Methyl substituent effect on one‐dimensional copper(II) coordination polymers containing biologically active ligands: Synthesis,characterization, DNA interactions and cytotoxicities

Three novel water‐soluble copper(II) complexes – {[Cu(phen)(trp)]ClO₄·3H₂O}_n ( 1 ), {[Cu(4‐mphen)(trp)]ClO₄·3H₂O}_n ( 2 ) and [[Cu(dmphen)(trp)(MeOH)][Cu(dmphen)(trp)(NO₃)]]NO₃ ( 3 ) (phen: 1,10‐phenanthroline; 4‐mphen: 4‐methyl‐1,10‐phenanthroline; dmphen: 4,7‐dimethyl‐1,10‐phenanthroline; trp: l ‐tryptophan) – have been synthesized and characterized using various techniques. Complexes 1 and 2 are isostructural, and exist as one‐dimensional coordination polymers. Complex 3 consists of two discrete copper(II) complexes containing [Cu(trp)(dmphen)(MeOH)]⁺, [Cu(trp)(dmphen)(NO₃)] and one nitrate anion. The binding interaction of the complexes with calf thymus DNA (CT‐DNA) was investigated using thermal denaturation, electronic absorption and emission spectroscopic methods, revealing that the complexes could interact with CT‐DNA via a moderate intercalation mode. The binding activity of the complexes to CT‐DNA follows the order: 3  >  2 > 1 . The pUC19 DNA cleavage activity of the complexes was investigated in the absence and presence of external agents using the agarose gel electrophoresis method. Especially, in the presence of H₂O₂ as an activator, the pUC19 DNA cleavage abilities of the complexes are clearly enhanced at low concentration. Addition of hydroxyl radical scavenger dimethylsulfoxide shows a marked inhibition of the pUC19 DNA cleavage activity of the complexes. In vitro cytotoxic effect of the complexes was examined on human tumor cell lines (Caco‐2, A549 and MCF‐7) and healthy cells (BEAS‐2B). The potent cytotoxic effect of complex 3 , with IC₅₀ values of 1.04, 1.16 and 1.72 μM, respectively, is greater relative to clinically used cisplatin (IC₅₀ = 22.70, 31.1 and 22.2 μM) against the Caco‐2, A549 and MCF‐7 cell lines.     

Synthesis,spectral, structural characterization and biological activity of new palladium(II) complexes containing 3‐acetyl‐8‐methoxy‐2H‐chromen‐2‐one derived Schiff bases

Four different mononuclear palladium(II) complexes of 3‐acetyl‐8‐methoxycoumarin Schiff bases were synthesized and characterized by spectrochemical techniques. Further analysis through X‐ray crystallography confirmed the structures of the complexes. Their interactive ability with Calf Thymus DNA and protein (Bovine Serum Albumin and Human Serum Albumin) were investigated by means of absorption and emission methods. The intercalative mode of binding with DNA was supported by EB displacement studies and viscosity measurements. Configurational changes that occurred in the proteins have been analysed with the help of 3D fluorescence studies. The complexes were shown to have good antimicrobial activity against the tested bacterial and fungal pathogens. In addition, antiproliferative activity of the complexes was evaluated on A549 and MCF‐7 cell lines and the complexes were comparatively more active than the standard drug cisplatin. Among the compounds, complex 3 was the most effective against MCF‐7 (IC₅₀ value of 5.20 ± 0.15 μM) and A549 (5.09 ± 0.13 μM) compared with the other complexes 1 (6.48 ± 0.17 μM; 5.98 ± 0.09 μM), 2 (5.53 ± 0.12 μM; 5.85 ± 0.11 μM), 4 (6.73 ± 0.19 μM; 6.63 ± 0.16 μM) and cisplatin (16.79 ± 0.08 μM; 15.10 ± 0.05 μM) respectively. LDH and NO release assays confirmed the cytotoxic potential of the synthesized complexes.     

