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Chiral enantiomers [Cu(phen)(L-ser)(H2O)]NO31 and [Cu(phen)(D-ser)(H2O)]NO32 (ser = serinato) underwent aldol-type condensation with formaldehyde, with retention of chirality, to yield their respective enantiomeric ternary copper(II) complexes, viz. L- and D-[Cu(phen)(OCA)(H2O)]NO3·xH2O (3 and 4; phen = 1,10-phenanthroline; OCA = oxazolidine-4-carboxylate; x = 1/2, 0–2) respectively. These chiral complexes were characterized by FTIR, elemental analysis, circular dichroism, UV-visible spectroscopy, fluorescence spectroscopy (FL), molar conductivity measurement, ESI-MS and X-ray crystallography. The crystal structures of 1 and 3 showed both the cationic complexes to have a square pyramidal geometry. These complexes were about nine fold more potent than cisplatin against metastatic MDA-MB-231 breast cancer cells, inducing apoptotic cell death via ROS generation and a massive drop in mitochondrial membrane potential. The results of monitoring EZH1, EZH2 and H3K27me3 revealed that the mode of action of 1–4 also involved the downregulation of EZH2 and it seemed to be independent of the H3K27me3 status.

The cobalt(II), copper(II) and zinc(II) complexes of 1,10-phenanthroline (phen) and maltol (mal) (complexes 1, 2, 3 respectively) were prepared from their respective metal(II) chlorides and were characterized by FT-IR, elemental analysis, UV spectroscopy, molar conductivity, p-nitrosodimethylaniline assay and mass spectrometry. The X-ray structure of a single crystal of the zinc(II) analogue reveals a square pyramidal structure with distinctly shorter apical chloride bond. All complexes were evaluated for their anticancer property on breast cancer cell lines MCF-7 and MDA-MB-231, and normal cell line MCF-10A, using (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and morphological studies. Complex 2 was most potent for 24, 48 and 72 h treatment of cancer cells but it was not selective towards cancer over normal cells. The mechanistic studies of the cobalt(II) complex 1 involved apoptosis assay, cell cycle analysis, dichloro-dihydro-fluorescein diacetate assay, intracellular reactive oxygen species assay and proteasome inhibition assay. Complex 1 induced low apoptosis, generated low level of ROS and did not inhibit proteasome in normal cells. The study of the DNA binding and nucleolytic properties of complexes 1–3 in the absence or presence of H2O2 or sodium ascorbate revealed that only complex 1 was not nucleolytic.

Three ternary copper(II) complexes, [Cu(phen)(L-phe)Cl]·2H2O, [Cu(phen)(L-leu)Cl]·4½H2O, and [Cu(phen)(L-tyr)Cl]·3H2O, and four binary copper(II) complexes, [Cu(phen)Cl2], Cu(L-phe)2·½H2O, Cu(L-leu)2·½H2O, and Cu(L-tyr)2·H2O (where phen = 110-phenanthroline, L-phe = L-phenylalanine, L-tyr = L-tyrosine, L-leu = L-leucine and Cl- = chloride), were synthesized and characterized by elemental analysis, spectroscopic techniques (FTIR, UV–visible, fluorescence spectroscopy), magnetic susceptibility, molar conductivity, and lipophilicity measurement. X-ray diffraction determination of a single crystal of [Cu(phen)(L-tyr)Cl] showed two independent molecules in the asymmetric unit, each with the same distorted square pyramidal geometry about copper(II). p-Nitrosodimethylaniline assay revealed that the three ternary complexes were better inducers of reactive oxygen species over time than binary complexes, CuCl2, and free ligands. All the copper(II) complexes in this series inhibited the three proteolytic act...

