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1.  μ-Oxalato-bis­[(2,2′-bipyridyl)­copper(II)] bis(perchlorate) dimethyl­formamide disolvate monohydrate 
The title compound, [Cu2(C2O4)(C10H8N2)4](ClO4)2·2C3H7NO·H2O, contains doubly charged centrosymmetric dinuclear oxalato-bridged copper(II) complex cations, perchlorate anions, and DMF and water solvate mol­ecules. In the complex cation, the oxalate ligand is coordinated in a bis-bidentate bridging mode to the Cu atoms. Each Cu atom has a distorted tetra­gonal-bipyramidal environment, being coordinated by two N atoms of the two chelating bipy ligands and two O atoms of the doubly deprotonated oxalate anion. Pairs of perchlorate anions and water mol­ecules are linked into recta­ngles by O—H⋯O bonds in which the perchlorate O atoms act as acceptors and the water mol­ecules as donors. Methyl groups of the DMF solvent molecule are disordered over two sites with occupancies of 0.453 (7):0.547 (7), and the water molecule is half-occupied.
PMCID: PMC3008067  PMID: 21588513
2.  Bioactivation of the human carcinogen aristolochic acid 
Carcinogenesis  2014;35(8):1814-1822.
N-hydroxyaristolactams, stable products of the partial reduction of aristolochic acids, serve as substrates for several sulfotransferases. In turn, the sulfated intermediate reacts with DNA to form aristolactam–DNA adducts. NAD(P)H:quinone oxidoreductase-1-mediated reduction of aristolochic acids is facilitated by SULT1B1.
Aristolochic acids are potent human carcinogens; the role of phase II metabolism in their bioactivation is unclear. Accordingly, we tested the ability of the partially reduced metabolites, N-hydroxyaristolactams (AL-NOHs), and their N-O-sulfonated and N-O-acetylated derivatives to react with DNA to form aristolactam–DNA adducts. AL-NOHs displayed little or no activity in this regard while the sulfo- and acetyl compounds readily form DNA adducts, as detected by 32P-post-labeling analysis. Mouse hepatic and renal cytosols stimulated binding of AL-NOHs to DNA in the presence of adenosine 3'-phosphate 5'-phosphosulfate (PAPS) but not of acetyl-CoA. Using Time of Flight liquid chromatography/mass spectrometry, N-hydroxyaristolactam I formed the sulfated compound in the presence of PAPS and certain human sulfotransferases, SULT1B1 >>> SULT1A2 > SULT1A1 >>> SULT1A3. The same pattern of SULT reactivity was observed when N-hydroxyaristolactam I was incubated with these enzymes and PAPS and the reaction was monitored by formation of aristolactam–DNA adducts. In the presence of human NAD(P)H:quinone oxidoreductase, the ability of aristolochic acid I to bind DNA covalently was increased significantly by addition of PAPS and SULT1B1. We conclude from these studies that AL-NOHs, formed following partial nitroreduction of aristolochic acids, serve as substrates for SULT1B1, producing N-sulfated esters, which, in turn, are converted to highly active species that react with DNA and, potentially, cellular proteins, resulting in the genotoxicity and nephrotoxicity associated with ingestion of aristolochic acids by humans.
PMCID: PMC4123648  PMID: 24743514
Inorganic chemistry  2007;46(22):9192-9200.
The occurence of a heteroatom X (C, N, or O) in the MoFe7S9X core of the iron-molybdenum cofactor of nitrogenase has encouraged synthetic attempts to prepare high nuclearity M-Fe-S-X clusters containing such atoms. We have previously shown that reaction of the edge-bridged double cubane [(Tp)2Mo2Fe6S8(PEt3)4] (1) with nucleophiles HQ− affords the clusters [(Tp)2Mo2Fe6S8Q(QH)2]3− (Q = S, Se) in which HQ− is a terminal ligand and Q2− is a μ2-bridging atom in the core. Reactions with OH- used as such or oxygen nucleophiles generated in acetonitrile from (Bu3Sn)2O or Me3SnOH and fluoride were examined. Reaction of 1 with Et4NOH in acetonitrile/water generates [(Tp)2Mo2Fe6S9(OH)2]3− (3), isolated as [(Tp)2Mo2Fe6S9(OH)(OC(=NH)Me)(H2O)]3− and shown to have the [Mo2Fe6(μ2-S)2(μ3-S)6(μ6-S)] core topology very similar to the PN cluster of nitrogenase. The reaction system 1/Et4NOH in acetonitrile/methanol yields the PN-type cluster [(Tp)2Mo2Fe6S9(OMe)2(H2O)]3− (5). The system 1/Me3SnOH/F− affords the oxo-bridged double PN-type cluster {[(Tp)2Mo2Fe6S9(μ2-O)]2}5− (7), convertible to the oxidized cluster {[(Tp)2Mo2Fe6S9(μ2-O)]2}4− (6), which is prepared independently from [(Tp)2Mo2Fe6S9F2(H2O)]3−/(Bu3Sn)2O. In the preparations of 3–5 and 7, hydroxide liberates sulfide from 1 leading to the formation of PN-type clusters. Unlike reactions with HQ−, no oxygen atoms are integrated into the core structures of the products. However, the half-dimer composition [Mo2Fe6S9O] relates to the MoFe7S9 consitution of the putative native cluster with X = O. (Tp = hydrotris(pyrazolyl) borate(1-)).