Synthesis,Structural, Biological Evaluation,Molecular Docking and DFT Studies of Co(II), Ni(II), Cu(II), Zn(II), Cd(II) and Hg(II) Complexes bearing Heterocyclic Thiosemicarbazone ligand

A new ligand, 2‐aminonicotinaldehyde N‐methyl thiosemicarbazone (ANMTSC) and its metal complexes [Co(II) ( 1 ); Ni(II) ( 2 ); Cu(II) ( 3 ); Zn(II) ( 4 ); Cd(II) ( 5 ) or Hg(II) ( 6 )] were synthesized. The compounds were characterized by analytical methods and various spectroscopic (infrared, magnetic, thermal, ¹H, ¹³C NMR, electronic and ESR) tools. The structure of ANMTSC ligand was confirmed by single crystal X‐ray diffraction study. The spectral data of metal complexes indicate that the ligand acts as mononegative, bidentate coordination through imine nitrogen (N) and thiocarbonyl sulphur (S^?) atoms. The proposed geometries for complexes were octahedral ( 1 – 2 ), distorted octahedral ( 3 ) and tetrahedral ( 4 – 6 ). Computational details of theoretical calculations (DFT) of complexes have been discussed. The compounds were subjected to antimicrobial, antioxidant, antidiabetic, anticancer, ROS, studies and EGFR targeting molecular docking analysis. Complex 5 has shown excellent antibacterial activity and the complexes 2 and 5 have shown good antifungal activity. The complexes 1 and 4 displayed good antioxidant property with IC₅₀ values of 11.17 ± 1.92 μM and 10.79 ± 1.85 μM, respectively compared to standard. In addition, in vitro anticancer activity of the compounds was investigated against HeLa, MCF‐7, A549, IMR‐32 and HEK 293 cell lines. Among all the compounds, complex 4 was more effective against HeLa (IC₅₀ = 10.28 ± 0.69 μM), MCF‐7 (IC₅₀ = 9.80 ± 0.83 μM), A549 (IC₅₀ = 11.08 ± 0.57 μM) and IMR‐32 (10.41 ± 0.60 μM) exhibited superior anticancer activity [IC₅₀ = 9.80 ± 0.83 ( 4 ) and 9.91 ± 0.37 μM ( 1 )] against MCF‐7 compared with other complexes.     

Synthesis,characterization and biological evaluation of a cobalt(II) complex with 5‐chloro‐8‐hydroxyquinoline as anticancer agent

A new cobalt(II) complex ( 1 ) of 5‐chloro‐8‐hydroxyquinoline was prepared and structurally characterized using infrared spectroscopy, electrospray ionization mass spectrometry, elemental analysis, single‐crystal X‐ray diffraction as well as powder X‐ray diffraction. Its biological activities including DNA binding and anticancer activity were investigated. The DNA binding study of complex 1 suggested that it interacted with calf thymus DNA mainly via an intercalative binding mode. The in vitro anticancer activity of complex 1 was screened against a series of tumor cell lines as well as the normal liver cell line HL‐7702 using MTT assay. complex 1 showed much higher cytotoxicity than corresponding metal salt and ligand towards the five tested tumor cell lines, in which T‐24 was the most sensitive tumor cell line towards 1, with IC₅₀ value of 7.04 ± 0.06 μM. complex 1 was found to greatly induce cell cycle arrest in T‐24 cells at S phase, and consequently to induce cell apoptosis in a dose‐dependent mode suggested by cell apoptosis analysis via Hoechst 33258 and acridine orange/ethidium bromide staining assays. The cell apoptosis mechanism of 1 was studied targeting the mitochondrion‐mediated pathway, since the apoptotic mechanism in the T‐24 cells treated by 1 was investigated by reactive oxygen species (ROS) detection, intracellular calcium concentration measurement and caspase‐9/3 activity assay. The results suggested that the cell apoptosis induced by 1 was closely related to the loss of mitochondrial membrane potential, ROS production and enhancement of intracellular [Ca²⁺], which would trigger the caspase‐9/3 activation via a mitochondrial dysfunction pathway. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis,structural characterization and DNA binding affinity of new bioactive nano‐sized transition metal complexes with sulfathiazole azo dye for therapeutic applications