The four copper(II) complexes involving ethylenediamine-N,N-diacetic acid (H2edda) and ethylenediamine (en), viz. [Cu(edda)(en)] H2O 1, [Cu(en)Cl2] 2, [Cu(edda)] 3 and [Cu2(Hedda)2Cl2] 4, were synthesized and characterized by various physical means. The crystal structures of 1 and 4 established them as mononuclear and dichlorido-bridged dicopper(II) complexes respectively. Complexes 1 and 4 showed weak and strong antiferromagnetic Cu…Cu interaction. Dynamic light scattering data of 3 suggested it to be a 3-dimensional coordination polymer in aqueous solution, gel and solid forms. The copper(II) species of 1–4 in aqueous solution were analysed by UV–visible and molar conductivity data. The weak hydroxyl radical-inducing property of free copper(II) ions in solution was enhanced by the chelation of both types of ligands. However, chelation of each or both of these ligands reduce the strong proteasome inhibitory property of the copper(II). All complexes inhibited the three proteolytic sites of the 20S proteasome, with the Trypsin-like site been mostly selectively inhibited.

The d- and l-enantiomers of the ternary complex [Cu(phen)(ala)(H2O)]NO3 [phen = 1,10-phenanthroline; ala = alanine; l-enantiomer (1a); d-enantiomer (1b)] both undergo an aldol-type condensation with formaldehyde under mild acidic conditions to yield racemic rac-[Cu(phen)(4MeOCA)(H2O)(NO3)] (2) (4MeOCA = 4-methyl-oxazolidine-4-carboxylate). The precursors and the products were characterized by circular dichroism, FTIR, UV–Vis, fluorescence spectroscopy, molar conductivity and electrospray ionization mass spectrometry. The racemic nature of the product was established by X-ray crystallography . In the crystal structure, the copper atom has a tetragonally elongated octahedral geometry in which the water and an oxygen atom of a nitrate group are mutually trans. A possible mechanism for the racemization of the ligand is proposed.

The hydrated and anhydrous forms of the copper(II) complex of 3-methylpicolinic acid, monomeric [Cu(3Me-pic) 2 (H 2 O)]·H 2 O 1 and polymeric [Cu(3Me-pic) 2 ] n 2 , were synthesized and characterized by FTIR, UV–visible spectroscopy, conductivity measurement, magnetic susceptibility determination, electron paramagnetic resonance (EPR) and light scattering. Crystal structure analysis of 2 shows that it has a doubly-bridged polymeric structure, involving diagonally stacked Cu(3Me-pic) 2 units which are linked via carbonyl oxygen atoms of the 3Me-pic moieties. Analysis of EPR spectra at 133 K and 293 K suggests isotropic intermolecular spin interaction only in 2 . Complex 2 dissolved in DMF and DMSO solvents to yield nano-size particles. Solution studies show aqueous solutions of 1 and 2 contain the same neutral Cu(3Me-pic) 2 species, which generates less hydroxyl radicals from the reaction with hydrogen peroxide than their precursor CuCl 2 . The Cu(3Me-pic) 2 species exhibit more selective inhibition of the β2 site of the 20S proteasome, among the three proteolytic sites.

The interaction of simple and ternary Cu(II) complexes of 1,10-phenanthrolines with DNA has been studied extensively because of their various interesting and important functions such as DNA cleavage activity, cytotoxicity towards cancer cells, and DNA based asymmetric catalysis. Such functions are closely related to the DNA binding modes of the complexes such as intercalation, groove binding, and electrostatic surface binding. A variety of spectroscopic methods have been used to study the DNA binding mode of the Cu(II) complexes. Of all these methods, DNA-fiber electron paramagnetic resonance (EPR) spectroscopy affords unique information on the DNA binding structures of the complexes. In this review we summarize the results of our DNA-fiber EPR studies on the DNA binding structure of the complexes and discuss them together with the data accumulated by using other measurements.

A set of copper(II) complexes of glycine and methylated glycine derivatives, Cu(aa)2, consisting of C-dimethylglycine, l-alanine, N-dimethylglycine and sarcosine, was investigated for their DNA binding and nucleolytic properties by means of EPR and visible spectroscopy, and electrophoresis. They bind weakly to DNA with apparent binding constants in the range 1.8–2.9 × 103 M−1 with very similar orientation. No DNA cleavage is observed in the absence of exogenous agents. Copper(II) complexes of N-methylated derivatives bind to DNA more stereo-specifically and less strongly, and their oxidative DNA cleavage is less efficient than those of the corresponding C-methylated derivatives in the presence of hydrogen peroxide (H2O2) alone, or sodium ascorbate (NaHA) alone or tandem H2O2–NaHA. The oxidative DNA cleavage mechanism in the three systems involves a common copper(I) species. Neocuproine can inhibit DNA cleavage by these complexes.