PMCID: PMC2527064  PMID: 17892284
Toxicology and applied pharmacology  2006;215(2):158-167.
Cutaneous drug reactions (CDRs) associated with sulfonamides are believed to be mediated through the formation of reactive metabolites that result in cellular toxicity and protein haptenation. We evaluated the bioactivation and toxicity of sulfamethoxazole (SMX) and dapsone (DDS) in normal human dermal fibroblasts (NHDF). Incubation of cells with DDS or its metabolite (D-NOH) resulted in protein haptenation readily detected by confocal microscopy and ELISA. While the metabolite of SMX (S-NOH) haptenated intracellular proteins, adducts were not evident in incubations with SMX. Cells expressed abundant N-acetyltransferase-1 (NAT1) mRNA and activity, but little NAT2 mRNA or activity. Neither NAT1 nor NAT2 protein were detectable. Incubation of NHDF with S-NOH or D-NOH increased reactive oxygen species formation and reduced glutathione content. NHDF were less susceptible to the cytotoxic effect of S-NOH and D-NOH than are keratinocytes. Our studies provide the novel observation that NHDF are able to acetylate both arylamine compounds and bioactivate the sulfone, DDS, giving rise to haptenated proteins. The reactive metabolites of SMX and DDS also provoke oxidative stress in these cells in a time- and concentration-dependent fashion. Further work is needed to determine the role of the observed toxicity in mediating CDRs observed with these agents.
PMCID: PMC1615915  PMID: 16603214
sulfonamides; cutaneous drug reactions; fibroblasts; protein haptenation; toxicity; N-acetyltransferase
5.  Tris(1,10-phenanthroline-κ2 N,N′)nickel(II) hexa­oxido-μ-peroxido-disulfate­(VI) N,N-dimethyl­formamide disolvate monohydrate 
The asymmetric unit of the title complex, [Ni(C12H8N2)3]S2O8·2C3H7NO·H2O, consists of a complex [Ni(phen)3]2+ cation and one isolated pds anion, with two DMF mol­ecules and one water mol­ecule as solvates (where phen is 1,10-phenanthroline, pds is the hexa­oxido-μ-peroxoido-di­sulf­ate dianion and DMF is dimethyl­formamide). The [Ni(phen)3]2+ cation is regular, with an almost ideal NiII bond-valence sum of 2.07 v.u. The group, as well as the water solvent mol­ecule, are well behaved in terms of crystallographic order, but the remaining three mol­ecules in the structure display different kinds of disorder, viz. the two DMF mol­ecules mimic a twofold splitting and the pds anion has both S atoms clamped at well-determined positions but with a not-too-well-defined central part. These peculiar behaviours are a consequence of the hydrogen-bonding inter­actions: the outermost SO3 parts of the pds anion are heavily connected to the complex cations via C—H⋯O hydrogen bonding, generating an [Ni(phen)3]pds network and providing for the stability of the terminal pds sites. Also, the water solvent mol­ecule is strongly bound to the structure (being a donor of two strong bonds and an acceptor of one) and is accordingly perfectly ordered. The peroxide O atoms in the pds middle region, instead, appear as much less restrained into their sites, which may explain their tendency to disorder. The cation–anion network leaves large embedded holes, amounting to about 28% of the total crystal volume, which are occupied by the DMF mol­ecules. The latter are weakly inter­acting with the rest of the structure, which renders them much more labile and, accordingly, prone to disorder.
PMCID: PMC3588241  PMID: 23476355
6.  Bis[N′-(2-oxo-1H-indol-3-ylidene)furan-2-carbohydrazidato-κ3 O,N′,O′]manganese(II) N,N-dimethyl­formide monosolvate monohydrate 
In the title compound, [Mn(C13H8N3O3)2]·C3H7NO·H2O, the metal atom is O,N,O′-chelated by two deprotonated Schiff bases and exists in a distorted octa­hedral geometry. The N–H groups, the carbonyl group of the DMF mol­ecule and the uncoord­inated water mol­ecule engage in N—H⋯O and O—H⋯O hydrogen-bonding inter­actions, generating a hydrogen-bonded ribbon that propagates along [110].