The azo dye ligand 4‐(5‐chloro‐2‐hydroxyphenylazo)‐N‐thiazol‐2‐ylbenzenesulfonamide (H₂L) formed by the coupling reaction of sulfathiazole and p‐chlorophenol was synthesized and characterized using elemental analysis and Fourier transform infrared (FT‐IR) as well as UV–visible spectra. Nano‐sized divalent Cu, Co, Ni, Mn and Zn complexes of the synthesized azo dye ligand were prepared and investigated using various spectroscopic and analytical techniques. Elemental and thermal analyses indicated the formation of the Cu(II), Ni(II) and Mn(II) complexes in a molar ratio of 1:2 (L:M) while Co(II) and Zn(II) complexes exhibited a 1:1 (M:L) ratio. FT‐IR spectral studies confirmed the coordination of the ligand to the metal ions through the phenolic hydroxyl oxygen, azo nitrogen, sulfonamide oxygen and/or thiazole nitrogen. The geometric arrangements around the central metal ions were investigated applying UV–visible and electron spin resonance spectra, thermogravimetric analysis and molar conductance measurements. X‐ray diffraction patterns revealed crystalline nature of H₂L and amorphous nature of all synthesized complexes. Transmission electron microscopy images confirmed nano‐sized particles and their homogeneous distribution over the complex surface. Antibacterial, antifungal and antitumour activities of the investigated complexes were screened compared with familiar standard drugs to confirm their potential therapeutic applications. The Cu(II) complex showed IC₅₀ of 3.47 μg ml^?1 (5.53 μM) against hepatocellular carcinoma cells, which means that it is a more potent anticancer drug compared with the standard cisplatin (IC₅₀ = 3.67 μg ml^?1 (12.23 μM)). Furthermore, the Co(II), Ni(II), Cu(II) and Zn(II) complexes displayed IC₅₀ greater than that of an applied standard anticancer agent (5‐flurouracil) towards breast carcinoma cells. Hence, these complexes can be considered as promising anticancer drugs. The mode of binding of the complexes with salmon serum DNA was determined through electronic absorption titration and viscosity studies.     

Ferrocene conjugated copper(II) complexes of terpyridine and traditional Chinese medicine (TCM) anticancer ligands showing selective toxicity towards cancer cells

Six novel mixed‐ligand copper(II) complexes, namely, [Cu(R‐tpy)(L)]NO₃ ( 1–6 ), where R‐tpy is 4′‐phenyl‐2,2′:6′,2′′‐terpyridine (Ph‐tpy; 1–3 ) and 4′‐ferrocenyl‐2,2′:6′,2′′‐terpyridine (Fc‐tpy; 4–6 ), L is the bidentate O,O donor monoanion of plumbagin (5‐hydroxy‐2‐methyl‐1,4‐naphthoquinone; plum in 1 , 4 ), chrysin (5,7‐dihydroxyflavone; chry in 2 , 5 ) and curcumin (bis(4‐hydroxy‐3‐methoxyphenyl)‐1,6‐diene‐3,5‐dione; curc in 3 , 6 ) have been synthesized and characterized and their in vitro cytotoxicity against cancer cells is evaluated. The energy optimized structures and the frontier orbitals of the complexes have been obtained from the DFT calculations. Complexes 4–6 with a conjugated ferrocenyl moiety and TCM anticancer ligands, namely, plum (in 4 ), chry (in 5 ) and curc (in 6 ) showed potent cytotoxicity giving respective IC₅₀ values of 1.2 μM, 0.62 μM and 0.21 μM in HeLa and 2.0 μM and 1.0 μM and 0.34 μM in MCF‐7 cancer cells while being much less toxic to MCF‐10A normal cells (IC₅₀: 8.3‐17.1 μM). In contrast, complexes 1–3 with a conjugated phenyl moiety were appreciably less toxic to HeLa cells with respective IC₅₀ values of 10.4 μM, 8.1 μM and 5.5 μM when compared with their ferrocenyl analogues 4–6 . Mechanistic studies using Hoechst staining and Annexin‐V‐FITC assays on cancer cells revealed an apoptotic pathway of cell death induced by the complexes. Fluorescence imaging study showed that complex 6 having curcumin as ligand localized primarily in the mitochondria of HeLa cells. Thus, we demonstrate in this study that ferrocene conjugation to copper(II) complexes of TCM anticancer ligands significantly increases the selectivity and cytotoxicity of the resulting complexes towards cancer cells over normal cells.     

