A Copper(II) Phenanthroline Metallopeptide That Targets and Disrupts Mitochondrial Function in Breast Cancer Stem Cells

The breast cancer stem cell (CSC) and bulk breast cancer cell potency of a series of metallopeptides containing dichloro(1,10‐phenanthroline)copper(II) and various organelle‐targeting peptide sequences is reported. The mitochondria‐targeting metallopeptide 1 exploits the higher mitochondrial load in breast CSCs over the corresponding non‐CSCs and the vulnerability of breast CSCs to mitochondrial damage to potently and selectively kill breast CSCs. Strikingly, 1 reduces the formation and size of mammospheres to a greater extent than salinomycin, an established CSC‐potent agent. Mechanistic studies show that 1 enters CSC mitochondria, induces mitochondrial dysfunction, generates reactive oxygen species (ROS), activates JNK and p38 pathways, and prompts apoptosis. To the best of our knowledge, 1 is the first metallopeptide to selectivity kill breast CSCs in vitro.     

A Triangular Platinum(II) Multinuclear Complex with Cytotoxicity Towards Breast Cancer Stem Cells

The preparation of multinuclear metal complexes offers a route to novel anticancer agents and delivery systems. The potency of a novel triangular multinuclear complex containing three platinum atoms, Pt‐3 , towards breast cancer stem cells (CSCs) is reported. The trinuclear platinum(II) complex, Pt‐3 exhibits selective toxicity towards breast CSCs over bulk breast cancer cells and non‐tumorigenic breast cells. Remarkably, Pt‐3 inhibits the formation, size, and viability of mammospheres to a better extent than salinomycin, an established CSC‐potent agent, and cisplatin and carboplatin, clinically used platinum drugs. Mechanism of action studies show that Pt‐3 effectively enters breast CSCs, penetrates the nucleus, induces genomic DNA damage, and prompts caspase‐dependent apoptosis. To the best of our knowledge, Pt‐3 is the first multinuclear platinum complex to selectively kill breast CSCs over other breast cell types.     

Salinomycin Derivatives Kill Breast Cancer Stem Cells by Lysosomal Iron Targeting

Salinomycin ( 1 ) exhibits a large spectrum of biological activities including the capacity to selectively eradicate cancer stem cells (CSC), making it and its derivatives promising candidates for the development of drug leads against CSC. It has been previously shown that salinomycin and its C20-propargylamine derivative (Ironomycin ( 2 )) accumulate in lysosomes and sequester iron in this organelle. Herein, a library of salinomycin derivatives is reported, including products of C20-amination, C1-esterification, C9-oxidation, and C28-dehydration. The biological activity of these compounds is evaluated against transformed human mammary epithelial HMLER CD24^low/CD44^high cells, a well-established model of breast CSC, and HMLER CD24^high/CD44^low cells deprived of CSC properties. Unlike other structural alterations, derivative 4 , which displays a cyclopropylamine at position C20, showed a strikingly low IC₅₀ value of 23 nm against HMLER CD24^low/CD44^high cells. This study provides highly selective molecules to target the CSC niche, a potential interesting advance for drug development to prevent cancer resistance.     

Breast Cancer Stem Cell Potency of Nickel(II)-Polypyridyl Complexes Containing Non-steroidal Anti-inflammatory Drugs

We report the breast cancer stem cell (CSC) potency of two nickel(II)-3,4,7,8-tetramethyl-1,10-phenanthroline complexes, 1 and 3 , containing the non-steroidal anti-inflammatory drugs (NSAIDs), naproxen and indomethacin, respectively. The nickel(II) complexes, 1 and 3 kill breast CSCs and bulk breast cancer cells in the micromolar range. Notably, 1 and 3 display comparable or better potency towards breast CSCs than salinomycin, an established CSC-active agent. The complexes, 1 and 3 also display significantly lower toxicity towards non-cancerous epithelial breast cells than breast CSCs or bulk breast cancer cells (up to 4.6-fold). Mechanistic studies suggest that 1 and 3 downregulate cyclooxygenase-2 (COX-2) in breast CSCs and kill breast CSCs in a COX-2 dependent manner. Furthermore, the potency of 1 and 3 towards breast CSCs decreased upon co-treatment with necroptosis inhibitors (necrostatin-1 and dabrafenib), implying that 1 and 3 induce necroptosis, an ordered form of necrosis, in breast CSCs. As apoptosis resistance is a hallmark of CSCs, compounds like 1 and 3 , which potentially provide access to alternative (non-apoptotic) cell death pathways could hold the key to overcoming hard-to-kill CSCs. To the best of our knowledge, 1 and 3 are the first compounds to be associated to COX-2 inhibition and necroptosis induction in CSCs.     

