Halogen bonding in substituted cobaloximes

Aquabis(dimethylglyoximato)nitrocobalt(III) reacts with halogen-substituted pyridines to give nitro complexes in which the pyridine donors substitute the aqua ligand; reaction with halogen-substituted pyridinium chlorides directly displaces both the coordinated water molecule and the nitro ligand in a one-pot reaction and affords the analogous chloro complexes. Ten crystal structures of eight new compounds are reported: among these, the nitro complex bis(dimethylglyoximato)nitro(4-chloropyridine)cobalt(III) is characterized by a remarkably long bond between the metal and the nitro ligand whereas the analogous chloro complex chlorobis(dimethylglyoximato)(4-chloropyridine)cobalt(III) features a very long Co-Cl distance. The structures communicated comprise three isomorphous pairs which are particularly suited for the comparative study of chloro and bromo derivatives. The most relevant intermolecular interactions in these compounds are due to very short oxygen?halogen contacts of ca. 2.9 Å whereas shortest interhalogen distances are slightly longer than the sum of the van der Waals radii. For both types of interactions, contact distances involving bromine are shorter than those associated with chlorine.     

An overview of halogen bonding

Halogen bonding (XB) is a type of noncovalent interaction between a halogen atom X in one molecule and a negative site in another. X can be chlorine, bromine or iodine. The strength of the interaction increases in the order Cl<Br<I. After a brief review of experimental evidence relating to halogen bonding, we present an explanation for its occurrence in terms of a region of positive electrostatic potential that is present on the outermost portions of some covalently-bonded halogen atoms. The existence and magnitude of this positive region, which we call the σ-hole, depends upon the relative electron-attracting powers of X and the remainder of its molecule, as well as the degree of sp hybridization of the s unshared electrons of X. The high electronegativity of fluorine and its tendency to undergo significant sp hybridization account for its failure to halogen bond. Some computed XB interaction energies are presented and discussed. Mention is also made of the importance of halogen bonding in biological systems and processes, and in crystal engineering. Figure The computed B3PW91/6-31G(d,p) electrostatic potential, in kcal mol⁻¹, on the 0.001 electrons/bohr³ surface of NC–C≡C–Cl. The chlorine atom is at the right. The color ranges are: red, more positive than 15; yellow between 7 and 15; green, between 0 and 7; blue, between −10 and 0; purple, more positive than −10. Proceedings of “Modeling Interactions in Biomolecules II”, Prague, September 5th–9th, 2005.     

Monohalogenated maleimides as potential agents for the inhibition of Pseudomonas aeruginosa biofilm

New monohalogenated maleimide derivatives (with bromine, chlorine or iodine) were synthesized to test the effect of halogen atoms in inhibiting the formation of Pseudomonas aeruginosa biofilm. The evaluation of their biological activities clearly defines a structure–activity relationship. In this study, the bactericidal action of the three compounds was observed at the concentration range 0.3–5.0 mM on Luria-Bertani agar plates. The halogen atom of these molecules was critical in modulating the antibacterial activity, with a slightly higher effectiveness for chlorine. Confocal laser scanning microscopy was used to examine P. aeruginosa biofilms cultivated in flow cells. At concentration as low as 40 μM, the bromine and iodine compounds displayed a total inhibition towards the formation of bacterial biofilm. At this concentration, the bacterial attachment to glass surfaces was strongly affected by the presence of bromine and iodine whereas the chlorine derivative behaved as a bactericidal compound. A bioluminescent reporter strain was then used to detect the effect of the chemically synthesized maleimides on quorum sensing (QS) in P. aeruginosa. At the concentration range 10–100 μM, bioluminescence assays reveal that halogenated maleimides were able to interfere with the QS of the bacterium. Although the relationship between the weak inhibition of cell-to-cell communication (15–55% of the signal) and the high inhibition of biofilm formation has not been elucidated clearly, the results demonstrate that bromo- and iodo-N-substituted maleimides bromine and iodine may be used as new potent inhibitors that control bacterial biofilms.     