Studies of proteasome inhibition and apoptosis induction in triple‐negative breast cancer cells by novel amino acid–polypyridine–copper complex

An innovative ternary copper(II) complex, [Cu(Cl‐PIP)(Tyr)Cl]_n, has been synthesized and characterized using infrared spectroscopy, elemental analysis and single‐crystal X‐ray diffraction analysis. X‐ray crystallography indicates that the Cu atom is five‐coordinated in a square‐pyramidal configuration. The unit forms a one‐dimensional chain along the crystallographic c‐axis. The complex was screened for cytotoxicity against a panel of eight human cancer cell lines, namely MDA‐MB‐231, CAL‐51, K562, HeLa, SGC‐7901, A549, MCF‐7 and SMMC‐7721. The best anticancer activity was obtained with triple‐negative breast cancer CAL‐51 and MDA‐MB‐231 cell lines, with IC₅₀ values in the range 0.035–0.10 μM, and this was better than using carboplatin. The complex inhibits proteasomal chymotrypsin‐like activity, and docking studies reveal its interaction with 20S proteasome. In addition, the complex causes accumulation of ubiquitinated proteins, induces apoptosis and inhibits cell proliferation, indicating its great potential as a novel therapy for triple‐negative breast cancer.     

A copper(II) complex of the Schiff base from l-valine and 2-hydroxy-1-naphthalidene plus 1,10-phenanthroline: synthesis, crystal structure, and DNA interaction

A new Cu(II) complex, [Cu(naph-val)phen] (naph-val = Schiff base derived from 2-hydroxy-1-naphthaldehyde and l-valine, phen = 1,10-phenanthroline), has been synthesized and characterized by physicochemical methods. The crystal structure of the complex showed that there are four independent molecular structures in the crystallographic asymmetric unit, and each of them shows a distorted square-pyramidal CuN₃O₂ coordination geometry. In the crystal, the π − π stacking and intermolecular hydrogen bonds form a 2D network. The interactions between the Cu(II) complex and calf thymus DNA (CT-DNA) have been studied by spectroscopic methods, as well as viscosity and thermal denaturation measurements. The results indicate that the Cu(II) complex binds to CT-DNA in an intercalative mode. The cleavage reaction on pBR322 plasmid DNA has been investigated by agarose gel electrophoresis in the absence and presence of mercaptopropionic acid. The Cu(II) complex exhibits an efficient DNA cleavage activity.     

Synthesis,characterization, DNA interaction,cytotoxicity, and apoptosis induction of a mixed-ligand copper(II) complex

A mixed-ligand complex, [Cu(Hptc)(Me₂bpy)(H₂O)]·3H₂O (1) (H₃ptc = pyridine-2,4,6-tricarboxylic acid; Me₂bpy = 4,4′-dimethyl-2,2′-dipyridine), has been synthesized and characterized by elemental analysis, IR, and single-crystal X-ray diffraction. In the discrete mononuclear structure of 1, the copper core is in a distorted octahedral environment (CuN₃O₃) derived from tridentate chelate Hptc^2?, bidentate chelate Me₂bpy and a coordinated water. The interaction of 1 with CT-DNA was investigated by UV–vis spectra, fluorescence spectra and viscosity, which reveals that 1 binds to CT-DNA by partial intercalation. Gel electrophoresis assay demonstrated that the complex displays efficient oxidative cleavage of supercoiled DNA with H₂O₂ as an oxidant. The in vitro cytotoxicity of 1 on HeLa cells was assessed by MTT and clonogenic assay, where IC₅₀ equals 4.24 ± 0.03 μM. Fluorescence microscopic observations indicated that 1 can induce apoptosis of HeLa cells.     

New less toxic zeolite‐encapsulated Cu(II) complex nanomaterial for dual applications in biomedical field and wastewater remediation

A new dual‐functional Cu(II) complex and its nanohybrid form encapsulated into NaY zeolite cavities were synthesized. The synthesized compounds were characterized using elemental analyses, X‐ray fluorescence, infrared, ¹H NMR, electronic, electron spin resonance and mass spectra, powder X‐ray diffraction, surface area and transmission electron microscopy in addition to conductivity and magnetic susceptibility measurements. The encapsulated Cu(II) complex was catalytically tested for degradation of industrial wastewater. The decolorization and mineralization results indicate that the Cu(II) complex encapsulated into zeolite host is an effective heterogeneous catalyst for real industrial wastewater remediation. In addition, both free and encapsulated Cu(II) complexes were tested as anti‐microbial and anti‐tumour agents. The results show that the Cu(II) complex encapsulated into zeolite has a high activity (IC₅₀ = 14.4 μg ml^?1). The results of in vivo toxicity experiments indicate that the Cu(II) complex encapsulated into zeolite is a less toxic biocompatible material (LD₅₀ = 1245 mg kg^?1). The catalytic properties, cytotoxicity and toxicity of the new nanohybrid Cu(II) complex encapsulated into zeolite make it a promising eco‐friendly and biocompatible material for water remediation and biomedical applications.     