Ultrasensitive Label‐free Electrochemical Immunosensors for Multiple Cell Surface Biomarkers on Liver Cancer Stem Cells

Liver cancer is one of the most widely spread cancers in the world. Cancer stem cells (CSCs) are a small subpopulation of liver cancer cells that are thought to be responsible for relapse of cancer and the resistance to chemotherapy. Detection of CSCs is highly demanded for screening patients who are at high risk for developing metastatic cancers. However, the current methodologies for CSCs detection are sophisticated, expensive and not reliable. Here, we report the development of a label‐free impedance immunosensors for liver CSC quantification using four established CSC surface biomarkers (CD44, CD90, CD133/2 and OV‐6). The immunosensors were simply fabricated by the covalent attachment of four biomarkers specific antibodies on gold electrodes using cysteamine/phenylene isothiocyanate linker. Electrochemical impedance spectroscopy was employed to detect the binding of the cells to the immunosensors. The binding of the CSCs to the gold electrode surface retards the access of ferri‐ferrocyanide redox molecules to the electrode leading to enhancement in the charge transfer resistance (R_ct) which represents the basis of the detection signal. The developed electrochemical immunosensors showed high sensitivity and selectivity for CSC detection with a wide linear range from 1 × 10¹ to 1× 10⁴ cells/mL with a limit of detection of 1 cell/ml. This work represents a new, accurate, simple and low cost method for the detection of liver CSC that might help in the early diagnosis of metastatic disease and cancer relapse.     

Anomalous coordination behaviour of 6‐methyl‐2‐oxo‐1,2‐dihydroquinoline‐3‐carboxaldehyde‐4(N)‐substituted Schiff bases in Cu(II) complexes: Studies of structure,biomolecular interactions and cytotoxicity

A series of copper(II) complexes containing 6‐methyl‐2‐oxo‐1,2‐dihydroquinoline‐3‐carboxaldehyde‐derived Schiff bases have been synthesized and characterised using various analytical and spectroscopic techniques. X‐ray crystallographic analysis confirmed the true coordinating nature of ligands with copper ion. The ligands exhibited ONS tridentate neutral and monobasic coordination. The spectroscopic results evidenced the interaction of the ligands and their copper(II) complexes with nucleic acid/serum albumin. Further, the complexes showed significant activity against human skin cancer cell line (A431) and less toxicity against human keratinocyte cell line (HaCaT). Acridine orange/propidium iodide dual staining studies indicated that the major cause of A431 cell death was through necrosis. By comparing the biological activity of all the ligands, Cu(II) complexes and standard (cisplatin), complex [Cu(H‐6MOQtsc‐Ph)(H₂O)]?NO₃ ( 4 ) exhibited better activity than others, the activity being arranged as follows: 4  >  1  > cisplatin >  3  >  2 .     

Homo‐ and heteropolynuclear copper(II) complexes containing a new diimine–dioxime ligand and 1,10‐phenanthroline: synthesis,characterization, solvent‐extraction studies,catalase‐like functions and DNA cleavage abilities

