Nick Hadjiliadis

Electron spin echo envelope modulation (ESEEM) spectroscopy as a tool to investigate the coordination environment of metal centers

Abstract The applications of electron spin echo envelope modulation (ESEEM) spectroscopy to study paramagnetic metal centers in metalloproteins and bioinorganic complexes are reviewed, with special attention to the novel spectroscopic techniques applied and the structural information obtained. We summarize the physical principles and experimental techniques of ESEEM, the spectral shapes and the methods for their analysis. The physical meaning of the spin Hamiltonian parameters is highlighted in conjunction with their utilization for obtaining structural information.

Metal complex-DNA interactions

A Basic Structural and Kinetic Aspects 1. Sequence-Selective Binding of Transition Metal Complexes to DNA 2. Thermodynamic Models of Metal Ion -DNA.Interactions 3. Metal Ion Coordination in G-quadruplexes 4. Supramolecular Chemistry of Metal-Nucleobase Complexes B Medical Applications 5. Platinum Drugs, Nucleotides, and DNA: the Role of Interligand Interactions, nucleotides and DNA 6. Role of DNA Repair in Antitumor Effects of Platinum Drugs 7. Telomeres and Telomerase: Potential Targets for Platinum Complexes 8. Toward Photodynamic Therapy of Cancer with Platinum Group Metal Polyazine Complexes 9. Platinated Oligonucleotides: Synthesis and Applications for the Control of Gene Expression 10. New Titanium and Ruthenium Anticancer Drugs and their Interaction with DNA C DNA-Recognition - Nucleases and Sensors 11. Groove-Binding Ruthenium(II) Complexes as Probes of DNA Recognition 12. DNA Recognition and Binding by Peptide-Metal Complex conjugate 13. Artificial Restriction Agents - Hydrolytic Agents for DNA Cleavage 14. New Metallo-DNAzymes: Fundamental Studies of Metal-DNA Interactions and Metal Sensing Applications 15. Two-metal Ion Dependent Catalysis in Nucleic Acid Enzymes D Toxicological aspects 16. Mercury- DNA Interactions. Structural Studies on Mercury II -Mediated T-T Base-Pair with NMR Spectroscopy 17. Chromium-Induced DNA Damage and Repair 18. Arsenic and nickel: Mechanisms Affecting DNA Integrity

Synthesis, structural characterization and in vitro cytotoxicity of organotin(IV) derivatives of heterocyclic thioamides, 2-mercaptobenzothiazole, 5-chloro-2-mercaptobenzothiazole, 3-methyl-2-mercaptobenzothiazole and 2-mercaptonicotinic acid.

Five new organotin(IV) molecules with the heterocyclic thioamides; 2-mercaptobenzothiazole (Hmbzt), 5-chloro-2-mercaptobenzothiazole (Hcmbzt), 3-methyl-2-mercaptobenzothiazole (mmbzt) and 2-mercaptonicotinic acid (H(2)mna) of formulae [(n-C(4)H(9))(2)Sn(mbzt)(2)] (1), [(C(6)H(5))(2)Sn(mbzt)(2)] (2), [(CH(3))(2)Sn(cmbzt)(2)].1.7(H(2)O)] (3), [(n-C(4)H(9))(2)SnCl(2)(mmbzt)(2).(CH(2)Cl(2))] (4) and [[(C(6)H(5))(3)Sn](2)(mna).[(CH(3))(2)CO]] (5) have been synthesized and characterized by elemental analysis, 1H-, 13C-NMR, FT-IR and Mössbauer spectroscopic techniques. Crystal structures of molecules 1, 3 and 5 have been determined by X-ray diffraction at 173(1) K (1 and 5) and 293(2) K (3). Compound 1 C(22)H(26)N(2)S(4)Sn, is monoclinic, space group C2/c, a=44.018(2), b=8.8864(5), c=12.8633(7) A, beta=104.195(5) degrees, Z=8. Compound 3 is also monoclinic, space group P2(1)/c and a=17.128(2) A, b=17.919(2) A, c=7.3580(10) A, beta=98.290(10) degrees, Z=4. In both molecules 1 and 3, two carbon atoms from aryl groups, two sulfur and two nitrogen atoms from thione ligands form a distorted octahedral geometry around tin(IV) with trans-C(2), cis-N(2), cis-S(2) configurations. Compound 5 C(45)H(39)NO(3)SSn(2) is monoclinic, space group P2(1)/n, a=9.1148(2) A, b=29.2819(6), c=15.5556(4) A, beta=106.2851(9) degrees, Z=4. Complex 5 contains two [(C(6)H(5))(3)Sn(IV)] moieties linked by a double deprotonated 2-mercaptonicotinic acid (H(2)mna). Both tin(IV) ions are five coordinated. This complex is the an example of a pentacoordinated Ph(3)SnXY system with an axial-equatorial arrangement of the phenyl groups at Sn(1) atom. Compounds 1, 3 and 5 were tested for in vitro cytotoxicity against the cancer cell line of sarcoma cells (mesenchymal tissue) from the Wistar rat, polycyclic aromatic hydrocarbons (benzo[a]pyrene) carcinogenesis. Compound 5 exhibits strong cytotoxic activity, while complexes 1 and 3 show less cytotoxic activity.