Three pairs of enantiomers bearing mitochondria‐targeted TPP+ groups as potential anti‐cancer agents

Six complexes with chiral Schiff‐base ligands containing TPP⁺ groups, [VO L ^R,R/^S,S](ClO₄)₂( 1 for RR, 2 for SS), [Ni L ^R,R/S,S](ClO₄)₂·C₂H₅OH ( 3 for RR, 4 for SS) and [CuL^R,R/S,S](ClO₄)₂·CHCl₃·CH₃CH₂OH ( 5 for RR, 6 for SS) ( L ^R,R/S,S = N,N′‐Bis{5‐[(triphenylphosphonium)‐methyl]salicylidine}‐(1R,2R/1S,2S)‐diphenylethane‐1,2‐diamine, were synthesized to serve as mitochondrion‐targeting anticancer drugs. The introduction of TPP⁺ group(s) might markedly influence the properties of complexes. Compounds 3 and 5 were structurally characterized by X‐ray crystallography. Complexes 1–6 could be moderate intercalating agents to CT‐DNA which is determined by several spectroscopy methods. DNA cleavage experiments revealed that all compounds could promote oxidative cleavage of pBR322 plasmid DNA in the presence of H₂O₂. MTT assay indicated 1–6 exhibited effective cytotoxicity on A549 and MCF‐7 cell lines. Notably, the IC₅₀ values of 5 (1.24 ± 0.33 μM) or 6 (1.47 ± 0.52 μM) were approximately 9–11 fold lower than that of cisplatin (IC₅₀ = 13.56 ± 0.88 μM) on A549 cells. 5 and 6 were picked for further study, which indicated that the cytotoxicity seems to result from multiple mechanisms of action, including effectively suppress the growth and proliferation of A549 cells, generation of reactive oxygen species, dissipation of mitochondrial membrane potential, cell cycle perturbation and apoptosis induction. Compounds 1–6 could highly accumulate in the mitochondria by means of ICP‐MS assay. This study demonstrates that 1–6 with mitochondrion‐targeting function could be efficient anticancer drugs.     

Isomeric Effect on the anticancer Behavior of two Zinc (II) complexes based on 3,5‐bis(1‐imidazoly) pyridine: Experimental and Theoretical Approach

Two isomeric Zinc (II) complexes constructed by 3,5‐bis(1‐imidazoly) pyridine has been synthesized and characterized by single crystal X‐ray diffraction, elemental analyses and infrared spectroscopy. The binding mode and ability of complex 1–2 with CT‐DNA were studied by UV and fluorescence spectra. The intrinsic binding constant K_b (K_b1 = 2.305 × 10⁴ M^?1, K_b2 = 3.095 × 10⁴ M^?1) and the observed association constant K_obs (K_obs1 = 1.523*10⁶ M^?1, K_obs2 = 2.057*10⁶ M^?1) indicated that the insertion ability of complex 2 with CT‐DNA is stronger than complex 1. Gel electrophoresis showed that complexes have a good ability to hydrolyze cleavage pBR322 plasmid DNA. The cytotoxicity and apoptosis studies showed that complexes exhibited excellent cytotoxic activity against HeLa cells, especially complex 2 had better growth inhibition than Cisplatin. Molecular docking study simulated the binding model of complexes with DNA (PDB:4av1), showing an imidazole plane of complex 2 can be inserted into a DNA base pair in relative parallel. Both complexes can be used as potential anticancer agents.     

DNA binding and oxidative cleavage activity of ternary (l-proline)copper(II) complexes of heterocyclic bases

