An efficient, sequence-specific method for crosslinking complementary oligonucleotides using binuclear platinum complexes.

The binuclear PtII complexes [(trans-Pt(NH3)2Cl)2 (NH2(CH2)nNH2)]Cl2 (n = 4, 5 or 6), crosslink oligodeoxynucleotide-5'-phosphorothioates rapidly, specifically and efficiently to complementary single-stranded oligodeoxynucleotide targets. In the case that we investigated in detail, the most abundant crosslink is formed to the G residue complementary to the 5'-terminal C residue of the phosphorothioate. Less efficient crosslinking occurs to many other residues of the target. The same PtII complexes also bring about crosslinking efficiently to the polypurine tract in triple-helical DNA.     

Studies on the synthesis,characterisation and antimicrobial activity of new Co(II), Ni(II) and Zn(II) complexes of Schiff base derived from ninhydrin and glycine

Summary For the first time, Co(II), Ni(II) and Zn(II) complexes have been synthesized involving an intermediate Schiff base, indane-1,3-dione-2-imine-N-acetic acid the condensed product of ninhydrin and glycine. These coloured complexes were characterised by elemental analysis, molar conductivity, thermogravimetric analyses/differential thermal analysis, infrared, magnetic susceptibility, NMR and electronic spectral studies. Mechanisms for their formation have been proposed. The experimental studies reveal that the complexes possess octahedral stereochemistry whereas the Schiff base behaves as a monobasic tridentate ligand. A molecular structure for the metal complexes is also proposed. A comparative study of the antimicrobial activity of ninhydrin and the corresponding metal complexes againstEscherichia coli, Proteus mirabilis, Staphylococcus aureus andStreptococcus faecalis has been undertaken and the results are discussed.     

Spectral properties of cytochrome c' from Rhodopseudomonas capsulata B100 and its CO complex

The spectral properties of cytochrome c' from photosynthetic bacterium Rhodopseudomonas capsulata (= Rhodobacter capsulatus) B100 and its CO complex are reported. The electronic absorption, MCD, and EPR spectra have been compared with those of the other cytochromes c' and horse heart cytochrome c. EPR and electronic spectral results for the ferric cytochrome c' suggest that the ground state of heme-iron(III) at neutral pH consists of a quantum mechanical admixture of an intermediate-spin and a high-spin state and that at pH 11.0 is in a high-spin state. In the MCD spectrum of the CO-ferrous cytochrome c', the MCD intensity in the Soret band region was much higher than that of CO complexes of hemoproteins with a protoheme. The differences in a stereochemistry of the sixth-coordination position is discussed.     

Synthesis and characterization of electronically varied XCX palladacycles with functional arene groups

X-ray crystallographic studies show that varying the nature of the S-aryl ligands in SCS-Pd(II) pincer complexes and the electronic nature of the aryl substituent para to the Pd(II) group in PCP-Pd(II) pincer complexes do not lead to structural changes in these palladacycles that can be correlated with the changing nature of the ligands. While the original C2 symmetry for the S-aryl groups in SCS-Pd(II) pincer complexes seen in the case of the 2,5-bis(thiophenylmethyl)phenylpalladium chloride pincer complex is also seen in other SCS-Pd(II) pincer complexes, the relative stereochemistry of the S-aryl rings is not consistently maintained in 2,5-bis((4-dimethylaminothiophenyl)methyl)-phenylpalladium chloride.     

Aluminium(III), chromium(III) and iron(III) complexes with 5-iodouracil and 5-iodouracil-histidine and their antitumour activity

Complexes of the type [Al(HL)(OH)Cl(2)], [M(HL)(OH)(2)Cl] and [M'(HL)(L')(OH)Cl], where HL = 5-iodouracil; HL' = histidine; M = Cr(III), Fe(III) and M' = Al(III), Cr(III), Fe(III), were synthesized and characterized. The complexes are polymeric showing high decomposition points and are insoluble in water and common organic solvents. The mu(eff) values, electronic spectral bands and ESR spectra suggest a polymeric 6-coordinate spin-free octahedral stereochemistry for the Cr(III) and Fe(III) complexes. 5-Iodouracil acts as a monodentate ligand coordinating to the metal ion through the O atom of C((4)) = O while histidine through the O atom of -COO(- ) and the N atom of -NH(2) group. In vivo antitumour effect of 5-iodouracil and its complexes was examined on C(3)H /He mice against P815 murine mastocytoma. As evident from their T/C values, Cr(III) and Fe(III) complexes display significant and higher antitumour activity compared to the 5-iodouracil ligand. The in vitro results of the complexes on the same cells indicate that Cr(III) and Fe(III) complexes show higher inhibition on (3)H-thymidine and (3)H-uridine incorporation in DNA and RNA replication, respectively, at a dose of 5 microg/mL.     