Like chiral organic drugs, the chemical and biological properties of metal complexes can be dependent on chirality. Two pairs of [Cu(phen)(ala)(H2O)]X·xH2O (phen=1.10-phenanthroline: X=NO3(-); ala: l-alanine (l-ala), 1 and d-alanine (d-ala) 2; and (X=Cl(-); ala: l-ala, 3 and d-ala, 4) complex salts (x=number of lattice water molecules) have been synthesized and characterized. The crystal structure of 3 has been determined. The same pair of enantiomeric species, viz. [Cu(phen)(l-ala)(H2O)](+) and [Cu(phen)(d-ala)(H2O)](+), have been identified to be present in the aqueous solutions of both 1 and 3, and in those of both 2 and 4 respectively. Both 3 and 4 bind more strongly to ds(AT)6 than ds(CG)6. There is no or insignificant effect of the chirality of 3 and 4 on the production of hydroxyl radicals, binding to deoxyribonucleic acid from calf thymus (CT-DNA), ds(CG)6, G-quadruplex and 17-base pair duplex, and inhibition of both topoisomerase I and proteasome. Among the three proteasome proteolytic sites, the trypsin-like site is inhibited most strongly by these complexes. However, the chirality of 3 and 4 does affect the number of restriction enzymes inhibited, and their binding constants towards ds(AT)6 and serum albumin.

Aquabis(N,N-dimethylglycinato)copper(II) dihydrate, [Cu(dmg)2(H2O)]·2H2O, has been synthesized and characterized by elemental analysis, FT-IR, magnetic data, thermal analysis, solution UV-visible spectroscopy, X-ray crystal structure analysis and electrospray ionization mass spectroscopy. The square pyramidal copper(II) complex crystallizes in the orthorhombic space group P212121. The complex cleaves circular plasmid DNA (pBR322) in the presence of H2O2. The extent of cleavage varies with the concentration range of the complex, the type of buffer used, pH of buffer and the concentration of H2O2. Hydroxyl radical scavenger can inhibit the nucleolytic ability of this complex.

The Mannich aminomethylation of bis( l -alaninato)copper(II), Cu( l -ala)2, with formaldehyde and acetamide yields the bis[N-(N′-methylacetamido)- l -alaninato]copper(II) (1) and bis[N,N-di-(N′-methylacetamido)- l -alaninato]copper(II) (2) complexes. The crystal structure of 2 shows the amide N–H of the uncoordinated N-methylacetamido substituents and that of the coordinated N-methylacetamido substituents forming intra- and inter-molecular hydrogen bonding. Both complexes have been characterized by elemental analysis, UV–Vis spectroscopy, magnetic susceptibility measurements and EI mass spectroscopy. A gel electrophoresis experiment on the soluble complex 1 in Tris–NaCl buffer at pH 8.3, from which 2 is formed, shows oxidative cleavage of DNA by 1 in the presence of hydrogen peroxide. The cleavage efficiency of 1 is greater than that of its precursor, Cu( l -ala)2.

The reactions of a series of bis(α-substituted glycinato)copper(II) complexes, Cu(aa) 2 , with formaldehyde and acetamide have been carried out. For Cu(aa) 2 with an activating α-alkyl or reactive α-hydroxyalkyl substituent, they undergo both aldol-type condensation and Mannich aminomethylation to yield complexes with an oxazolidine-ring and one methylacetamido pendant. The crystal structure of one of these complexes is reported. The Cu(aa) 2 with a non-activating α-alkyl substituent is diacetamidomethylated. A proposed mechanism to account for the above differences and an analysis of thermal decomposition data of the two types of complexes are further described.

Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4. The complex significantly inhibited tumor growth in nasopharyngeal carcinoma xenograft bearing mice models at doses which were well tolerated without causing significant or permanent toxic side effects. However, higher doses which resulted in better inhibition of tumor growth also resulted in toxicity.

In the reactions of bis(α-amino acidato)copper(II) with formaldehyde and benzamide, competing processes occur and the preferred pathway depends on the nature and number of the α-carbon substituents of the chelated amino acid, and the pH of the reaction medium. Aldol-type condensation yields complexes with oxazolidine ring(s) while Mannich aminomethylation results in the formation of complexes with N-methylbenzamido pendant arm(s). The crystal structure determination of bis(3-methylbenzamido-5-methyloxazolidine-4-carboxylato)copper(II) dihydrate establishes its formation from a combination of both processes, in which aldol condensation occurs first. The chemistry of these reactions is rationalized with a proposed reaction scheme. The synthesized compounds are characterized by infrared spectroscopy and microanalysis.

Copper compounds can be alternatives to platinum-based anticancer drugs. This study investigated the effects of a series of ternary copper(II) complexes, [Cu(phen)(aa)(H2O)]NO3·xH2O 1–4 (phen = 1,10-phenanthroline; aa = gly (1), DL-ala (2), sar (3), C-dmg (4)), on metastatic and cisplatin-resistant MDA-MB-231 breast cancer cells and MCF10A non-cancerous breast cells, and some aspects of the mechanisms. These complexes were distinctively more antiproliferative towards and induced greater apoptotic cell death in MDA-MB-231 than in MCF10A cells. 2 and 4 could induce cell cycle arrest only in cancer cells. Further evidence from DCFH-DA assay showed higher induction of reactive oxygen species (ROS) in treated cancer cells but minimal ROS increase in normal cells. DNA double-strand breaks, via a γ-H2AX assay, were only detected in cancer cells treated with 5 μM of the complexes. These complexes poorly inhibited chymotrypsin-like activity in the 20S rabbit proteasome while they did not inhibit the three proteolytic sites of MDA-MB-231 cells at 10 μM. However, the complexes could inhibit degradation of ubiquinated proteins of MDA-MB-231 cells. In addition, compound 4 was found to be effective against cervical (Hela), ovarian (SKOV3), lung (A549, PC9), NPC (Hone1, HK1, C666-1), breast (MCF7, T47D), lymphoma and leukemia (Nalmawa, HL60) and colorectal (SW480, SW48, HCT118) cancer cell lines with IC50 values (24 h) in the 1.7–19.0 μM range. Single dose NCI60 screening of 4 showed the complex to be highly cytotoxic to most cancer cell types and more effective than cisplatin.

The Mannich reaction involving bis(glycinato)copper(II), formaldehye and ammonia over the pH range 6.0–6.5 results in the formation of the title compound, aqua[3N,5N-methylamino(1,3,5-oxadiazacyclohexyl)diacetato]copper(II) monohydrate (2), in which one of the amino nitrogen atoms of bis(glycinato)copper(II) is fully substituted while the other experiences only partial substitution. The crystal structure of 2 shows the copper atom to have square pyramidal geometry with a N2O2 basal plane and a water molecule in the apical site. Crystals of 2 are monoclinic, space group P21/c with unit cell dimensions a = 11.756(2), b = 7.903(1), c = 12.583(1) A, β = 95.27(1)°, V = 1164.0(3) A3, Z = 4. The structure was refined by a full-matrix least-squares procedures to R = 0.037 for 2253 observed reflections.

The Mannich reaction of bis(glycinato)copper(II) with formaldehyde and acetamide results in the formation of bis[(N,N-di-N′-methylacetamido)glycinato]copper(II) dihydrate, C16H28N6O8Cu.2H2O, which crystallizes in the monoclinic space group P21/c with unit cell dimensions a = 11.300(2), b = 13.041(2), c = 8.799(1)A, β = 99.51(1)° and Z = 2. The structure has been refined to final R = 0.034 and R w = 0.049 for 2508 reflections with F > 4.0σ(F).