Ternary copper(II) complexes [Cu(l-pro)(B)(H₂O)](NO₃) (1, 2) where l-pro = l-proline, B is a N,N-donor heterocyclic base, viz. 2,2′-bipyridine (bpy, 1), 1,10-phenanthroline (phen, 2), are synthesized, characterized, and their DNA binding and cleavage activity studied. The bpy complex (1) is structurally characterized by single-crystal X-ray crystallography. The complexes show the presence of a distorted square-pyramidal (4 + 1) CuN₃O₂ coordination geometry. Complex [Cu(l-pro)(bpy)(H₂O)](NO₃) (1) crystallizes in the triclinic space group P1 with unit cell parameters: a = 7.082(3) Å, b = 10.483(5) Å, c = 11.581(5) Å, α = 89.700(7)°, β = 83.488(8)°, γ = 84.109(8)° and V = 849.7(7) Å³. The one-electron paramagnetic complexes display a d–d band near 600 nm in water and show a cyclic voltammetric response due to Cu(II)/Cu(I) couple near 0.1 V (versus SCE) in Tris–HCl buffer–0.1 M KCl. Binding interactions of the complexes with calf thymus (CT) DNA have been investigated by emission, absorption, viscosity and DNA thermal denaturation studies. The phen complex displays significant binding propensity to the CT DNA giving an order: 2 (phen)  1 (bpy). The bpy complex does not show any apparent binding to the DNA and hence poor cleavage efficiency. Complex 2 shows efficient oxidative cleavage of SC-DNA in the presence of 3-mercaptopropionic acid (MPA) involving hydroxyl radical species as evidenced from the control data showing inhibition of DNA cleavage in the presence of DMSO and catalase.     

Water‐soluble Schiff base Cu(II) and Zn(II) complexes: Synthesis,DNA targeting ability and chemotherapeutic potential of Cu(II) complex for hepatocellular carcinoma – in vitro and in vivo approach

Reliable compounds with low toxicity are tempting potential chemotherapeutics. With an aim of achieving less toxic but more potent metallodrugs, four new‐generation hydrophilic Cu(II) and Zn(II) complexes with DNA‐targeting properties were synthesized and characterized using various physicochemical data. The excellent DNA binding and cleavage results confirmed the mode of binding of DNA with the complexes and their ability to denature it. The profound in vitro cytotoxicity exhibited by complex 3 against a panel of cell lines (HeLa, MCF‐7 and HepG‐2) along with NHDF (normal human dermal fibroblasts) with distinct activity towards HepG‐2 and low toxicity to NHDF prompted in vivo studies of induced hepatocellular carcinoma‐affected Swiss albino rats. On evaluating various serum hepatic, biological and histopathological parameters, complex 3 showed excellent activity in restoring the damaged liver to normal. As a means of identifying the pathway of DNA damage, flow cytometric evaluation of cell cycle analysis was performed, which revealed S phase arrest‐induced apoptosis in HepG‐2 cells by complex 3 , making it a cell cycle‐specific drug.     

DNA interaction,antimicrobial and molecular docking studies of biologically interesting Schiff base complexes incorporating 4‐formyl‐N,N‐dimethylaniline and propylenediamine

Four new transition metal complexes incorporating a Schiff base ligand derived from propylenediamine and 4‐formyl‐N ,N ‐dimethylaniline have been synthesized using transition metal salts. The characterization of the newly formed complexes was done from physicochemical parameters and using various techniques like ¹H NMR, ¹³C NMR, IR, UV, electron paramagnetic resonance and mass spectroscopies, powder X‐ray diffraction and magnetic susceptibility. All the complexes were found to be monomeric in nature with square planar geometry. X‐ray powder diffraction illustrates that the complexes have a crystalline nature. The interaction of metal complexes with calf thymus DNA was investigated using UV–visible absorption, viscosity measurements, cyclic voltammetry, emission spectroscopy and docking analysis. The results indicate that the Cu(II), Co(II), Ni(II) and Zn(II) complexes interact with DNA by intercalative binding mode with optimum intrinsic binding constants of 4.3 × 10⁴, 3.9 × 10⁴, 4.7 × 10⁴ and 3.7 × 10⁴ M⁻¹, respectively. These DNA binding results were rationalized using molecular docking in which the docked structures indicate that the metal complexes fit well into the A‐T rich region of target DNA through intercalation. The metal complexes exhibit an effective cleavage with pUC19 DNA by an oxidative cleavage mechanism. The synthesized ligand and the complexes were tested for their in vitro antimicrobial activity. The complexes show enhanced antifungal and antibacterial activities compared to the free ligand.     