PMCID: PMC3009305  PMID: 21588862
7.  Bis[N′-(2-oxo-1H-indol-3-ylidene)thiophene-2-carbohydrazidato-κ3 O,N′,O′]zinc(II) N,N-dimethyl­formide mono­solvate monohydrate 
The metal atom of the title compound, [Zn(C13H8N3O2S)2]·C3H7NO·H2O, is O,N,O′-chelated by two deprotonated Schiff bases and it exists in a distorted octa­hedral geometry. The N–H groups of the ligands, the carbonyl group of the DMF mol­ecule and uncoordinated water mol­ecule engage in N—H⋯O and O—H⋯O inter­actions, generating a hydrogen-bonded ribbon that propagates along [110]. One thienyl ring is disordered over two positions in a 1:1 ratio.
PMCID: PMC3009315  PMID: 21588861
8.  Bis[μ-N′-(adamantan-1-ylcarbon­yl)-2-oxidobenzohydrazidato(3−)]tetra­pyridine­trinickel(II) dimethyl­formamide monosolvate monohydrate 
In the title trinuclear NiII compound, [Ni3(C18H19N2O3)2(C5H5N)4]·C3H7NO·H2O, three NiII cations are bridged by two N′-(adamantan-1-ylcarbon­yl)-2-oxidobenzohydrazidate trianions. The central NiII cation has a distorted octa­hedral N4O2 coordination environment where a reverse torsion occurs between the two bridging ligands, whereas the two NiII cations on the sides each adopt an N2O2 square-planar coordination. Weak intra­molecular C—H⋯O and C—H⋯N inter­actions help to stabilize the mol­ecular structure. In the crystal, the lattice water mol­ecule links with the NiII complex and dimethyl­formamide solvent mol­ecule via O—H⋯O hydrogen bonding.
PMCID: PMC3344353  PMID: 22590119
9.  Developing ICP-MS/MS for the detection and determination of synthetic DNA-protein crosslink models via phosphorus and sulfur detection 
Analytical and bioanalytical chemistry  2015;407(9):2433-2437.
Various endogenous and exogenous agents drive the un-directed formation of covalent bonds between proteins and DNA. These complex molecules are of great biological relevance, as can derive in mutations, but are difficult to study because of their heterogeneous chemical properties. New analytical approaches with sufficient detection capabilities to detect and quantify these compounds can help to standardize study models based on synthesized standards. The use of atomic spectrometry can provide quantitative information on the DNA-protein cross-link reaction yield along with basic stoichiometry of the products, based on internal elemental tags, sulfur from Cys and Met amino acids, and phosphorus from the DNA. A new instrumental approach to remove isobaric and poly-atomic interferences from 31P+ and 32S+ was developed recently, with state-of-the-art for interference removal that captures 31P+ in Q1; it reacts with O2 in an octopole collision-reaction cell generating 47PO+, therefore allowing detection in Q3 without 31NOH+/48Ca/47Ti interferences. Similarly, 32S+ is reacted to 48SO+, eliminating the polyatomic interferences at m/z=32. In conjunction with the high resolving power of high-performance liquid chromatography (HPLC), this newer technology was applied by to the product purification of a DNA-protein cross link model and some preliminary structural studies.
PMCID: PMC4593307  PMID: 25651903
Bioanalytical methods; Speciation; Spectroscopy/instrumentation; Nucleic acids (DNA | RNA)
10.  Recent advances in synthesis and biological activity of triterpenic acylated oximes 
Phytochemistry Reviews  2014;14(2):203-231.
During the last few decades more and more attention has been paid to triterpenes—a group of compounds with five- or four-ring skeleton and carboxyl, hydroxyl or oxo groups. Triterpenes with unsubstituted C-3 hydroxyl group can be easily transformed into appropriate ketones and then into oximes. The carbonyl group can be created not only from the hydroxyl group at C-3 position, but also at C-2, C-12 or C-28 positions. Several methods of creation of two = NOH groups within one molecule of triterpene are known. There are also known triterpenes with two carbonyl groups, e.g. at C-3 and C-11 positions, which differ in reactivity: among them only C-3 group can be transformed into oxime. A reactive hydroxyimine group can undergo the action of acylating agents, such as carboxylic acids or their derivatives, also the ones with significant pharmacological activity. Acyl derivatives of triterpenic oximes exhibit important pharmacological activity. The biological tests performed with the use of cell cultures inoculated with viruses showed inhibitory activity of some triterpenic acyloximes against type 1 HSV (H7N1), ECHO-6 and HIV-1 viruses. Another acylated oximes derived from triterpenes shown cytotoxic or antiproliferative activity against many lines of cancer cells. In many cases the pharmacological effects of the tested acyloxyiminotriterpenes were comparable to those of appropriate standard drugs. One of the newest application of acyl derivatives of triterpenic oximes is their ability to form organogels.
