin in vitro antiproliferative activities toward hepatocellular carcinoma cell line with the half maximal inhibitory concentration value of 0.2 and 2 µM, respectively. A series of spectroscopic assays and the DNA cleavage experiments showed that both complexes can change and distort the conformation of DNA. Molecular docking experiment further demonstrated that complex 1 binds to DNA mainly in groove mode. Meanwhile, benefiting from their good liposolubility, complexes 1 and 2 could easily enter cells, which further triggers cell cycle arrest and apoptosis. Moreover, complexes 1 and 2 caused serious mitochondrial damage, associating with increased the level of reactive oxygen species (ROS) and Ca2+, decreased adenosine triphosphate (ATP) content and mitochondrial membrane potential (Δψm), and transformed mitochondrial morphology. These findings indicated that complexes 1 and 2 might exert their anticancer activity by inducing DNA and mitochondrial damage simultaneously.

Bis{µ-1,3-bis-[(2-methyl-1H-benzimid-azol-1-yl)meth-yl]benzene-κN:N}bis-(diiodidocadmium).

In the title compound, [Cd(2)I(4)(C(24)H(22)N(4))(2)], the 1,3-bis-[(2-methyl-1H-benzimidazol-1-yl)meth-yl]benzene ligand bridges two CdI(2) units, forming a centrosymmetric dinuclear complex. The Cd(II) atom adopts a distorted tetra-hedral coordination geometry. In the crystal, complex mol-ecules are linked into columns parallel to [101] by π-π stacking inter-actions, with centroid-centroid distances of 3.558 (2) Å.

Construction of a Ag(12) high-nuclearity metallamacrocyclic 3D framework.

An unprecedented high-nuclearity metallamacrocycle-based 3D silver framework with formula {[Ag(2)(C(25)H(27)N(6)O)(2)](CH(3)OH)(H(2)O)(0.17)}(n) (1), built on the basis of dodecanuclear silver building blocks, has been synthesized and characterized, and it shows strong phosphorescence emission at 10 K, which is a consequence of the presence of intersystem crossing from singlet to triplet caused by the heavy-atom effect of silver ions.

Theoretical investigation into the cooperativity effect of 1,4-dimethoxy-D-glucosamine complex with Na+ and H2O.

In order to explore the essence of the hydration process of chitin or chitosan in the presence of cation, the cooperativity effects between the H-bonding and Na+···molecule interactions in the 1,4-dimethoxy-D-glucosamine (DMGA) complexes with H2O and Na+ were investigated at the B3LYP/6-311++G(d,p), M06-2X/6-311++G(2df,2p), and ωB97X-D/6-311++G(2df,2p) levels. The result shows that the complexes in which Na+ or H2O is bonded simultaneously to the -NH and -OH groups connected to the C3 atom of DMGA are the most stable. The cooperativity and anti-cooperativity effects occur in DMGA···H2O···DMGA and DMGA···Na+···H2O, while only the cooperativities are confirmed in DMGA···Na+···DMGA. The cooperativity occurs in the DMGA···Na+···H2O complexes without the hydration, while the anti-cooperativity occurs in those with the hydration. Furthermore, the cooperativity and anti-cooperativity in DMGA···Na+···H2O are far stronger than those in DMGA···Na+···DMGA or DMGA···H2O···DMGA. Therefore, a deduction is given that the cooperativity and anti-cooperativity effects play an important role in the hydration of chitin or chitosan in the presence of Na+. When only Na+ is linked with -OH and -NH groups of chitosan or chitin, due to the cooperativity effect, the hydration does not occur. When both Na+ and H2O are linked with -OH and -NH groups, the anti-cooperativities are dominant in controlling of the aggregation process of Na+, H2O, chitosan, and chitin, leading to the possible hydration. Atoms in molecules (AIM) analysis confirms the cooperativity and anti-cooperativity effects. Graphical abstract.

Influence of the introduction of a triphenylphosphine group on the anticancer activity of a copper complex.