1:1 Metal complexes of 2-(2′-pyridyl)quinoxaline, a ligand unexpectedly formed by the reaction between 2-acetylpyridine and 1,2-phenylenediamine

The complexes [MLCl2] (M=Co, Ni, Cu, Zn), where L is the new ligand 2-(2′-pyridyl)quinoxaline derived unexpectedly from 2-acetylpyridine and 1,2-phenylenediamine, were isolated. The ligand and its complexes have been characterized by a variety of physical and spectroscopic techniques. L behaves as a bidentate chelating ligand in the monomeric pseudotetrahedral Zn∥ compound; all three nitrogen atoms of L are involved in coordination in the polymeric Co∥, Ni∥ and Cu∥ complexes giving five-coordinate (Co∥) or six-coordinate (Ni∥, Cu∥) structures.

Complex compounds of platinum (II) and (IV) with amino acids, peptides and their derivatives

Abstract This article reviews all the known Pt(II) and Pt(IV) complexes with amino acids, peptides and their analogues referred in the literature. It gives details on the work done after 1975 since excellent reviews on the subject before that date have been published previously. The compounds described have been classified, in the first place, according to the metal ion oxidation state and in the second according to the binding site(s) of the ligand(s). Section 1 refers briefly to the reasons for studying platinum complexes with amino acids and similar molecules and gives the orientation of the research on the topic in recent years. In Sect. 2, the known Pt(II) complexes are reviewed in four sub-sections. The first describes the complexes with the metal ion binding to the terminal amino group or/and to a ring nitrogen of a side chain of the amino acid. This coordination mode is easily achieved and results in various products when the ligand contains more than one nitrogen donor atom. The second sub-section describes the complexes with the metal simultaneously binding to a nitrogen and one or more oxygen donor atoms of the ligand. A large number of stable chelates are thus formed. In contrast, binding of an amino acid or analogue through only an oxygen donor atom is not easily achieved. The third sub-section describes the complexes formed with sulphur-containing ligands. In such complexes, coordination of sulphur, which is the primary binding site, may result in bridged or oligomeric complexes. The fourth sub-section refers to the organometallic Pt(II) complexes which contain an amino acid or analogue coordinated through an amino terminal group or chelated through nitrogen and oxygen donor atoms. In Sect. 3, the known Pt(IV) complexes are reviewed in four sub-sections corresponding to those in Sect. 2. The same amino acid coordination modes are also found here. Finally, Sect. 4 summarizes the conclusions drawn from the previous three sections and emphasizes their most important features.

Synthesis, structural characterization and biological study of new organotin(IV), silver(I) and antimony(III) complexes with thioamides☆