A series of homo‐, heterodinuclear and homotrinuclear copper(II) complexes containing a new Schiff base ligand and 1,10‐phenanthroline were synthesized. Based on results of elemental analyses, FTIR, ¹H‐ and ¹³C‐NMR spectra, conductivity measurements and magnetic susceptibility measurements, the complexes had general compositions {[Cu(L)(H₂O)M(phen)₂](ClO₄)₂ [M = Cu(II), Mn(II), Co(II)]} and {[Cu₃(L)₂(H₂O)₂](ClO₄)₂}. The metal:L:phen ratio is 2:1:2 for the dinuclear copper(II) complexes and the metal:L ratio was 3:2 for the trinuclear copper(II) complex. The liquid–liquid extraction of various transition metal cations [Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Pb(II), Cd(II), Hg(II)] from the aqueous phase to the organic phase was carried out using the diimine–dioxime ligand. It was concluded that the ligand can effectively be used in solvent extraction of copper(II) from the aqueous phase to the organic phase. Furthermore, catalytic activitiy of the complexes for the disproportionation of hydrogen peroxide was also investigated in the presence of imidazole. Dinuclear copper(II)–manganese(II) complex has some similarity to manganese catalase in structure and activity. The interaction between these complexes and DNA has also been investigated by agarose gel electrophoresis; we found that the homo‐ and heterodinuclear copper complexes can cleave supercoiled pBR322 DNA to nicked and linear forms in the presence of H₂O₂. Copyright © 2009 John Wiley & Sons, Ltd.     

3‐(4‐Cyano­phenyl)­pentane‐2,4‐dione and its copper(II) complex

The β‐diketone 3‐(4‐cyano­phenyl)­pentane‐2,4‐dione crystallizes as the enol tautomer 4‐(2‐hydroxy‐4‐oxopent‐2‐en‐3‐yl)­benzo­nitrile, C₁₂H₁₁NO₂, (I), with an intramolecular O—H⋯O hydrogen bond [O⋯O = 2.456 (2) Å]. Reaction of (I) with copper acetate monohydrate in the presence of triethyl­amine leads to the formation of the copper(II) complexbis­[3‐(4‐cyano­phenyl)­pentane‐2,4‐dionato‐κ²O,O]copper(II), [Cu(C₁₂H₁₀NO₂)₂], (II). In the structure of (II), the Cu atom is coordinated by four β‐diketonate O atoms in a slightly distorted square‐planar geometry, with Cu—O distances in the range 1.8946 (11)–1.9092 (11) Å. The nitrile moieties in (II) make it a candidate for reaction with other metal ions to produce supramolecular structures.     

Dinukleare Kupfer(II)‐Komplexe mit chiralen makrocyclischen Liganden vom Schiff‐Basen‐Typ: Synthesen und Strukturen

Complexes with Macrocyclic Ligands. V Dinuclear Copper(II) Complexes with Chiral Macrocyclic Ligands of Schiff‐Base Type: Syntheses and Structures The synthesis and properties of four chiral, dinuclear, macrocyclic, cationic copper(II) complexes, [Cu₂(L^m,n)]²⁺ ( 1 – 4 ), are described. The two symmetrical compounds [Cu₂(L^2,2)][ClO₄]₂ ( 1 and 2 ) were synthesized in a one‐step reaction from 2,6‐diformyl‐4‐tert.‐butylphenol, copper(II)‐perchlorate and the chiral diamine (1S,2S)‐1,2‐diphenylethylenediamine (synthesis of 1 ) and (1R,2R)‐1,2‐diaminocyclohexane (synthesis of 2 ), respectively. For the synthesis of the two unsymmetrical compounds [Cu₂(L^Ph,n)][ClO₄]₂ ( 3 and 4 ) the mononuclear, neutral copper(II) complex [CuL^Ph] ( 5 ) [synthesized from 2,6‐diformyl‐4‐tert.‐butylphenol, copper(II)‐acetate and 1,2‐phenylenediamine] was reacted with (1R,2R)‐1,2‐diaminocyclohexane (synthesis of 3 ) and (S)‐1,1′‐binaphthyl‐2,2′‐diamine (synthesis of 4 ), respectively. The structures of the two unsymmetrical copper(II) compounds ( 3 and 4 ) were determined by X‐ray diffraction.     

High‐Throughput,Label‐Free Isolation of Cancer Stem Cells on the Basis of Cell Adhesion Capacity

Herein we report a microfluidics method that enriches cancer stem cells (CSCs) or tumor‐initiating cells on the basis of cell adhesion properties. In our on‐chip enrichment system, cancer cells were driven by hydrodynamic forces to flow through microchannels coated with basement membrane extract. Highly adhesive cells were captured by the functionalized microchannels, and less adhesive cells were collected from the outlets. Two heterogeneous breast cancer cell lines (SUM‐149 and SUM‐159) were successfully separated into enriched subpopulations according to their adhesive capacity, and the enrichment of the cancer stem cells was confirmed by flow cytometry biomarker analysis and tumor‐formation assays. Our findings show that the less adhesive phenotype is associated with a higher percentage of CSCs, higher cancer‐cell motility, and higher resistance to chemotherapeutic drugs.     