PMCID: PMC4379416  PMID: 25859175
Acyl derivatives of triterpenic oximes; Derivatives of triterpenes; Triterpenes; Triterpenic oximes
11.  Lignin-Derived Compounds as Efficient Laccase Mediators for Decolorization of Different Types of Recalcitrant Dyes 
Ten phenols were selected as natural laccase mediators after screening 44 different compounds with a recalcitrant dye (Reactive Black 5) as a substrate. Their performances were evaluated at different mediator/dye ratios and incubation times (up to 6 h) by the use of Pycnoporus cinnabarinus and Trametes villosa laccases and were compared with those of eight known synthetic mediators (including -NOH- compounds). Among the six types of dyes assayed, only Reactive Blue 38 (phthalocyanine) was resistant to laccase-mediator treatment under the conditions used. Acid Blue 74 (indigoid dye), Reactive Blue 19 (anthraquinoid dye), and Aniline Blue (triarylmethane-type dye) were partially decolorized by the laccases alone, although decolorization was much more efficient and rapid with mediators, whereas Reactive Black 5 (diazo dye) and Azure B (heterocyclic dye) could be decolorized only in the presence of mediators. The efficiency of each natural mediator depended on the type of dye to be treated but, with the only exception being Azure B (<50% decolorization), nearly complete decolorization (80 to 100%) was attained in all cases. Similar rates were attained with the best synthetic mediators, but the reactions were significantly slower. Phenolic aldehydes, ketones, acids, and esters related to the three lignin units were among the best mediators, including p-coumaric acid, vanillin, acetovanillone, methyl vanillate, and above all, syringaldehyde and acetosyringone. The last two compounds are especially promising as ecofriendly (and potentially cheap) mediators for industrial applications since they provided the highest decolorization rates in only 5 to 30 min, depending on the type of dye to be treated.
PMCID: PMC1082544  PMID: 15812000
12.  catena-Poly[[[aqua­chlorido­manganese(II)]-bis­[μ-1,1′-(oxydi-p-phenyl­ene)di-1H-imidazole-κ2 N 3:N 3′]] chloride dimethyl­formamide mono­solvate monohydrate] 
The title coordination polymer, {[MnCl(C18H14N4O)2(H2O)]Cl·C3H7NO·H2O}n, obtained by the solvothermal reaction of BIDPE and manganese(II) salt in H2O/DMF (DMF is dimethyl­formamide), is composed of a chain of [Mn2(BIDPE)2] [BIDPE is 1,1′-(oxydi-p-phenyl­ene)di-1H-imidazole] metallocyclic rings that exhibit inversion symmetry. The coordination about the Mn(II) ions is distorted octahedral with a MnClN4O coordination set. In the crystal, the polymeric chains are linked by O—H⋯Cl hydrogen bonds, forming a two-dimensional network parallel to (100). A number of C—H⋯Cl and C—H⋯O inter­actions are also present.
PMCID: PMC3051568  PMID: 21522845
13.  Safe and targeted anticancer therapy for ovarian cancer using a novel class of curcumin analogs 
A diagnosis of advanced ovarian cancer is the beginning of a long and arduous journey for a patient. Worldwide, approximately half of the individuals undergoing therapy for advanced cancer will succumb to the disease, or consequences of treatment. Well-known and widely-used chemotherapeutic agents such as cisplatin, paclitaxel, 5-fluorouracil, and doxorubicin are toxic to both cancer and non-cancerous cells, and have debilitating side effects Therefore, development of new targeted anticancer therapies that can selectively kill cancer cells while sparing the surrounding healthy tissues is essential to develop more effective therapies. We have developed a new class of synthetic curcumin analogs, diarylidenyl-piperidones (DAPs), which have higher anticancer activity and enhanced bio-absorption than curcumin. The DAP backbone structure exhibits cytotoxic (anticancer) activity, whereas the N-hydroxypyrroline (-NOH) moiety found on some variants functions as a cellular- or tissue-specific modulator (antioxidant) of cytotoxicity. The anticancer activity of the DAPs has been evaluated using a number of ovarian cancer cell lines, and the safety has been evaluated in a number of non-cancerous cell lines. Both variations of the DAP compounds showed similar levels of cell death in ovarian cancer cells, however the compounds with the -NOH modification were less toxic to non-cancerous cells. The selective cytotoxicity of the DAP–NOH compounds suggests that they will be useful as safe and effective anticancer agents. This article reviews some of the key findings of our work with the DAP compounds, and compares this to some of the targeted therapies currently used in ovarian cancer therapy.