Preparation,Structural characterization and DNA binding/cleavage affinity of new bioactive nano‐sized metal (II/IV) complexes with oxazon‐Schiff's base ligand

A novel oxazon‐Schiff's base ligand named (E)‐3‐(2‐(4‐(diethylamino)‐2‐hydroxybenzylidene)hydrazineyl)‐2H‐benzo[b][1,4]oxazin‐2‐one (HL) has been synthesized in addition to its nano‐sized divalent and tetravalent Mn (II), Co (II), Ni (II), Cu (II), Zn (II) and Pt (IV) complexes. The structures and geometries of the synthesized compounds have been confirmed using the different analytical and spectroscopic tools such as elemental analysis, uv–vis., IR, HR‐MS, ¹H NMR, ESR, TGA, XRD, EDX, TEM, SEM, AFM, magnetic and molar conductivity measurements. The elemental analyses confirm 1 M: 2 L stoichiometry of the type [PtL₂].2Cl and [ML₂] (M = Mn (II), Co (II), Ni (II), Cu (II) and Zn (II)). The FT‐IR spectral studies illustrated that the ligand bind to the metal ions through the phenolic hydroxy oxygen, azo methine nitrogen carbonyl oxazin oxygen. The spectral tools; UV–Vis, ligand field parameters and ESR in addition to the magnetic moment measurements confirmed octahedral geometry around the metal centres. The absence of coordinated or hydrated water complexes were confirmed by thermal analysis data of the complexes. The electron transfer reactions for the complexes have been studied by cyclic voltammetry. XRD, SEM, TEM, and AFM images confirmed nano‐sized particles and homogeneous distribution over the complex surface. The mode of binding of the complexes with DNA has been performed through electronic absorption titration and viscosity studies. The reaction between the metal complexes and DNA were studied by DNA cleavage. In general, MCF‐7 cell were least sensitive to the tested compounds and all compounds were considerably more toxic to the studied cancer cell lines than to the normal cell line HepG‐2. The binding mode of the compounds and DNA was preferably via intercalation. In addition, these results were confirmed based on theoretical studies . Finally, a linear and exponential correlation between interaction constant (K_b) and IC₅₀ for two human cancer cell was observed.     

Synthesis of Substituted Quinolinyl Ether‐based Inhibitors of PI3K as Potential Anticancer Agents

A new strategy for the preparation of 8‐quinolyl ethers 3 ( a – g ), 5 ( a – g ), and 7 ( a – d ) was studied by copper (II)‐catalyzed methodology in the presence of Cs₂CO₃ and acetone–water mixture (1:1). Screening of quinolinyl‐8‐ethers was investigated against anticancer expressive studies to validate new chemical entity in medicinal chemistry. Approaches were evaluated against breast cancer (MCF‐7), skin cancer (G‐361), and colon cancer (HCT 116) cell lines. Inhibitory potentials against phosphoinositide‐3‐kinase (PI3K) enzyme responsible for cancer development have been evaluated by competitive ELISA studies. In PI3K assay, 3a – c were inactive (IC₅₀ > 5 μM), while 3e – g , 5a , 5c – e , 5g , 7a , and 7d showed a moderate activity (IC₅₀ ≥ 0.05 μM). Compounds ( 5b , 5f , 7b , and 7c ) showed significant activity (IC₅₀ < 1.0 μM); thus, their anticancer activities were carried out. Anticancer activity was found to be selective towards breast cancer (MCF‐7); 5b , 5f , 7b , and 7c showed predominant relative percentage activities of 74.12%, 79.04%, 72.56%, and 78.47%, with IC₅₀ values of 5b (2.27 ± 0.88 μM), 5f (1.38 ± 0.60 μM), 7b (2.64 ± 0.86 μM), and 7c (1.87 ± 0.68 μM) compared with the standard doxorubicin 73.14% inhibition (IC₅₀ = 1.98 ± 0.75 μM). Docking study also conducted to find out the binding interactions with p110α (PDB ID: 3T8M) enzyme. Compounds 5b , 5f , 7b , and 7c showed best docking score into the active site of PI3K 12.59, 10.51, 56.52, and 8.61 nM. Structure–activity relationship studies demonstrated that the synthesized compounds are the potential PI3K inhibitors to treat various cancer‐related diseases.     

