Metal-Nucleotide Interactions: Crystal Structures of Alkali (Li+, Na+, K+) and Alkaline Earth (Ca2+, Mg2+) Metal Complexes of Adenosine 2'-Monophosphate

Crystal structures of lithium, sodium, potassium, calcium and magnesium salts of adenosine 2'-monophosphate (2'-AMP) have been obtained at atomic resolution by X-ray crystallographic methods. 2'-AMP.Li belongs to the monoclinic space group P21 with a = 7.472(3)Å, b = 26.853(6) Å, c = 9.184(1)Å, b = 113.36(1)Å and Z= 4. 2'-AMP.Na and 2'-AMP.K crystallize in the trigonal space groups P31 and P3121 with a = 8.762(1)Å, c = 34.630(5)Å, Z= 6 and a = 8.931(4), Åc = 34.852(9)Å and Z= 6 respectively while 2'-AMP.Ca and 2'-AMP.Mg belong to space groups P6522 and P21 with cell parameters a = 9.487(2), c = 74.622(13), Z = 12 and a = 4.973(1), b = 10.023(2), c = 16.506(2), beta = 91.1(0) and Z = 2 respectively. All the structures were solved by direct methods and refined by full matrix least-squares to final R factors of 0.033, 0.028, 0.075, 0.069 and 0.030 for 2'-AMP.Li, 2'-AMP.Na, 2'- AMP.K, 2'-AMP.Ca and 2'-AMP.Mg, respectively. The neutral adenine bases in all the structures are in syn conformation stabilized by the O5'-N3 intramolecular hydrogen bond as in free acid and ammonium complex reported earlier. In striking contrast, the adenine base is in the anti geometry (cCN = -156.4(2)°) in 2'-AMP.Mg. Ribose moieties adopt C2'-endo puckering in 2'-AMP.Li and 2'-AMP.Ca, C2'-endo-C3'-exo twist puckering in 2'-AMP.Na and 2'-AMP.K and a C3'-endo-C2'-exo twist puckering in 2'-AMP.Mg structure. The conformation about the exocyclic C4'-C5' bond is the commonly observed gauche-gauche (g+) in all the structures except the gauche- trans (g-) conformation observed in 2'-AMP.Mg structure. Lithium ions coordinate with water, ribose and phosphate oxygens at distances 1.88 to 1.99Å. Na+ ions and K+ ions interact with phosphate and ribose oxygens directly and with N7 indirectly through a water oxygen. A distinct feature of 2'-AMP.Na and 2'-AMP.K structures is the involvement of ribose O4' in metal coordination. The calcium ion situated on a two-fold axis coordinates directly with three oxygens OW1, OW2 and O2 and their symmetry mates at distances 2.18 to 2.42Å forming an octahedron. A classic example of an exception to the existence of the O5'-N3 intramolecular hydorgen bond is the 2'-AMP.Mg strucure. Magnesium ion forms an octahedral coordination with three water and three phosphate oxygens at distances ranging from 2.02 to 2.11Å. A noteworthy feature of its coordination is the indirect link with N3 through OW3 oxygen resulting in macrochelation between the base and the phosphate group. Greater affnity of metal clays towards 5' compared to 2' and 3' nucleotides (J. Lawless, E. Edelson, and L. Manring, Am. Chem. Soc. Northwest Region Meeting, Seattle. 1978) due to macrochelation infered from solution studies (S. S. Massoud, H. Sigel, Eur. J. Biochem. 179, 451-458 (1989)) and interligand hydrogen bonding induced by metals postulated from metal-nucleotide structures in solid state (V. Swaminathan and M. Sundaralingam, CRC. Crit. Rev. Biochem. 6, 245-336 (1979)) are borne out by our structures also. The stacking patterns of adenine bases of both 2'-AMP.Na and 2'-AMP.K structures resemble the 2'-AMP.NH4 structure reported in the previous article. 2'-AMP.Li, 2'-AMP.Ca and 2'-AMP.Mg structures display base-ribose O4' stacking. An overview of interaction of monovalent and divalent cations with 2' and 5'-nucleotides has been presented.

PIM2 Induced COX-2 and MMP-9 Expression in Macrophages Requires PI3K and Notch1 Signaling