High‐Throughput,Label‐Free Isolation of Cancer Stem Cells on the Basis of Cell Adhesion Capacity

Herein we report a microfluidics method that enriches cancer stem cells (CSCs) or tumor‐initiating cells on the basis of cell adhesion properties. In our on‐chip enrichment system, cancer cells were driven by hydrodynamic forces to flow through microchannels coated with basement membrane extract. Highly adhesive cells were captured by the functionalized microchannels, and less adhesive cells were collected from the outlets. Two heterogeneous breast cancer cell lines (SUM‐149 and SUM‐159) were successfully separated into enriched subpopulations according to their adhesive capacity, and the enrichment of the cancer stem cells was confirmed by flow cytometry biomarker analysis and tumor‐formation assays. Our findings show that the less adhesive phenotype is associated with a higher percentage of CSCs, higher cancer‐cell motility, and higher resistance to chemotherapeutic drugs.     

CD133 and CD133‐regulated nucleophosmin linked to 5‐fluorouracil susceptibility in human colon cancer cell line SW620

Cancer stem cells (CSCs) are known to be resistant to conventional chemotherapy and radiotherapy. Specific CSC targeting and eradication is therefore a therapeutically important challenge. CD133 is a colorectal CSC marker with unknown function(s). Assessing proteomic changes induced by CD133 may provide clues not only to new CD133 functions but also to the chemotherapy and radiation susceptibility of colon cancer cells. To identify the proteins affected by CD133, CD133‐positive (CD133+), and CD133‐negative (CD133–) human colon cancer cells were obtained by cell sorting. Whole proteomes were profiled from SW620/CD133+ and SW620/CD133– cells and analyzed by 2D‐based proteome analysis. Nucleophosmin (NPM1) was identified as a protein regulated by CD133. CD133 protein level was not affected by NPM1, and an interaction between the two proteins was not observed. CD133 and NPM1 protein levels were positively correlated in 11 human colon cancer cell lines. The CD133+ subpopulation percentage or its value normalized against CD133 protein level was only linked to intrinsic susceptibility of human colon cancer cells to 5‐fluorouracil (5‐FU). However, either suppression of CD133 or NPM1 significantly increased 5‐FU susceptibility of SW620. The present study suggests that CD133‐regulated NPM1 protein level may provide a clue to novel CD133 function(s) linked to human colon cancer cell susceptibility to chemotherapy.     

Two‐dimensional square‐grid frameworks formed by self‐associating copper(II) complexes with 1‐(3‐pyridyl)‐ and 1‐(4‐pyridyl)‐substituted butane‐1,3‐diones

In bis­[1‐(3‐pyridyl)butane‐1,3‐dionato]copper(II) (the Cu atom occupies a centre of inversion), [Cu(C₉H₈NO₂)₂], (I), and bis­[1‐(4‐pyridyl)butane‐1,3‐dionato]copper(II) methanol solvate, [Cu(C₉H₈NO₂)₂]·CH₃OH, (II), the O,O′‐chelating diketonate ligands support square‐planar coordination of the metal ions [Cu—O = 1.948 (1)–1.965 (1) Å]. Weaker Cu⋯N inter­actions [2.405 (2)–2.499 (2) Å], at both axial sides, occur between symmetry‐related bis­(1‐pyridylbutane‐1,3‐dion­ato)copper(II) mol­ecules. This causes their self‐organization into two‐dimensional square‐grid frameworks, with uniform [6.48 Å for (I)] or alternating [4.72 and 6.66 Å for (II)] inter­layer separations. Guest methanol mol­ecules in (II) reside between the distal layers and form weak hydrogen bonds to coordinated O atoms [O⋯O = 3.018 (4) Å].     