Optimization of the efficiency of cross-linking PtII oligonucleotide phosphorothioate complexes to complementary oligonucleotides.

We have investigated the efficiency with which PtII complexes cross-link phosphorothioates of oligonucleotides to complementary DNA targets. The A and G residues 2-5 bases downstream from the 5'-phosphorothioate group are preferred sites for cross-linking. Replacement of residues in this part of the target by T residues results in greatly decreased cross-linking when cis platinum diammine dichloride (cisPtII) or potassium platinous chloride (K2PtCl4) are used. Trans platinum diammine dichloride (transPtII) forms cross-links with T residues if A and G residues are absent from the susceptible region of the target. Oligomers containing an internal phosphorothioate group can also be linked to their templates with transPtII, but not with cisPtII or K2PtCl4. Cross-linking via an internal phosphorothioate group tends to be less efficient than cross-linking via a 5'-terminal phosphorothioate. The Sp isomers of internal phosphorothioates are cross-linked more efficiently than the Rp isomers. Preliminary experiments suggest that the efficiency of cross-linking to RNA targets will prove similar to that found for DNA targets.     

Synthesis,structure and catechol-oxidase activity of copper(II) complexes of 17-hydroxy-16-(N-3-oxo-prop-1-enyl)amino steroids

Copper is next to iron the most important element in the biological transport, storage and in redox reactions of dioxygen. A bioanalogous activation of dioxygen with copper complexes is used for catalytical epoxidation, allylic hydroxylation and oxidative coupling of aromatic substrates, for example. With stereochemical information in form of chiral ligands, enantioselective reactions may be possible. Another aspect of interest on copper catalyzed reactions with dioxygen is that the exact mechanism and biological function of some enzymes (especially catechol oxidase) is yet not fully clear. For studies mimicking the copper-containing catechol oxidase appropriate chiral steroid ligands with defined stereochemistry and conformation have been synthesized. The four diastereomeric 16,17-aminoalcohols of the 3-methoxy-estra-1,3,5(10)-triene series have been condensed with salicylic aldehyde and different beta-ketoenols to the chiral ligand types 1-5. These compounds with different steric and electronic properties and different arrangements of the neighboring hydroxy and nitrogen functions were reacted with copper(II) acetate to copper complexes. The structure of these complexes will be discussed. The bioanalogous oxidation of 3,5-di-tbutyl-catechol (dtbc) to the corresponding quinone was catalyzed by most of the complexes, indicating their ability to activate dioxygen. The trans configurations c and d showed an activity one magnitude higher than the cis configurations a and b. Comparing compounds with the same diastereomeric configuration, the main influence was that of the peripheral R(1-3) substituents at the beta-ketoenaminic group which are useful for the fine-tuning of the properties of the copper atoms like redox potential and Lewis acidity.     

Binding of 9-aminoacridine to deoxydinucleoside phosphates of defined sequence: Preferences and stereochemistry

The effect of sequence on the binding of 9-aminoacridine to DNA has been investigated by studying its interaction with deoxydinucleoside phosphates of different sequences using proton nuclear magnetic resonance. Quantitative binding information can be obtained by comparison of the proton chemical shift behavior of 9-aminoacridine upon addition of dinucleoside phosphate to various models for the interaction using least-squares computer fitting procedures. The simplest model that fits the data includes (1) dimerization of 9-aminoacridine and (2) a mixture of 1:1 and 2:1 (dinucleoside phosphate/9-aminoacridine) complexes. The computed parameters allow comparison of binding constants and stereochemistry for different sequences. The 1:1 complexes seem to involve interaction of the ring nitrogen with the backbone phosphate and stacking of one or both chromophores on the acridine; preference in binding is observed for alternating (purine-pyrimidine or pyrimidine-purine) over non-alternating (purine-purine) dinucleoside phosphates. The 2:1 complexes involve intercalation of the acridine between two complementary dinucleoside phosphate strands with weak sequence preferences in binding. The stereochemistry of intercalation differs between non-alternating purine-purine sequences and the alternating pyrimidine-purine or purine-pyrimidine sequences in having the 9-aminoacridine stacked with the purines of one strand rather than straddling the purines on opposite strands. The difference in stereochemistry could possibly be a determining factor in frameshift sequence specificity.     