Activation of inflammatory immune responses during granuloma formation by the host upon infection of mycobacteria is one of the crucial steps that is often associated with tissue remodeling and breakdown of the extracellular matrix. In these complex processes, cyclooxygenase-2 (COX-2) plays a major role in chronic inflammation and matrix metalloproteinase-9 (MMP-9) significantly in tissue remodeling. In this study, we investigated the molecular mechanisms underlying Phosphatidyl-myo-inositol dimannosides (PIM2), an integral component of the mycobacterial envelope, triggered COX-2 and MMP-9 expression in macrophages. PIM2 triggers the activation of Phosphoinositide-3 Kinase (PI3K) and Notch1 signaling leading to COX-2 and MMP-9 expression in a Toll-like receptor 2 (TLR2)-MyD88 dependent manner. Notch1 signaling perturbations data demonstrate the involvement of the cross-talk with members of PI3K and Mitogen activated protein kinase pathway. Enforced expression of the cleaved Notch1 in macrophages induces the expression of COX-2 and MMP-9. PIM2 triggered significant p65 nuclear factor-kappa B (NF-kappa B) nuclear translocation that was dependent on activation of PI3K or Notch1 signaling. Furthermore, COX-2 and MMP-9 expression requires Notch1 mediated recruitment of uppressor of Hairless (CSL) and NF-kappa B to respective promoters. Inhibition of PIM2 induced COX-2 resulted in marked reduction in MMP-9 expression clearly implicating the role of COX-2 dependent signaling events in driving the MMP-9 expression. Taken together, these data implicate PI3K and Notch1 signaling as obligatory early proximal signaling events during PIM2 induced COX-2 and MMP-9 expression in macrophages.

Iron(III) Schiff base complexes of arginine and lysine as netropsin mimics showing AT-selective DNA binding and photonuclease activity

Iron(III) complexes [Fe(L)(2)]Cl (1-3), where L is monoanionic N-salicylidene-arginine (sal-argH for 1), hydroxynaphthylidene-arginine (nap-argH for 2) and N-salicylidene-lysine (sal-lysH for 3), were prepared and their DNA binding and photo-induced DNA cleavage activity studied. Complex 3 as its hexafluorophosphate salt [Fe(sal-lysH)(2)](PF6)center dot 6H(2)O (3a) was structurally characterized by single crystal Xray crystallography. The crystals belonged to the triclinic space group P-1. The complex has two tridentate ligands in FeN2O4 coordination geometry with two pendant cationic amine moieties. Complexes 1 and 2 with two pendant cationic guanidinium moieties are the structural models for the antitumor antibiotics netropsin. The complexes are stable and soluble in water. They showed quasi-reversible Fe(III)/Fe(II) redox couple near 0.6 V in H2O-0.1 M KCl. The high-spin 3d(5)-iron(III) complexes with mu(eff) value of similar to 5.9 mu(B) displayed ligand-to-metal charge transfer electronic band near 500 mm in Tris-HCl buffer. The complexes show binding to Calf Thymus (CT) DNA. Complex 2 showed better binding propensity to the synthetic oligomer poly(dA)center dot poly(dT) than to CT-DNA or poly(dG)center dot poly(dC). All the complexes displayed chemical nuclease activity in the presence of 3-mercaptopropionic acid as a reducing agent and cleaved supercoiled pUC19 DNA to its nicked circular form. They exhibited photo-induced DNA cleavage activity in UV-A light and visible light via a mechanistic pathway that involves the formation of reactive hydroxyl radical species. (C) 2010 Elsevier Inc. All rights reserved.

Synthesis, structure and magnetic behavior of a new three-dimensional Manganese phosphite-oxalate: [C2N2H10][Mn-2(II)(OH2)(2)(HPO3)(2)(C2O4)]

A novel manganese phosphite-oxalate, [C2N2H10][Mn-2(II)(OH2)(2)(HPO3)(2)(C2O4)] has been hydothermally synthesized and its structure determined by single-crystal X-ray diffraction. The structure consists of neutral manganese phosphite layers, [Mn(HPO3)](infinity), formed by MnO6 octahedra and HPO3 units, cross-linked by the oxalate moieties. The organic cations occupy the middle of the 8-membered one dimensional channels. Magnetic studies indicate weak antiferromagnetic interactions between the Mn2+ ions. (C) 2009 Elsevier Inc. All rights reserved.

Uniqueness of Walkup's 9-vertex 3-dimensional Klein bottle

Via a computer search, Altshuler and Steinberg found that there are 1296+1 combinatorial 3-manifolds on nine vertices, of which only one is non-sphere. This exceptional 3-manifold View the MathML source triangulates the twisted S2-bundle over S1. It was first constructed by Walkup. In this paper, we present a computer-free proof of the uniqueness of this non-sphere combinatorial 3-manifold. As opposed to the computer-generated proof, ours does not require wading through all the 9-vertex 3-spheres. As a preliminary result, we also show that any 9-vertex combinatorial 3-manifold is equivalent by proper bistellar moves to a 9-vertex neighbourly 3-manifold.