Retracted: Studies of proteasome inhibition and antitumor activity by novel amino acid‐polypyridine‐copper complexes

Five innovative ternary copper (II) complexes [Cu (OH‐PIP)(Phe)Cl]( 1 ), [Cu (OH‐PIP)(Gly)(H₂O)]NO₃·2H₂O ( 2 ), [Cu (OH‐PIP)(Ala)(Cl)]·H₂O ( 3 ), [Cu (OH‐PIP)(Met)]PF₆·2H₂O ( 4 ), and [Cu (OH‐PIP)(Gln)(H₂O)]Cl·3H₂O ( 5 ) have been synthesized and characterized by infrared spectroscopy, elemental analysis, and single crystal X‐ray diffraction analysis. X‐ray crystallography showed that all Cu atoms were five‐coordinated in a square‐pyramidal configuration. They are screened for in vitro cytotoxicity against a panel of human cancer cell lines CAL‐51, MDA‐MB‐231, HeLa, MCF‐7, SGC‐7901, A549, K562, and SMMC‐7721. The most promising results were achieved for complexes 1 to 5 , with the IC₅₀ values in the range of 0.082μM to 0.69μM (against CAL‐51 cell lines). The anticancer activities against CAL‐51, MDA‐MB‐231, and MCF‐7 were higher than that of Carboplatin. The mechanism studies showed that complexes 1 to 5 could inhibit proteasome activity, induce apoptosis, and inhibit cell proliferation, indicating their great potential as proteasome inhibitors for triple‐negative breast cancer therapy.     

Syntheses,Crystal Structures,and Properties of Three Copper(II) Complexes Constructed by 4‐(4,6‐Bis(1H‐pyrazol‐1‐yl)‐1,3,5‐triazin‐2‐yl)morpholine

Three copper(II) complexes of the polydentate N‐donor ligand [4‐(4,6‐bis(1H‐pyrazol‐1‐yl)‐1,3,5‐triazin‐2‐yl)morpholine] (L) with chlorides, nitrates, and perchlorates as anions, namely, [CuCl₂(L)] · 0.5(MeCN) ( 1 ), [Cu(NO₃)₂(H₂O)(L)] · (MeCN) ( 2 ), and [Cu(L)₂](ClO₄)₂ · (MeCN) ( 3 ) were synthesized and structurally characterized by IR, elemental analysis and X‐ray crystallographic analysis. In these complexes, the L ligand binds the copper(II) cation in the tridentate N₃ form. The coordination arrangement around the central copper(II) atom is distorted square‐pyramidal in 1 but it is distorted octahedral in 2 and 3 . The interesting noncovalent interactions such as hydrogen bonds, π–π stacking, and anion–π interactions present in the solid‐state structures are discussed. The crystal results reveal that the counteranions play important roles in determining the diverse structures of these complexes. Moreover, the PXRD, TG, DRS, and fluorescence properties of compounds 1 – 3 were investigated.     

In vitro anti‐proliferative and in silico docking studies of heteroleptic copper(II) complexes of pyridazine‐based ligands and ciprofloxacin

Three heteroleptic copper(II) complexes of the type [Cu(L^1–3)(cf)(ClO₄)] ( 1 – 3 ), where cf = ciprofloxacin, have been synthesized using pyridazine‐based ligands 3‐chloro‐6‐(salicylidenehydrazinyl)pyridazine (HL¹), 3‐chloro‐6‐(4‐diethylaminosalicylidenehydrazinyl)pyridazine (HL²) and 3‐chloro‐6‐(5‐bromosalicylidenehydrazinyl)pyridazine (HL³). Electronic spectral data and magnetic moment values suggest octahedral geometry for the synthesized copper(II) complexes. Electrochemical data of the copper(II) complexes present an irreversible one‐electron reduction wave in the cathodic potential region (E_pc) between ?0.631 and ?0.670 V. Frontier molecular orbital calculations were carried out, and the obtained low‐energy gap supports the bio‐efficacy of the complexes. All the complexes were screened for their in vitro cytotoxicity activity against three human cancerous (breast adenocarcinoma (MCF‐7), hepatoma (HepG‐2) and cervical (HeLa)) and one non‐cancerous (non‐tumorigenic human dermal fibroblast (NHDF)) cell lines using MTT assay, in which complex 2 exhibited higher activity. The apoptosis induction by the complexes was analysed using the Hoechst dye staining method with MCF‐7 cell line, which indicates higher apoptotic activity of complex 2 . A molecular docking study was carried out to ascertain the binding affinity of the synthesized heteroleptic copper(II) complexes with phosphoinositide 3‐kinase gamma (PI3Kγ) receptor.     