Macrocyclic polyphosphane ligands: cobalt(II) and nickel(II) complexes of 1,10-dipropyl-4RS, 7SR, 13SR, 16RS-tetraphenyl-1,10-diaza-4,7,13,16-tetraphospha-cyclooctadecane and crystal structure of the cobalt tetraphenylborate monohydrate complex

The X-ray crystal structure of the title compound has been carried out. The crystals are triclinic, space group P$\text{1}$, a = 13.252(2), b = 13.943(2), c = 24.316(5) Å, α = 70.660(14), β = 75.219(14), γ = 69.231(13)° for Z = 2. The structure has been refined to an R factor of 0.069 by the least-squares technique. The cobalt atom is five-coordinated by the four phosphorus atoms of the macrocycle and by a water molecule forming a distorted square-pyramidal geometry. The stereochemistry of some cobalt(II) and nickel(II) complexes of the same ligand were investigated, in the solid state and in solution, by electronic spectroscopy.     

Group IIB metal chloride complexes with some 2-(methylpyridyl or -quinolyl)benz-X-azoles

The complexes formed by Zn(II), Cd(II) and Hg(II) chlorides with benzimidazole, benzoxazole and benzothiazole linked to 4-methylpyridine and 4-methylquinoline have been prepared and characterized by chemical analysis, infrared spectra and conductivity data.The coordination behaviour of these ligands toward the metal salts and the stereochemistry of the obtained complexes have been investigated.     

Circularly polarized luminescence studies of the ternary complexes formed by Tb(III) with (S,S)-ethylenediamine-N,N′-disuccinic acid and achiral substrate ligands

Circularly polarized luminescence spectroscopy has been used to study the ternary complexes formed by Tb(III) with (S,S)-ethylenediamine-N,N′-disuccinic acid (EDDS) and a series of achiral carboxylate ligands. The 1:1 Tb(EDDS) complexes form polynuclear species at low pH values, and only oxalic acid was able to interfere with this process. At elevated pH values the Tb(EDDS) compounds become monomeric, and are capable of forming ternary complexes. When the steric requirements of the substrate ligand were small, no perturbation of the EDDS stereochemistry was noted. However, certain strongly binding bidentate ligands with larger steric requirements were found to interact with the coordinated EDDS ligand. Evidence was also obtained which indicated that strongly binding terdentate ligands could partially displace one or more of the ligating carboxylates of the EDDS ligand.     

Hydrogen bond stereochemistry in protein structure and function

Fifty high resolution protein structures from the Brookhaven Protein Data Bank have been analyzed for recurring motifs in hydrogen bond stereochemistry. Although an exhaustive analysis of hydrogen bond statistics has been presented by Baker & Hubbard, a detailed stereochemical analysis of classical donor (N-H, O-H, or S-H) and acceptor (N:, O:, or S:) structure within proteins is lacking. Here, we describe the preferential hydrogen bond stereochemistry for the side-chains of glutamate and aspartate (carboxylate), glutamine and asparagine (carboxamide), arginine (guanidinium), histidine (imidazole/imidazolium), tryptophan (indole), tyrosine (phenolic hydroxyl), lysine (ammonium), serine and threonine (alkyl hydroxyl), cysteine (thiol), methionine (thioether) and cystine (disulfide). Preferential hydrogen bond stereochemistry is governed by (1) the electronic configuration of acceptor atoms, (2) the steric accessibility of donor atoms and (3) the conformation of amino acid side-chains. Applications of hydrogen bond stereochemistry are useful in the interpretation of protein structure, function and stability. Additionally, this stereochemistry is a prerequisite to the interpretation of protein-other molecule recognition and biological catalysis.     

Ternary interactions of spermine with DNA: 4''-epiadriamycin and other DNA: anthracycline complexes.