Redox active and inactive binuclear cobalt(II) and zinc(II) complexes with N6O/N3O coordinating ligands: synthesis,biological activities and cytotoxicity

Four complexes, namely [Zn₂L¹(OAc)₂](PF₆) ( 1 ); [Zn₂L¹(OAc)₂](BPh₄) ( 2 ); [Co₂L¹Cl₂](PF₆) ( 3 ); and [Zn₂L²(PhCOO)₂Cl] ( 4 ) (L¹ = 2,6‐bis(((2‐(dimethylamino)ethyl)(pyridine‐2‐ylmethyl)amino)methyl)‐4‐methoxyphenol; L² = 2‐(((2‐(dimethylamino)ethyl)(pyridin‐2‐ylmethyl)amino)methyl)‐4‐methoxyphenol), have been synthesized. Single‐crystal diffraction reveals that the metal atoms in the four complexes are in different coordination environments. The interactions of the complexes with calf thymus DNA (CT‐DNA) have been investigated using UV absorption, fluorescence and circular dichroism spectroscopies and viscosity measurements, and the modes of CT‐DNA binding for the complexes have been proposed. Further experiments show that the Zn(II)/H₂O₂ system displays significant oxidative cleavage of supercoiled DNA attributed to the peroxide ion coordinated to the Zn(II) ions enhancing their nucleophilicity. This is a rare phenomenon. DNA cleavage mechanism shows that the complexes examined here may be capable of promoting DNA cleavage through an oxidative DNA damage pathway, which is indicative of the involvement of singlet oxygen in the cleavage process. In vitro cytotoxicity of complexes against three human tumor cell lines (HeLa, MCF‐7 and HepG2) demonstrates that these complexes have the potential to act as effective metal‐based anticancer drugs. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis,characterization, bioactivities of copper complexes with N-allyl di(picolyl)amine

Four copper(II) complexes with N-allyl di(picolyl)amine were synthesized and characterized by physico-chemical and spectroscopic methods. The spectrophotometric and fluorescence titration data indicate that the [(Aldpa)Cu(L)](ClO₄)₂ (L = dppz, dione, phen) with conjugated aromatic rings as coordinated ligands can be inserted into the base stacks of DNA more deeply than the [(Aldpa)CuCl₂]. The copper(II) complexes [(Aldpa)Cu(L)](ClO₄)₂ (L = dppz, dione, phen) can inhibit the proliferation of the four cancer cells (Mcf-7, Eca-109, A549 and HeLa) with IC₅₀ 0.5–19.2 μM, which is larger than that (23.2–84.3 μM) of [(Aldpa)CuCl₂], suggesting their inhibiting activities on the four cancer cells are correlated with their DNA-binding properties. However, the selectivity of [(Aldpa)CuCl₂] to cancer cells is better than that of the other three complexes [(Aldpa)Cu(L)](ClO₄)₂, which indicates the substituents introduced on the secondary amino nitrogen atom of dpa have great contribution to the antitumor activities of these copper(II) complexes.     

Organoruthenium (II) complexes featuring pyrazole‐linked Schiff base ligands: Crystal structure,DNA/BSA interactions,cytotoxicity and molecular docking

Half‐sandwiched ruthenium (II) arene complexes with piano stool‐like geometry with the general formula [(p‐cymene)RuClL¹] and [(p‐cymene)RuClL²] [where L¹ = (Z)‐N′‐((1,3‐diphenyl‐1H‐pyrazol‐4‐yl)methylene)furan‐2‐carbohydrazide and L² = (Z)‐N′‐((1,3‐diphenyl‐1H‐pyrazol‐4‐yl)methylene)thiophene‐2‐carbohydrazide] were synthesized and characterized. The single crystal X‐ray data revealed that the complexes belong to the same crystal system (monoclinic) with octahedral geometry, where the ruthenium atom is surrounded by hydrazone ligand coordinated through ON atoms, one chloride labile co‐ligand and the remaining three coordination sites covered by an electron cloud of p‐cymene moiety. The interaction between the complexes and DNA/bovine serum albumin (BSA) was evaluated using absorption and emission titration methods showing intercalative modes of interaction. The DNA cleavage ability of the complexes was checked by agarose gel electrophoresis method exhibiting the destruction of DNA duplex arrangement. To understand the interaction between ruthenium complex and DNA/BSA molecule, molecular docking studies were performed. In vitro cytotoxicity of the complexes was examined by the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay on human lung cancer cell line, A549, and found that at lower IC₅₀, cell growth inhibition has occurred. Similarly, the IC₅₀ values of the complexes treated with cancerous cell lines have produced a significant amount of lactase dehydrogenase and nitrite content in the culture medium, which were evaluated as apoptosis‐inducing factors, suggesting that the ruthenium (II) arene hydrazone complexes with pyrazole ligands have promising anticancer activities.