An overview of our work on the synthesis and biological activity of a series of tin(IV), silver(I) and antimony(III) complexes with thioamides is reported. Organotin(IV) complexes of formulae (n-Bu)2Sn(MBZT)2 (1), Me2Sn(CMBZT)(2) (2), {(Ph3Sn)2(MNA) (Me2CO)} (3), Ph3Sn(MBZT) (4), Ph3Sn(MBZO) (5), Ph3Sn(CMBZT) (6), Ph2Sn(CMBZT)2 (7) and (n-Bu)2Sn(CMBZT)2 (8), Me2Sn(PMT)2 (9), (n-Bu)2Sn(PMT)2 (10), Ph2Sn(PMT)2 (11), Ph3Sn(PMT) (12) {where MBZT=2-mercapto-benzothiazole, CMBZT=5-chloro-2-mercapto-benzothiazole, H2MNA=2-mercapto-nicotinic acid, MBZO=2-mercapto-benzoxazole and PMTH=2-mercapto-pyrimidine} were characterized by spectroscopic (NMR, IR, Mossbauer, etc.) and X-ray diffraction techniques and their influence on the peroxidation of oleic acid was studied. They were found to inhibit strongly the peroxidation of linoleic acid by the enzyme lipoxygenase. In addition, organotin(IV) complexes were found to exhibit stronger cytotoxic activity in vitro, against leiomyosarcoma cells, than cisplatin. The antiproliferative activity of the organotin complexes studied, against leiomyosarcoma cells follow the same order of LOX activity inhibition. This is, 3>>12>7>6 approximately 8 approximately 10>5 approximately 4>>2>9. Thus, among organotin(IV)-CMBZT complexes, 7 exhibits higher activity than the others and this is explained by a free radical mechanism, as it is revealed by an EPR study. The results are compared with the corresponding ones found for the silver(I) complexes of formulae complexes {[Ag6(mu3-HMNA)4(mu3-MNA)2](2-).[(Et(3)NH)+]2.(DMSO)2.(H2O)} (13), {[Ag4Cl4(mu3-STHPMH2)4]n} (14), {[Ag6(mu2-Br)6(mu2-STHPMH2)4(mu3-STHPMH2)2]n} (15), {[Ag4(mu2STHPMH2)6](NO3)4}(n) (16), {[AgCl(TPTP)]4} (17), [AgX(TPTP)3] with X=Cl (18), Br (19), I (20) (where STHPMH2=2-mercapto-3,4,5,6-tetrahydro-pyrimidine, TPTP=tri(p-toly)phosphine) and those of antimony(III) complexes {[SbCl2(MBZIM)4](+).Cl(-).2H2O.(CH3OH)} (21), {[SbCl2(MBZIM)4]+.Cl(-).3H2O.(CH3CN)} (22), [SbCl3(MBZIM)2] (23), [SbCl3(EMBZIM)2] (24), [SbCl3(MTZD)2] (25), {[SbCl3(THPMT)2]} (26) and {[Sb(PMT)3].0.5(CH3OH)} (27) (where MBZIM is 2-mercapto-benzimidazole, EMBZIM=5-ethoxy-2-mercapto-benzimidazole and MTZD is 2-mercapto-thiazolidine), which they have characterized with similar techniques as in case of organotin(IV) complexes. Silver(I) and antimony(III) complexes were found to be cytotoxic against various cancer cell lines.

A NMR Study of the Interaction of a Three-domain Construct of ATP7A with Copper(I) and Copper(I)-HAH1 THE INTERPLAY OF DOMAINS

ATP7A is a P-type ATPase involved in copper(I) homeostasis in humans. It possesses a long N-terminal tail protruding into the cytosol and containing six copper(I)-binding domains, which are individually folded and capable of binding one copper(I) ion. ATP7A receives copper from a soluble protein, the metallochaperone HAH1. The exact role and interplay of the six soluble domains is still quite unclear, as it has been extensively demonstrated that they are strongly redundant with respect to copper(I) transport in vivo. In the present work, a three-domain (fourth to sixth, MNK456) construct has been investigated in solution by NMR, in the absence and presence of copper(I). In addition, the interaction of MNK456 with copper(I)-HAH1 has been studied. It is proposed that the fourth domain is the preferential site for the initial interaction with the partner. A significant dependence of the overall domain dynamics on the metallation state and on the presence of HAH1 is observed. This dependence could constitute the molecular mechanism to trigger copper(I) translocation and/or ATP7A relocalization from the trans-Golgi network to the plasmatic membrane.