The recently developed anthracycline 4'-epiadriamycin, an anti-cancer drug with improved activity, differs from adriamycin by inversion of the stereochemistry at the 4'-position. We have cocrystallized 4'-epiadriamycin with the DNA hexamer d(CGATCG) and solved the structure to 1.5 A resolution using x-ray crystallography. One drug molecule binds at each d(CG) step of the hexamer duplex. The anthracycline sugar binds in the minor groove. A feature of this complex which distinguishes it from the earlier DNA:adriamycin complex is a direct hydrogen bond from the 4'-hydroxyl group of the anthracycline sugar to the adenine N3 on the floor of the DNA minor groove. This hydrogen bond results directly from inversion of the stereochemistry at the 4'-position. Spermine molecules bind in the major groove of this complex. In anthracycline complexes with d(CGATCG) a spermine molecule binds to a continuous hydrophobic zone formed by the 5-methyl and C6 of a thymidine, C5 and C6 of a cytidine and the chromophore of the anthracycline. This report discusses three anthracycline complexes with d(CGATCG) in which the spermine molecules have different conformations yet form extensive van der Waals contacts with the same hydrophobic zone. Our results suggest that these hydrophobic interactions of spermine are DNA sequence specific and provide insight into the question of whether DNA:spermine complexes are delocalized and dynamic or site-specific and static.     

Contribution of protein conformation to stereochemistry and reactivity of the active center of heme proteins and enzymes. The existence of horseradish peroxidase conformations and their possible role in the catalysis mechanism

In the spectral region 350-800 nm at 4.2 K we measured magnetic circular dichroism (MCD) spectra of the pentacoordinated complex of protcheme with 2-methylimidazole, deoxyleghemoglobin, neutral and alkaline forms of reduced horseradish peroxidase in the equilibrium states, as well as in non-equilibrium states produced by low-temperature photolysis of their carbon monoxide derivatives. Earlier the corresponding results have been obtained for myoglobin, hemoglobin and cytochromes P-450 and P-420. The energies of Fe-N (proximal His) and Fe-N(pyrroles) bonds and their changes upon ligand binding in heme proteins and enzymes were compared with those in the model heme complex thus providing conformational contribution into stereochemistry of the active site. The examples of weak and strong conformational "pressure" on stereochemistry were analysed and observed. If conformational energy contribution into stereochemistry prevails the electronic one the heme stereochemistry remains unchanged on ligand binding as it was observed for leghemoglobin and alkaline horseradish peroxidase. The change of bond energies in myoglobin and hemoglobin on ligand binding are comparable with those in protein free pentacoordinated protoheme, giving an example of weak conformational contribution to heme stereochemistry. The role of protein conformation energy in the modulation of ligand binding properties of heme in leghemoglobin relative to those in myoglobins is discussed. The most striking result were obtained in the study of reduced horseradish peroxidase in the pH region of 6.0-10.2. It was found that such different perturbations as ligand binding and heme-linked ionization of the distal amino acid residue induce identical changes in heme stereochemistry. Neither heme-linked ionization in the carbon monoxide complex nor the geometry of Fe-Co bond affect the heme local structure of photoproducts. These and other findings suggest a very low conformation mobility of horseradish peroxidase whose protein constraints appear to allow only two preferable geometries of specific amino acid residues that form the heme pocket. The role of the two tertiary structure constraints on the heme in the mechanism of horseradish peroxidase function is discussed. It is supposed that one conformation produces a heme environment suitable for two-electron oxidation of the native enzyme to compound I by hydrogen peroxide while another conformation changes the heme stereochemistry in the direction favourable for back reduction of compound I by the substrate to the resting enzyme through two one-electron steps. The switch from one tertiary structure to another is expected to be induced by substrate bind     

Complexation of Pd(II) with nucleosides. Evidence for a strong interaction Pd⋯HN by NMR

Bis-derivatives of phenylantimony(III) with some monothio-β-diketones have been synthesized and characterized as five coordination species by elemental analyses, molecular weight and spectral data. The stereochemistry of the complexes having asymmetrical ligands is discussed.     