Aiming at obtaining new copper complexes with good cytotoxicity against cancer cells, triphenylphosphine (TPP) was introduced to obtain insight into the influence of the co-ligands. In this paper, two copper complexes, Cu(2-pbmq)(CH3OH)Br2 (1) and [Cu(2-pbmq)(TPP)Br]2 (2) were designed, synthesized, and characterized by X-ray crystallography, 2-((2-(pyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)methyl))quinolone (2-pbmq), to investigate the influence of the TPP group on the anticancer activity of the metal complex. Although the presence of the TPP group diminished the intensity of the interaction properties of the complex with DNA, the in vitro anticancer activity and cellular uptake of the TPP-containing complex were markedly superior to those of its TPP-lacking counterpart. Detailed studies on the more potently cytotoxic complex 2 revealed that it accumulated in nucleus, arrested the cell cycle at the G0-G1 phase, causing mitochondrial dysfunction, involving the potential simultaneous mitochondrial membrane collapse, cellular ATP level depletion, and Ca2+ leakage, eventually inducing cell apoptosis. In summary, the introduction of a TPP group enhances the biological activity and cytotoxicity of the complex.

Synthesis and anticancer evaluation of benzo-N-heterocycles transition metal complexes against esophageal cancer cell lines.

Three novel transition metal complexes, Cu(p-2-bmq)Cl2 (1), Zn(p-2-bmq)Cl2 (2) and [Co(p-2-bmq)Cl2]2 (3) (where p-2-bmq = 2-((1-(pyridin-2-yl)-1H-benzoimidazol-2-yl)methyl) quinolone, have been synthesized. The complexes were detected for their cytotoxicity in vitro against four human esophageal cancer cell lines (SMMC7721, BGC823, HCT116 and HT29) by MTT assay. The results showed that they all have anti-tumor cell proliferation activity. E specially, complex 1 exhibited significant cytotoxicity with IC50 value of 15.89 µM against SMMC7721 cells for 72 h. The morphological changes of nuclei by fluorescence staining methods proved that complex 1 could induce intracellular DNA damage. The flow cytometry analysis revealed that the treatment of SMMC7721 cells with complex 1 induced intracellular ROS increased, mitochondrial potential collapse, G2/M-phase arrest, and even apoptosis. These studies should highly valuable for the development of transition metal-based compounds to the potential anticancer medicinal applications.

Novel binuclear and trinuclear metal (II) complexes: DNA interactions and in vitro anticancer activity through apoptosis.

A water soluble trinuclear copper(II) complex and a binuclear cobalt(II) complex, namely Cu3(ppbm)2(SO4)3 (1) and Co2(ppbm)2(NO3)4 (2) (ppbm = 2-(pyridin-2-yl)-1-(pyridin-3-ylmethyl)- 1H-benzo[d]imidazole), have been successfully synthesized and characterized by elemental analysis, IR Spectroscopy, electrospray ionization mass spectra (ESI-MS). The interaction of the new complexes with DNA has been explored using spectroscopy methods, indicating that the complexes 1 and 2 bind to DNA via noncovalent interactions. DNA cleavage experiment suggested that the complex 1 exhibits efficient DNA cleavage activities in the presence of ascorbate (Asc), hydrogen peroxide may serve as the major cleavage active species. The cytotoxicity assay showed that complex 1 exhibited significant inhibitory activity toward the proliferation of several tumor cell lines, with a lower IC50 value than cisplatin and complex 2, indicating that it had the potential to act as effective anticancer agent. The morphological staining assays showed that 1 apparently induced the TFK-1 cells apoptosis. Besides, cellular uptake experiment on TFK-1 cells revealed that complex 1 accumulates primarily inside the nucleus. The apoptosis was attributable to the metal-assisted generation of reactive oxygen species (ROS).

Chemical biology suggests pleiotropic effects for a novel hexanuclear copper(ii) complex inducing apoptosis in hepatocellular carcinoma cells.

A novel hexanuclear copper(ii)-based complex, [Cu6(tpbb)2(NO3)12] (1), was synthesized, which shows potent cytotoxicity to hepatoma carcinoma cells by inducing apoptosis and apoptosis-related processes. Furthermore, mechanistic investigations based on proteomes revealed that the induced apoptosis was mediated by acting on several targets and multiple pathways in a pleiotropic way.

Cation exchange induced tunable properties of a nanoporous octanuclear Cu(II) wheel with double-helical structure.

A double-helical octanuclear Cu(II) wheel 1 with 2.88 nm diameter was prepared through the reaction of a clinical medicine, telmisartan, with copper sulfate. Central copper ions can be partially replaced by bivalent zinc and cobalt ions and fully exchanged by trivalent iron ions. The properties of central metal ion-exchanged variants are much different from those of 1. Central metal ion exchange might be regarded as a powerful and effective method to modify properties from one crystalline material to another only by varying central metal ions under moderate conditions.