Influence of Cu(II) Ions on the Mechanism of the Ring Transformation of S‐(2‐Oxotetrahydrofuran‐3‐yl)‐N‐(4‐methoxyphenyl)isothiouronium Bromide

The effect of additional Cu(II) ions on the rate of transformation of S‐(2‐oxotetrahydrofuran‐3‐yl)‐N‐(4‐methoxyphenyl)isothiouronium bromide ( 1 ) into 5‐(2‐hydroxyethyl)‐2‐[(4‐methoxyphenyl)imino]‐1,3‐thiazolidin‐4‐one ( 2 ) has been studied in aqueous buffer solutions. The reaction acceleration in acetate buffers is caused by the formation of a relatively weakly bonded complex (K_c = 600 L·mol^?1) of substrate with copper(II) acetate in which the Cu(II) ion acts as a Lewis acid coordinating the carbonyl oxygen and facilitating the intramolecular attack, leading to the formation of intermediate T^±. The formation of the complex of copper(II) acetate with free isothiourea in the fast preequilibrium (K_c) is followed by the rate‐limiting transformation (k_Cu) of this complex. At the high concentrations of the acetate anions, the reaction is retarded by the competitive reaction of these ions with copper(II) acetate to give an unreactive complex [Cu(OAc)₄]^2?_. The influence of Cu(II) ions on the stability of reaction intermediates and the leaving group ability of the alkoxide‐leaving group compared to the Cu(II)‐uncatalyzed reaction is also discussed.     

Synthesis and structure of a new ternary monocopper(II) complex containing mixed ligands of 2,2′‐diamino‐4,4′‐bithiazole and picrate: in vitro anticancer activity,molecular docking and reactivity towards DNA

A new ternary monocopper(II) complex with co‐ligands of 2,2′‐diamino‐4,4′‐bithiazole (dabt) and picrate (pic), namely [Cu(dabt)(pic)₂], has been synthesized and characterized using elemental analyses, molar conductance measurements, infrared and electronic spectral studies and single‐crystal X‐ray diffraction. The crystal structure analyses revealed that the copper(II) ion has a {CuN₂O₄} distorted octahedral coordination environment. The hydrogen bonding interactions contribute to a three‐dimensional supramolecular structure in the crystal. The reactivity towards herring sperm DNA showed that the copper(II) complex can interact with DNA in the mode of intercalation. The molecular docking of the complex with DNA sequence d(ACCGACGTCGGT)₂ demonstrated that the copper(II) complex is stabilized by hydrogen bonding interaction. The in vitro anticancer activities suggested that the copper(II) complex is active against selected tumor cell lines. The effects of the two co‐ligands in the copper(II) complex on DNA‐binding events and in vitro anticancer activity are preliminarily discussed. Copyright © 2016 John Wiley & Sons, Ltd.     

Kristallstrukturen ferrocenhaltiger 1,3‐Diketon‐ und Enaminoketon‐Derivate

Crystal Structures of 1,3‐Diketone and Enaminoketone Derivatives Containing Ferrocene The crystal structures of the 1,3‐diketones 2,4‐dioxo‐4‐ferrocenyl‐butanoic acid ethylester ( 1 ) und ferrocene‐1,1′‐bis(2,4‐dioxo‐butanoic acid ethylester) ( 2 ) have been determined. Through conversion of 1 by Cu(ac)₂ · H₂O in THF the copper(II) complex aqua‐bis(3‐ethoxycarbonyl‐1‐ferrocenyl‐propane‐1,3‐dionato) copper(II) ( 1 a ) has been obtained, which is structurally characterized too. The structures of the enaminoketones 2,2′‐(1,4‐phenylenediamino)‐bis(4‐ferrocenyl‐4‐oxo‐but‐2‐enoic acid ethylester) ( 3 ) and ferrocene‐1,1′‐bis(4‐oxo‐2‐phenylamino‐but‐2‐enoic acid ethylester) ( 4 ) have been determined by X‐ray analysis as well. Electrochemical studies completed the structural investigations.