An NMR study of the interaction between the human copper(I) chaperone and the second and fifth metal‐binding domains of the Menkes protein

The interaction between the human copper(I) chaperone, HAH1, and one of its two physiological partners, the Menkes disease protein (ATP7A), was investigated in solution using heteronuclear NMR. The study was carried out through titrations involving HAH1 and either the second or the fifth soluble domains of ATP7A (MNK2 and MNK5, respectively), in the presence of copper(I). The copper‐transfer properties of MNK2 and MNK5 are similar, and differ significantly from those previously observed for the yeast homologous system. In particular, no stable adduct is formed between either of the MNK domains and HAH1. The copper(I) transfer reaction is slow on the time scale of the NMR chemical shift, and the equilibrium is significantly shifted towards the formation of copper(I)–MNK2/MNK5. The solution structures of both apo‐ and copper(I)‐MNK5, which were not available, are also reported. The results are discussed in comparison with the data available in the literature for the interaction between HAH1 and its partners from other spectroscopic techniques.

Interaction of Cu2+ with His–Val–His and of Zn2+ with His–Val–Gly–Asp, two peptides surrounding metal ions in Cu,Zn-superoxide dismutase enzyme

His-Val-His and His-Val-Gly-Asp are two naturally occurring peptide sequences, present at the active site of Cu,Zn-superoxide dismutase (Cu,Zn-SOD). The interactions of His-Val-His=A (copper binding site) with Cu(II) and of His-Val-Gly-Asp=B (zinc binding site) with Zn(II) have been studied by using both potentiometric and spectroscopic methods (visible, EPR, NMR). The stoichiometry, stability constants and solution structure of the complexes formed have been determined. The binding modes of the species [CuAH](2+) and [CuA](+) were characterized by histamine type of coordination. [CuA](+) is further stabilized by the formation of a macrochelate with the involvement of the imidazole of the C-terminal histidine. The existence of macrochelate results in a slight distortion of the coordination geometry providing good base for the development of enzyme models. The enhanced stability of the macrochelate suppresses the formation of bis-complexes as well as the amide deprotonation. This process, however, takes place at higher pH resulting in the formation of the 4 N(-) coordinated [NH(2),N(-),N(-),N(im)] species [CuAH(2-)](-). On the other hand, in the case of the Zn(II)-His-Val-Gly-Asp system, coordination takes place at the terminal carboxylate in species [ZnBH(2)](2+). Monodentate binding occurs via the N-terminal imidazole in [ZnBH](+) while histamine type of coordination is possible in [ZnB], [ZnB(2)H](-) and [ZnB(2)](2-) species. Amide deprotonation does not take place in the case of Zn(2+), hydroxo-complexes are formed instead.

Synthesis, study and structural characterization of a new water soluble hexanuclear silver(I) cluster with the 2-mercapto-nicotinic acid with possible antiviral activity

Abstract Silver(I) chloride reacts with 2-mercapto-nicotinic acid (H2mna, C6H5NO2S) in the presence of an excess of triethylamine in DMSO to form a hexanuclear, water soluble, cluster of formula {[Ag6(μ3-Hmna)4(μ3-mna)2]2−·[(Et3NH)+]2·(DMSO)2·(H2O)} (1). The complex 1 was characterized by elemental analyses, and FT-IR, UV–Vis and 1H NMR spectroscopy. Crystal structures of complex 1 and the ligand, 2-mecapto-nicotinic acid (2), have been determined by X-ray diffraction. Compound 1, C52H68Ag6N8O15S8, is monoclinic with a space group P21/c (No. 14) and a=11.7080(10), b=16.2920(10), c=18.3010(10) A, β=91.350(10)°, Z=4. The entire molecule is ionic and consists of a double anionic hexa-nuclear cluster and two protonated triethylamine counter cations while it is solvated by two DMSO and one water molecule. The 2-mercapto-nicotinic acid (2), C6H5NO2S, is orthorhombic (space group Pna21 (No. 33), a=8.3910(10), b=13.2720(10), c=5.892 A, Z=4). An extended inter-molecular hydrogen bonding via O⋯HN contacts (O(1)⋯H(5)[N(5)]=1.8998, O(1)⋯N(5)=2.8049 A) links the molecules forming a supramolecular two-dimensional network. Complex 1, was evaluated for anti-HIV-RT activity. It was found to inhibit the human immunodeficiency viral replication reverse transcriptase (HIV-RT) with calculated inhibiting concentration (IC50) 0.01275±0.00115 mg ml−1.