PMCID: PMC3665575  PMID: 23663277
Ovarian cancer; Targeted therapy; STAT3; Curcumin analog; Curcumin
14.  Tetra­kis(8-quinolinolato-κ2 N,O)hafnium(IV) dimethyl­formamide solvate monohydrate 
In the title compound, [Hf(C9H6NO)]·C3H7NO·H2O, the hafnium(IV) atom is coordinated by four 8-quinolinolate (Ox) ligands, forming a slightly distorted square-anti­prismatic coordination polyhedron. The crystal packing is controlled by O—H⋯O and C—H⋯O hydrogen-bonding inter­actions and π–π inter­actions between quinoline ligands of neighbouring mol­ecules. The inter­planar distances vary between 3.150 (1) and 3.251 (2) Å, while centroid–centroid distances vary from 3.589 (1) to 4.1531 (1) Å.
PMCID: PMC2979151  PMID: 21579072
15.  Synthesis, Crystal Structures, and DNA Binding Properties of Zinc(II) Complexes with 3-Pyridine Aldoxime 
The employment of 3-pyridine aldoxime, (3-py)CHNOH, in ZnII chemistry has afforded two novel compounds: [Zn(acac)2{(3-py)CHNOH}]·H2O (1·H2O) [where acac− is the pentane-2,4-dionato(-1) ion] and [Zn2(O2CMe)4{(3-py)CHNOH}2] (2). Complex 1·H2O crystallizes in the monoclinic space group P21/n. The ZnII ion is five-coordinated, surrounded by four oxygen atoms of two acac− moieties and by the pyridyl nitrogen atom of the (3-py)CHNOH ligand. Molecules of 1 interact with the water lattice molecules forming a 2D hydrogen-bonding network. Complex 2 crystallizes in the triclinic P-1 space group and displays a dinuclear paddle-wheel structure. Each ZnII exhibits a perfect square pyramidal geometry, with four carboxylate oxygen atoms at the basal plane and the pyridyl nitrogen of one monodentate (3-py)CHNOH ligand at the apex. DNA mobility shift assays were performed for the determination of the in vitro effect of both complexes on the integrity and the electrophoretic mobility of pDNA.
PMCID: PMC2971566  PMID: 21076521
16.  Poly[[[(1-ethyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydro­quinoline-3-carboxyl­ato)manganese(II)]-μ3-4,4′-oxydibenzoato] monohydrate] 
In the title compound, {[Mn(C16H18N3O3)(C14H8O5)]·H2O}n, the unique MnII ion is coordinated by two O atoms from a chelating 1-ethyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydro­quinoline-3-carboxyl­ate ligand and three O atoms from three 4,4′-oxydibenzoate ligands, forming a distorted square-pyramidal coordination environment. In the crystal structure, centrosymmetric dinuclear manganese units are linked via 4,4′-oxydibenzoate ligands into one-dimensional chains; these chains are, in turn, connected via inter­molecular N—H⋯O and O—H⋯O hydrogen bonds to form a two-dimensional supra­molecular network. The O atom of the solvent water mol­ecule is disordered over two sites with equal occupancies; the attached H atoms are common to both sites.
PMCID: PMC2914913  PMID: 21200557
17.  Nitroxyl Radical plus Hydroxylamine Pseudo Self-Exchange Reactions: Tunneling in Hydrogen Atom Transfer 
Journal of the American Chemical Society  2009;131(33):11985-11997.