DNA interactions and in vitro anticancer evaluations of pyridine-benzimidazole-based Cu complexes.

Copper is an essential element and has redox potential, thus copper complexes have been developed rapidly with the hope of curing cancer. To further develop anticancer agents and investigate their anticancer mechanisms, two Cu complexes, [Cu(bpbb)0.5·Cl·SCN]·(CH3OH) (1) and [Cu2(bpbb)·Br3·(OH)] n (2), were synthesized and characterized using 4,4'-bis((2-(pyridin-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)biphenyl (bpbb), with associated Cu(ii) salts. Complex 1 is a binuclear structure, whereas 2 is a one-dimensional complex. Compared with 2, complex 1 exhibited potent in vitro cytotoxicity toward four cell lines (HCT116, BGC823, HT29, and SMMC7721), and was most effective against HCT116 cells. Therefore, further in-depth investigation was carried out using complex 1. Absorption spectral titration experiments, ethidium bromide displacement assays, and circular dichroism spectroscopic studies suggested that complex 1 binds strongly to DNA by intercalation. Complex 1 exhibited a clear concentration-dependent pBR322 DNA cleavage activity. Inductively coupled plasma mass spectrometry testing implied that complex 1 could enter cells and that DNA was one important target. Cellular level assays suggested that complex 1 activates the generation of intracellular reactive oxygen species, causing DNA damage, promoting cell cycle arrest and mitochondria dysfunction, and inducing cellular apoptosis.

Cytotoxicity, dual-targeting apoptosis induction evaluation of multinuclear cu complexes based on pyrazine-benzimidazole derivative.

To investigate the cytotoxicity and mechanism of action of multinuclear Cu complexes against tumor cell lines, two complexes, Cu6(bpbib)4Br8 (1) and Cu2(bpbib)2(BF4)2Cl2 (2) (bpbib = 1,4-bis((2-(pyrazin-2-yl)-1H-benzo[d]imidazol-1-yl)methyl)benzene) were synthesized and characterized. Both Cu complexes showed high selectivity toward cancer and not normal cells, and the SMMC7721 cell line showed most sensitivity toward both complexes. Complex 1 exhibited more potent cytotoxicity and enhanced cellular uptake, and therefore, was comprehensively investigated. Complex 1 exhibited dual effects in the inhibition of tumor cell proliferation of SMMC7721 cells, causing nuclear DNA damage and mitochondrial dysfunction involving simultaneous reactive oxygen species (ROS) generation and Ca2+ increase. DNA binding studies suggest that intercalation might be the most probable binding mode. Fluorescence spectrometry also detected a medium affinity of complex 1 to bovine serum albumin (BSA) at distinct temperatures and resulted in BSA fluorescence static quenching.

miR­140­5p inhibits human glioma cell growth and invasion by targeting JAG1.

miR­140­5p has been reported to be a tumor suppressor in several types of human cancer, however, little is known about its expression and function in human gliomas. The present study aimed to detect the expression of miR­140­5p in human glioma tissues and cell lines, and to investigate the effect of miR­140­5p on glioma cell growth, invasion and adhesion using in vitro gain­of­function and loss­of­function experiments. Furthermore, the hypothesis that Jagged1 (JAG1) may be a target gene of miR­140­5p was tested. Reverse transcription­quantitative polymerase chain reaction analysis revealed that miR­140­5p was significantly downregulated in human glioma tissues and cell lines compared with normal tissues, and that its expression was correlated with the grade of gliomas. Transfection of a miR­140­5p mimic into SW1783 glioma cells promoted cell growth, invasion and adhesion, as determined by MTT, Transwell and cell adhesion assays respectively. By contrast, transfection of a miR­140­5p inhibitor had the opposite effect. A dual­luciferase reporter assay confirmed that JAG1 was a target gene of miR­140­5p, and miR­140­5p inhibited JAG1 expression both at the mRNA and protein level. In addition, JAG1 overexpression reversed the effect of miR­140­5p on glioma cell growth, invasion and adhesion. In conclusion, the present study is the first to reveal that miR­140­5p acts as a tumor suppressor in human gliomas. JAG1 was demonstrated to be a novel target of miR­140­5p, and miR­140­5p exerted its inhibitory effect on human glioma growth and invasion, partly by suppressing JAG1. The present study may provide useful information toward novel targets for the treatment of gliomas.