Preparation, characterization, and antitumor activity of new cisplatin analogs with homopiperazines: crystal structure of [PtII(1-methylhomopiperazine)(methylmalonato)].2H2O

A series of new platinum(II) and (IV) complexes with homopiperazine have been synthesized and characterized by elemental analysis, infrared, and 195Pt nuclear magnetic resonance spectroscopic techniques. The complexes are of two types: [PtIILX] (where L = homopiperazine (hpip), 1-methylhomopiperazine (mhpip), or 1,4-dimethylhomopiperazine (dmhpip), and X = 1,1-cyclobutanedicarboxylato (CBDCA), or methylmalonato ligand) and [PtIV(L-)trans-(Y)2Cl2] (where Y = hydroxo, acetato, or chloro ligand). Among the complexes synthesized, the crystal structure of [PtII(mhpip)(methylmalonato)].2H2O was determined by the single crystal X-ray diffraction method. The crystallographic parameters were orthorhombic, P2(1)2(1)2(1) (no. 19), a = 7.2014(14), b = 7.3348(15), c = 26.971(5) A, and Z = 4. The structure refinements converged to R1 = 0.0641 and wR2 = 0.1847. In this complex, platinum has a slightly distorted square planar geometry with the two adjacent corners being occupied by two nitrogens of the mhpip ligand, whereas the remaining cis positions are coordinated with two oxygen atoms of the methylmalonato group. The mhpip ligand is in a boat conformation and forms five and six membered chelating rings with platinum. The intricate network of intermolecular hydrogen bonds holds the crystal lattice together. Some of these synthesized cisplatin analogs have good in vitro cytotoxic activity against the cisplatin-sensitive human ovarian A2780 (IC50 = 0.083-17.8 microM) and the isogenic cisplatin-resistant 2780CP (IC50 = 20.1-118.1 microM) cell lines.     

Absolute stereochemistry of novel isochromanone derivatives from Leptosphaeria sp. KTC 727

A novel isochromanone, (S)-8-hydroxy-6-methoxy-4,5-dimethyl-3-methylene-isochromen-1-one (1), known 2 and previously reported metabolites from Leptosphaeria sp. KTC 727 (JCM 13076 = MAFF 239586) were isolated from the same source by culturing for a relatively long period. The results of the present study disclose their structures involving the absolute stereochemistry. The planar structures of these molecules were established by ESIMS and NMR spectral analyses. The absolute configuration of 1 was established by comparing its electronic circular dichroism (ECD) spectrum with that of structurally-related known compound 3. The relative stereochemistry of 2 was revealed by a combination of nuclear Overhauser effect (NOE) experiments and thermodynamic discussions. Successful transformation of 1 to 2 led us to assign the configuration of 2 after comparing their ECD spectra. These compounds exhibited weak antifungal activities against Cochliobolus miyabeanus.     

Stereochemistry of guanidine-metal interactions: implications for L-arginine-metal interactions in protein structure and function

The geometries of 150 guanidine-metal ion interactions retrieved from crystal structures deposited in the Cambridge Structural Database have been analyzed. Metal ions exhibit a preference for anti coordination stereochemistry in the plane of the unprotonated guanidine group, usually in chelate complexes with a diguanidine moiety, but syn-oriented interactions are occasionally found for single guanidine-metal interactions. Three L-arginine-metal coordination interactions are found in metalloenzyme structures deposited in the Protein Data Bank: biotin synthase from E. coli, His-67 --> Arg human carbonic anhydrase I, and inactivated B. caldovelox arginase complexed with L-arginine. In these proteins, L-arginine-metal coordination adopts syn/out-of-plane and anti/in-plane coordination stereochemistry. The implications of these results for L-arginine-metal interactions in protein structure and function are discussed. Although such interactions are rare, this analysis serves as a useful reference point for the growing interest in enzymes containing L-arginine residues that function as general bases or metal ligands.     

Contribution of protein conformation to heme stereochemistry and reactivity. Low-temperature magnetic circular dichroism data

Visible and near infrared magnetic circular dichroism (MCD) spectra of heme proteins and enzymes as well as those of a protein-free heme bound to 2-methylimidazole were recorded and compared at 4.2 K in unrelaxed metastable and relaxed equilibrium heme stereochemistry. The relaxed and unrelaxed stereochemistries of a 5-coordinate ferrous heme were generated by chemical reduction of iron at room temperature before freezing the sample and by photolysis of CO or O2 complexes at 4.2 K, respectively. The results are discussed in terms of a protein contribution into energies of the Fe-N epsilon(His) and Fe-N(pyrrols) bonds and their change on a ligand binding. We observed and analyzed cases of weak (myoglobin, hemoglobin) and strong (leghemoglobin, peroxidases) constraints imposed by the protein conformation on the proximal heme stereochemistry by comparing the bond energies in proteins with those in the protoheme-(2-methylimidazole) model compound. The role of a protein moiety in modulating the ligand binding properties of leghemoglobin and the heme reactivity of horseradish peroxidase is discussed.