Bimolecular rate constants have been measured for reactions that involve hydrogen atom transfer (HAT) from hydroxylamines to nitroxyl radicals, using the stable radicals TEMPO• (2,2,6,6-tetramethylpiperidine-1-oxyl radical), 4-oxo-TEMPO• (2,2,6,6-tetramethyl-4-oxo-piperidine-1-oxyl radical), di-tert-butylnitroxyl (tBu2NO•), and the hydroxylamines TEMPO-H, 4-oxo-TEMPO-H, 4-MeO-TEMPO-H (2,2,6,6-tetramethyl-N-hydroxy-4-methoxy-piperidine), and tBu2NOH. The reactions have been monitored by UV-vis stopped-flow methods, using the different optical spectra of nitroxyl radicals. The HAT reactions all have |ΔGo| ≤ 1.4 kcal mol−1 and therefore are close to self-exchange reactions. The reaction of 4-oxo-TEMPO• + TEMPO-H → 4-oxo-TEMPO-H + TEMPO• occurs with k2H,MeCN = 10 ± 1 M−1 s−1 in MeCN at 298 K (K2H,MeCN = 4.5 ± 1.8). Surprisingly, the rate constant for the analogous deuterium atom transfer reaction is much slower: k2D,MeCN = 0.44 ± 0.05 M−1 s−1 with k2H,MeCN/k2D,MeCN = 23 ± 3 at 298 K. The same large kinetic isotope effect (KIE) is found in CH2Cl2, 23 ± 4, suggesting that the large KIE is not caused by solvent dynamics or hydrogen bonding to solvent. The related reaction of 4-oxo-TEMPO• with 4-MeO-TEMPO-H(D) also has a large KIE, k3H/k3D = 21 ± 3 in MeCN. For these three reactions, the EaD – EaH values, between 0.3 ± 0.6 and 1.3 ± 0.6 kcal mol−1, and the log(AH/AD) values, between 0.5 ± 0.7 and 1.1 ± 0.6, indicate that hydrogen tunneling plays an important role. The related reaction of tBu2NO• + TEMPO-H(D) in MeCN has a large KIE, 16 ± 3 in MeCN, and very unusual isotopic activation parameters, EaD – EaH = −2.6 ± 0.4 and log(AH/AD) = 3.1 ± 0.6. Computational studies, using POLYRATE, also indicate substantial tunneling in the (CH3)2NO• + (CH3)2NOH model reaction for the experimental self-exchange processes. Additional calculations on TEMPO(•/H), tBu2NO(•/H), and Ph2NO(•/H) self-exchange reactions reveal why the phenyl groups make the last of these reactions several orders of magnitude faster than the first two. By inference, the calculations also suggest why tunneling appears to be more important in the self-exchange reactions of dialkylhydroxylamines than of arylhydroxylamines.
PMCID: PMC2775461  PMID: 19618933
18.  A Novel Helicase-Type Protein in the Nucleolus: Protein NOH61 
Molecular Biology of the Cell  2000;11(4):1153-1167.
We report the identification, cDNA cloning, and molecular characterization of a novel, constitutive nucleolar protein. The cDNA-deduced amino acid sequence of the human protein defines a polypeptide of a calculated mass of 61.5 kDa and an isoelectric point of 9.9. Inspection of the primary sequence disclosed that the protein is a member of the family of “DEAD-box” proteins, representing a subgroup of putative ATP-dependent RNA helicases. ATPase activity of the recombinant protein is evident and stimulated by a variety of polynucleotides tested. Immunolocalization studies revealed that protein NOH61 (nucleolar helicase of 61 kDa) is highly conserved during evolution and shows a strong accumulation in nucleoli. Biochemical experiments have shown that protein NOH61 synthesized in vitro sediments with ∼11.5 S, i.e., apparently as homo-oligomeric structures. By contrast, sucrose gradient centrifugation analysis of cellular extracts obtained with buffers of elevated ionic strength (600 mM NaCl) revealed that the solubilized native protein sediments with ∼4 S, suggestive of the monomeric form. Interestingly, protein NOH61 has also been identified as a specific constituent of free nucleoplasmic 65S preribosomal particles but is absent from cytoplasmic ribosomes. Treatment of cultured cells with 1) the transcription inhibitor actinomycin D and 2) RNase A results in a complete dissociation of NOH61 from nucleolar structures. The specific intracellular localization and its striking sequence homology to other known RNA helicases lead to the hypothesis that protein NOH61 might be involved in ribosome synthesis, most likely during the assembly process of the large (60S) ribosomal subunit.
PMCID: PMC14838  PMID: 10749921
19.  Bis(μ2-pyridine-2-carboxamide oximato)bis­[(pyridine-2-carboxamide oxime)zinc] dinitrate 
In the title dinuclear compound, [Zn2(C6H6N3O)2(C6H7N3O)2](NO3)2, the ZnII cation is N,N′-chelated by one pyridine-2-carboxamide oximate anion and one pyridine-2-carboxamide oxime mol­ecule, and is further bridged by an oxime O atom from the adjacent pyridine-2-carboxamide oximate anion, forming a distorted trigonal bipyramidal coordination. Two pyridine-2-carboxamide oximate anions bridge two ZnII cations to form the centrosymmetric dinuclear mol­ecule. Extensive O—H⋯O, N—H⋯O and O—H⋯N hydrogen bonds are present in the crystal structure.