A series of ternary copper(II)-1,10-phenanthroline complexes with glycine and methylated glycine derivatives, [Cu(phen)(aa)(H(2)O)]NO(3)·xH(2)O 1-4 (amino acid (aa): glycine (gly), 1; DL: -alanine (DL: -ala), 2; 2,2-dimethylglycine (C-dmg), 3; sarcosine (sar), 4), were synthesized and characterized by FTIR, elemental analysis, electrospray ionization-mass spectra (ESI-MS), UV-visible spectroscopy and molar conductivity measurement. The determined X-ray crystallographic structures of 2 and 3 show each to consist of distorted square pyramidal [Cu(phen)(aa)(H(2)O)](+) cation, a nitrate counter anion, and with or without lattice water, similar to previously reported structure of [Cu(phen)(gly)(H(2)O)]NO(3)·1½H(2)O. It is found that 1-4 exist as 1:1 electrolytes in aqueous solution, and the cationic copper(II) complexes are at least stable up to 24 h. Positive-ion ESI-MS spectra show existence of only undissociated [Cu(phen)(aa)](+) species. Electron paramagnetic resonance, gel electrophoresis, fluorescence quenching, and restriction enzyme inhibition assay were used to study the binding interaction, binding affinity and selectivity of these complexes for various types of B-form DNA duplexes and G-quadruplex. All complexes can bind selectively to DNA by intercalation and electrostatic forces, and inhibit topoisomerase I. The effect of the methyl substituents of the coordinated amino acid in the above complexes on these biological properties are presented and discussed. The IC(50) values (24 h) of 1-4 for nasopharyngeal cancer cell line HK1 are in the range 2.2-5.2 μM while the corresponding values for normal cell line NP69 are greater than 13.0 μM. All complexes, at 5 μM, induced 41-60 % apoptotic cell death in HK1 cells but no significant cell death in NP69 cells.

The reaction of bis(L-prolinato)copper(II) with formaldehyde results in the formation of the title compound which has been characterized by X-ray analysis and is found to possess a distorted square pyramidal geometry about the copper atom.

Mannich aminomethylation reactions involving bis(glycinato)metal(II) (metal = zinc, nickel, copper and cobalt), formaldehyde and acetamide result in the formation of the respective metal(II) complexes of ( N,N -di- N ′-methylacetamido)glycine, which are characterized by various physical means, including X-ray structural analyses of the zinc(II) and nickel(II) complexes.

The reaction of bis(β-alaninato)copper(II) with formaldehyde results in the formation of blue crystals of aquabis(N,N-dimethyl-β-alaninato)copper(II) hexahydrate, [Cu(C5H10NO2)2(OH2)].6H2O which crystallize in the monoclinic space group C2/c with unit cell dimensions a = 20.799(2), b = 8.112(1), c = 23.639(1)A, β = 96.50(1)° and Z = 8. The structure has been refined to final R = 0.047 and Rw = 0.053 for 1690 reflections with I ≥ 2.55σ(I).

The reaction of bis(β-alaninato)copper(II) with formaldehyde and ammonia over the pH range 6.6-8.8 results in the formation of [3N,7N-(1,3,5,7-tetraazabicyclo[3.3.1]nonyl)-di-3-propionato]copper(II) trihydrate, C11H24N4O7Cu, which crystallizes in the monoclinic space group P2t/c with a = 10.903(2), b = 7.340(2), c = 19.435(3) A, β = 98.27(1)[ddot] and Z = 4. The structure has been refined to R = 0.040 and R w = 0.044 based on 2655 reflections with I ≥ 2.5σ(I). The chelate molecules are linked in chains by a carbonyl oxygen to copper interaction which results in square pyramidal coordination of the copper ion.