Addition of hydrogen cyanide to 9-methyl- Δ4-octalone-3 and 9β-methyl-8β-hydroxy- Δ4-octalone-3

Addition of hydrogen cyanide to 9-methyl-Δ4-octalone-3 (IIb), as a model, yielded both cis- and trans-ketonitriles the configurations of which are assigned on the basis of IR spectra of the hydrolysed products. Similar addition of hydrogen cyanide to 9β-methyl-8β-hydroxy-Δ4-octalone-3 (IIc) gave the corresponding cis- and trans-hydroxy-keto-nitriles, configurations of which were proved by their conversion into cis- and trans-keto-nitriles obtained in the model study. In contrast to the model experiment where the trans-product predominated, the cis-isomer was the major product of addition to IIc.

Quinone studies—Istar, open: Evidence for a new type of substitution reaction of phenanthrene-9,10-quinone derivatives

The para orientation by the carbonyl groups in the bromination of phenanthrenequinone derivatives has been explained on the basis of an excited state resulting from thermal excitation of the quinone and/or from a n→π* transition of the nonbonding electrons of the oxygen atoms. A general preparative method for the syntheses of 3-bromophenanthrenequinone derivatives has been developed. The structure of 2-nitro-6-bromophenanthrenequinone has been established by degradation. Synthesis of 2-nitro-6-bromofluorenone is described. Direct bromination of phenanthrenequinone to 2-bromo and 2,7-dibromo derivatives has also been described.

Search for the Production of Narrow tb̅ Resonances in 1.9 fb-1 of pp̅ Collisions at √s=1.96 TeV

We present new limits on resonant tb production in proton-antiproton collisions at 1.96 TeV, using 1.9 fb^-1 of data recorded with the CDF II detector at the Fermilab Tevatron. We reconstruct a candidate mass in events with a lepton, neutrino candidate, and two or three jets, and search for anomalous tb production as modeled by W'->tb. We set a new limit on a right-handed W' with standard model-like coupling, excluding any mass below 800 GeV at 95% C.L. The cross-section for any narrow, resonant tb production between 750 and 950 GeV is found to be less than 0.28 pb at 95% C.L. We also present an exclusion of the W' coupling strength versus W' mass over the range 300 to 950 GeV.

Transverse momentum and pseudorapidity distributions of charged hadrons in pp collisions at sqrt(s) = 0.9 and 2.36 TeV

Measurements of inclusive charged-hadron transverse-momentum and pseudorapidity distributions are presented for proton-proton collisions at sqrt(s) = 0.9 and 2.36 TeV. The data were collected with the CMS detector during the LHC commissioning in December 2009. For non-single-diffractive interactions, the average charged-hadron transverse momentum is measured to be 0.46 +/- 0.01 (stat.) +/- 0.01 (syst.) GeV/c at 0.9 TeV and 0.50 +/- 0.01 (stat.) +/- 0.01 (syst.) GeV/c at 2.36 TeV, for pseudorapidities between -2.4 and +2.4. At these energies, the measured pseudorapidity densities in the central region, dN(charged)/d(eta) for |eta|

Kinetics and the mechanism of interaction of the endoplasmic reticulum chaperone, calreticulin, with monoglucosylated (Glc(1)Man(9)GlcNAc(2)) substrate

Calreticulin is a lectin-like molecular chaperone of the endoplasmic reticulum in eukaryotes. Its interaction with N-glycosylated polypeptides is mediated by the glycan, Glc(1)Man(9)GlcNAc(2), present on the target glycoproteins. In this work, binding of monoglucosyl IgG (chicken) substrate to calreticulin has been studied using real time association kinetics of the interaction with the biosensor based on surface plasmon resonance (SPR). By SPR, accurate association and dissociation rate constants were determined, and these yielded a micromolar association constant. The nature of reaction was unaffected by immobilization of either of the reactants. The Scatchard analysis values for K-a agreed web crith the one obtained by the ratio k(1)/k(-1). The interaction was completely inhibited by free oligosaccharide, Glc(1)Man(9)GlcNAc(2), whereas Man(9)GlcNAc(2) did not bind to the calreticulin-substrate complex, attesting to the exquisite specificity of this interaction. The binding of calreticulin to IgG was used for the development of immunoassay and the relative affinity of the lectin-substrate association was indirectly measured. The values are in agreement with those obtained with SPR. Although the reactions are several orders of magnitude slower than the diffusion controlled processes, the data are qualitatively and quantitatively consistent with single-step bimolecular association and dissociation reaction. Analyses of the activation parameters indicate that reaction is enthalpically driven and does not involve a highly ordered transition state. Based on these data, the mechanism of its chaperone activity is briefly discussed.

Total synthesis ofdl-9(11)-dehydrotestosterone anddl-testosterone

17β-Hydroxy-des-A-androst-9-en-5-one (II, R=OH), prepared fromtrans-1β-hydroxy-8-methyl-4, 5-(3′-methyl-4′-methoxybenzo)-hydrindane (I, R=CH3)′, has been converted intodl-9(II)-dehydrotestosterone (IV, R=OH) anddl-testosterone (IX) in very short sequences of steps, albeit in poor yields.