PMCID: PMC3200762  PMID: 22058897
20.  Synthesis, Characterization, and Interaction with Biomolecules of Platinum(II) Complexes with Shikimic Acid-Based Ligands 
Starting from the active ingredient shikimic acid (SA) of traditional Chinese medicine and NH2(CH2)nOH, (n = 2–6), we have synthesized a series of new water-soluble Pt(II) complexes PtLa–eCl2, where La–e are chelating diamine ligands with carbon chain covalently attached to SA (La–e = SA-NH(CH2)nNHCH2CH2NH2; La, n = 2; Lb, n = 3; Lc, n = 4; Ld, n = 5; Le, n = 6). The results of the elemental analysis, LC-MS, capillary electrophoresis, and 1H, 13C NMR indicated that there was only one product (isomer) formed under the present experimental conditions, in which the coordinate mode of PtLa–eCl2 was two-amine bidentate. Their in vitro cytotoxic activities were evaluated by MTT method, where these compounds only exhibited low cytotoxicity towards BEL7404, which should correlate their low lipophilicity. The interactions of the five Pt(II) complexes with DNA were investigated by agarose gel electrophoresis, which suggests that the Pt(II) complexes could induce DNA alteration. We also studied the interactions of the Pt(II) complexes with 5′-GMP with ESI-MS and 1H NMR and found that PtLbCl2, PtLcCl2, and PtLdCl2 could react with 5′-GMP to form mono-GMP and bis-GMP adducts. Furthermore, the cell-cycle analysis revealed that PtLbCl2, PtLcCl2 cause cell G2-phase arrest after incubation for 72 h. Overall, these water-soluble Pt(II) complexes interact with DNA mainly through covalent binding, which blocks the DNA synthesis and replication and thus induces cytotoxicity that weakens as the length of carbon chain increases.
PMCID: PMC3603162  PMID: 23533373
21.  Concerted Proton-Electron Transfer in a Ruthenium Terpyridyl-Benzoate System with a Large Separation between the Redox and Basic Sites 
In order to understand how the separation between the electron and proton-accepting sites affects proton-coupled electron transfer (PCET) reactivity, we have prepared ruthenium complexes with 4′-(4-carboxyphenyl)terpyridine ligands, and studied reactivity with hydrogen atom donors (H-X). RuII(pydic)(tpy-PhCOOH) (RuIIPhCOOH), was synthesized in one pot from [(p-cymene)RuCl2]2, sodium 4′-(4-carboxyphenyl)-2,2′:6′,2″-terpyridine ([Na+]tpy-PhCOO−), and disodium pyridine-2,6-dicarboxylate (Na2pydic). RuIIPhCOOH plus nBu4NOH in DMF yields the deprotonated Ru(II) complex, nBu4N[RuII(pydic)(tpy-PhCOO)] (RuIIPhCOO−). The Ru(III) complex (RuIIIPhCOO) has been isolated by one-electron oxidation of RuIIPhCOO− with triarylaminium radical cations (NAr3•+). The bond dissociation free energy (BDFE) of the O–H bond in RuIIPhCOOH is calculated from pKa and E1/2 measurements as 87 kcal mol-1, making RuIIIPhCOO a strong hydrogen atom acceptor. There are 10 bonds and ca. 11.2 Å separating the metal from the carboxylate basic site in RuIIIPhCOO. Even with this separation, RuIIIPhCOO oxidizes the hydrogen atom donor TEMPOH (BDFE = 66.5 kcal mol-1, ΔG°rxn = -21 kcal mol-1) by removal of an electron and a proton to form RuIIPhCOOH and TEMPO radical in a concerted proton-electron transfer (CPET) process. The second order rate constant for this reaction is (1.1 ± 0.1) × 105 M-1 s-1 with kH/kD = 2.1 ± 0.2, similar to the observed kinetics in an analogous system without the phenyl spacer, RuIII(pydic)(tpy-COO) (RuIIICOO−). In contrast, hydrogen transfer from 2,6-di-tert-butyl-p-methoxyphenol [tBu2(OMe)ArOH] to RuIIIPhCOO is several orders of magnitude slower than the analogous reaction with RuIIICOO.
PMCID: PMC2765064  PMID: 19569636
22.  Kidney dendritic cell activation is required for progression of renal disease in a mouse model of glomerular injury 
The Journal of Clinical Investigation  2009;119(5):1286-1297.
The progression of kidney disease to renal failure correlates with infiltration of mononuclear immune cells into the tubulointerstitium. These infiltrates contain macrophages, DCs, and T cells, but the role of each cell type in disease progression is unclear. To investigate the underlying immune mechanisms, we generated transgenic mice that selectively expressed the model antigens ovalbumin and hen egg lysozyme in glomerular podocytes (NOH mice). Coinjection of ovalbumin-specific transgenic CD8+ CTLs and CD4+ Th cells into NOH mice resulted in periglomerular mononuclear infiltrates and inflammation of parietal epithelial cells, similar to lesions frequently observed in human chronic glomerulonephritis. Repetitive T cell injections aggravated infiltration and caused progression to structural and functional kidney damage after 4 weeks. Mechanistic analysis revealed that DCs in renal lymph nodes constitutively cross-presented ovalbumin and activated CTLs. These CTLs released further ovalbumin for CTL activation in the lymph nodes and for simultaneous presentation to Th cells by distinct DC subsets residing in the kidney tubulointerstitium. Crosstalk between tubulointerstitial DCs and Th cells resulted in intrarenal cytokine and chemokine production and in recruitment of more CTLs, monocyte-derived DCs, and macrophages. The importance of DCs was established by the fact that DC depletion rapidly resolved established kidney immunopathology. These findings demonstrate that glomerular antigen–specific CTLs and Th cells can jointly induce renal immunopathology and identify kidney DCs as a mechanistic link between glomerular injury and the progression of kidney disease.