The reactions of formaldehyde with the metal(II) chelates of L threonine (metal = copper, nickel, cobalt and zinc) result in the formation of the metal(II) complexes of 5-methyloxazolidine-4-carboxylic acid. The copper(II) complex, C 10 H 20 N 2 O 8 Cu, is obtained from the recrystallization of its 3-hydroxymethyl derivative, C 12 H 24 N 2 O 10 Cu, which initially forms. C 10 H 20 N 2 O 8 Cu crystallizes in the orthorhombic space group P 2 1 2 1 2 1 with a =8.166(1), b =8.936(1), c =20.463(5) A and Z =4. The structure has been refined to R =0.021 and R w =0.021 based on 1444 reflections with l > 2.5σ( l ). The geometry about copper is based on a square pyramid with a coordinated water in the apical position. The synthesized compounds are characterized by microanalysis, magnetic and thermal data as weil as examinations of their electronic and infrared spectra.

The binding selectivity of the M(phen)(edda) (M=Cu, Co, Ni, Zn; phen=1,10-phenanthroline, edda=ethylenediaminediacetic acid) complexes towards ds(CG)(6), ds(AT)(6) and ds(CGCGAATTCGCG) B-form oligonucleotide duplexes were studied by CD spectroscopy and molecular modeling. The binding mode is intercalation and there is selectivity towards AT-sequence and stacking preference for A/A parallel or diagonal adjacent base steps in their intercalation. The nucleolytic properties of these complexes were investigated and the factors affecting the extent of cleavage were determined to be: concentration of complex, the nature of metal(II) ion, type of buffer, pH of buffer, incubation time, incubation temperature, and the presence of hydrogen peroxide or ascorbic acid as exogenous reagents. The fluorescence property of these complexes and its origin were also investigated. The crystal structure of the Zn(phen)(edda) complex is reported in which the zinc atom displays a distorted trans-N(4)O(2) octahedral geometry; the crystal packing features double layers of complex molecules held together by extensive hydrogen bonding that inter-digitate with adjacent double layers via pi...pi interactions between 1,10-phenanthroline residues. The structure is compared with that of the recently described copper(II) analogue and, with the latter, included in molecular modeling.

Chiral enantiomers [Cu(phen)(L-threo)(H2O)]NO3 1 and [Cu(phen)(D-threo)(H2O)]NO3 2 (threo = threoninate) underwent aldol-type condensation with formaldehyde, with retention of chirality, to yield their respective enantiomeric ternary copper(II) complexes, viz. L- and D-[Cu(phen)(5MeOCA)(H2O)]NO3·xH2O (3 and 4; phen = 1,10-phenanthroline; 5MeOCA = 5-methyloxazolidine-4-carboxylate; x = 0-3) respectively. These chiral complexes were characterized by FTIR, elemental analysis, circular dichroism, UV-Visible spectroscopy, fluorescence spectroscopy (FL), molar conductivity measurement, ESI-MS and X-ray crystallography. Analysis of restriction enzyme inhibition by these four complexes revealed modulation of DNA binding selectivity by the type of ligand, ligand modification and chirality. Their interaction with bovine serum albumin was investigated by FL and electronic spectroscopy. With the aid of the crystal structure of BSA, spectroscopic evidence suggested their binding at the cavity containing Trp134 with numerous Tyr residues in subdomain IA. The products were more antiproliferative than cisplatin against cancer cell lines HK-1, MCF-7, HCT116, HSC-2 and C666-1 except HL-60, and were selective towards nasopharyngeal cancer HK-1 cells over normal NP69 cells of the same organ type.

The Cu(II) atom in the title compound, [Cu(C(5)H(7)O(2))Cl(C(12)H(8)N(2))], shows a distorted square-planar coordination; the chelating N and O atoms occupy the basal sites and the Cl atom the apical site. The square-pyramidal character along the Berry D(3h)-C(4v) pseudorotation pathway is 92%.

The copper(II) atoms in the two independent mol-ecules of the title compound, [Cu(C(6)H(5)O(3))Cl(C(12)H(8)N(2))], both adopt square-pyramidal geometries. The two coordinating atoms of the two heterocyclic ligands comprise the square plane, and the chlorine atom occupies the apical position of the coordination environment.