PMCID: PMC2673875  PMID: 19381017
23.  6-{5-Amino-3-tert-butyl-4-[(E)-(3-methyl-1,2,4-thiadiazol-5-yl)diazen­yl]-1H-pyrazol-1-yl}-1,3,5-triazine-2,4(1H,3H)-dione–1-methyl­pyrrolidin-2-one–water (1/1/1) 
In the title compound, C13H16N10O2S·C5H9NO·H2O, the entire 1-methylpyrrolidin-2-one (NMP) mol­ecule is disordered over two sites with occupancies of 0.488 (5) and 0.512 (5). The six-membered triazine ring and the two five-membered pyrazole and thiadia­zole rings, together with the diazene (–N=N–) linkage are almost coplanar (r.m.s. deviation for the non-H atoms = 0.0256 Å) with methyl groups from the tert-butyl substituent on the pyrazole ring located above and below the plane. Three intra­molecular N—H⋯N hydrogen bonds contribute to the planarity of the system. The O atom of the NMP mol­ecule is hydrogen bonded to an O—H group of water. In turn, the water mol­ecule is hydrogen bonded to the mono-azo skeleton through inter­molecular N—H⋯O and O—H⋯N hydrogen bonds. At both ends of the long mol­ecular axis of the main mol­ecule there are inter­molecular N—H⋯N hydrogen bonds, arranged in a head-to-tail fashion, between the N—H group of the triazine ring of one mol­ecule and the N atom of the thia­diazole ring of a neighboring mol­ecule. These form a polymeric chain along [110] or [10]. The main mol­ecules are stacked alternately along the b axis, which effectively cancels their dipole moments. In addition, pairs of alternate molecules are dimerized via inter­molecular hydrogen bonds involving the solvent mol­ecules.
PMCID: PMC2983887  PMID: 21580749
24.  Bis[μ-5-(2-pyrid­yl)tetra­zolato]-κ3 N 1,N 5:N 2;κ3 N 2:N 1,N 5-bis­[triaqua­zinc(II)] bis­(trifluoro­acetate) monohydrate 
The title compound, [Zn2(C6H4N5)2(H2O)6](CF3CO2)2·H2O, was synthesized by hydro­thermal reaction of ZnBr2, CF3COOH and 2-(2H-tetra­zol-5-yl)pyridine. The ZnII cation is coordinated by one N atom from the 5-(2-pyrid­yl)tetra­zolate anion, two N atoms from another 5-(2-pyrid­yl)tetra­zolate anion and three O atoms from three water mol­ecules in a distorted octa­hedral geometry. The tetra­zole ligands bridge the metal ions of the dimeric structure, and the dimers are located on crystallographic inversion centers. An inter­stitial solvent water mol­ecule is located on a crystallographic mirror plane, and the CF3COO− counter-anions are also not coordinated to the metal complex. The F atoms of the anions are disordered with the F atoms statistically distributed over two positions in a 0.56 (3)/0.44 (3) ratio. All the water H atoms are involved in O—H⋯N and O—H⋯O hydrogen bonds with uncoordinated water O atoms, carboxyl­ate O atoms and tetra­zole N atoms. The inter­actions link the mol­ecules into a three-dimensional network.
PMCID: PMC2977136  PMID: 21583337
25.  Bis(tetra­ethyl­ammonium) oxalate dihydrate 
The title compound, 2C8H20N+·C2O4 2−·2H2O, synthesized by neutralizing H2C2O4·2H2O with (C2H5)4NOH in a 1:2 molar ratio, is a deliquescent solid. The oxalate ion is nonplanar, with a dihedral angle between carboxyl­ate groups of 64.37 (2)°. O—H⋯O hydrogen bonds of moderate strength link the O atoms of the water mol­ecules and the oxalate ions into rings parallel to the c axis. The rings exhibit the graph-set motif R 4 4(12). In addition, there are weak C—H⋯O inter­actions in the crystal structure.
PMCID: PMC3414309  PMID: 22904842

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