Comparison of Chlorine, Bromine, and Iodine as Disinfectants for Swimming Pool Water

Studies on the germicidal activity of chlorine, bromine, and iodine were made by use of the Association of Official Agricultural Chemists official first action method for determining effectiveness of swimming pool water disinfectants. In this procedure, 0.3 ppm of available chlorine as chlorine gas has activity equivalent to 0.6 ppm of available chlorine in the buffered sodium hypochlorite control when Escherichia coli is used as the test organism. With Streptococcus faecalis as the test organism, 0.45 ppm of available chlorine as gaseous chlorine gives activity equivalent to the control. Liquid bromine at 1.0 ppm is as effective as the 0.6 ppm of available chlorine hypochlorite control with E. coli as the test organism, but 2.0 ppm of liquid bromine is necessary to provide activity equivalent to the 0.6 ppm of available chlorine control when S. faecalis is employed. With iodine as metallic iodine, 2.0 ppm is necessary to provide a result equivalent to the 0.6 ppm of available chlorine control with both E. coli and S. faecalis. In the various systems tested, gaseous chlorine was the most active form of available chlorine; liquid bromine provided the most active form of bromine, and metallic iodine provided the most active form of iodine.     

Bromine levels in human serum,urine, hair

Much is known about the essentiality of the halogens fluorine (F), chlorine (Cl), and iodine (I), but very little has been discussed with respect to bromine (Br). As a member of the halogen family its chemical properties are comparable to those of other halogens, but its presence has been masked by the presence of I and Cl in chemical analyses. By virtue of new technology and a special computerized machine called the Kevex Model 0600 Energy Dispersive X-Ray Induced X-Ray Fluorescence Spectrometer (EDXRF), we can specifically identify bromine in different compartments and verify its concentration accurately. In order to establish standard values of Br concentrations and evaluate the nature of its presence in humans, samples of serum, urine, and hair were collected from ten healthy adult males and analyzed for bromine content. Our samples had normal distributions, with serum bromine levels ranging from 3.2 to 5.6 μg/mL, urine levels between 0.3 to 7.0 μg/mL, and hair levels determined from 1.1 to 49.0 μg/mL. These levels, especially those of serum bromine, have been encountered by other examiners whose samples also had normal distributions. These findings suggest to us that bromine may well be an essential trace element, as are its other halogen family members.     

Theoretical study of the triangular bonding complex formed by carbon tetrabromide, a halide, and a solvent molecule in the gas phase

MP2(full)/aug-cc-pVDZ(-PP) computations predict that new triangular bonding complexes (where X^? is a halide and H–C refers to a protic solvent molecule) consist of one halogen bond and two hydrogen bonds in the gas phase. Carbon tetrabromide acts as the donor in the halogen bond, while it acts as an acceptor in the hydrogen bond. The halide (which commonly acts as an acceptor) can interact with both carbon tetrabromide and solvent molecule (CH₃CN, CH₂Cl₂, CHCl₃) to form a halogen bond and a hydrogen bond, respectively. The strength of the halogen bond obeys the order CBr₄???Cl^? > CBr₄???Br^? > CBr₄???I^?. For the hydrogen bonds formed between various halides and the same solvent molecule, the strength of the hydrogen bond obeys the order C-H???Cl^? > C-H???Br^? > C-H???I^?. For the hydrogen bonds formed between the same halide and various solvent molecules, the interaction strength is proportional to the acidity of the hydrogen in the solvent molecule. The diminutive effect is present between the hydrogen bonds and the halogen bond in chlorine and bromine triangular bonding complexes. Complexes containing iodide ion show weak cooperative effects.

Interaction of bromine with iodine in the rat thyroid gland at enhanced bromide intake

In experiments with rats, we have found that at enhanced intake of bromide, bromine does not replace chlorine in the thyroid; it replaces iodine. Under our experimental conditions, more than onethird of the iodine content in the thyroid was replaced by bromine. In the thyroid, bromine probably remained in the form of bromide and, in proportional to its increased concentration, the production of iodinated thyronines decreased, with the sum of the iodine and bromine concentrations being constant at the value of 20.51±1.16 μmol/g dry wt of the thyroid. In contrast to other organs, the biological behavior of bromine in the thyroid is not similar to the biological behavior of chlorine but resembles more that of iodine.     

N-haloacetylimino neonicotinoids: potency and molecular recognition at the insect nicotinic receptor

This structure-activity relationship study for neonicotinoids with an N-haloacetylimino pharmacophore identifies several candidate compounds showing outstanding insecticidal potency and consequently leads to establishing their molecular recognition at an insect nicotinic receptor structural model, wherein the neonicotinoid halogen atoms (fluorine, chlorine, bromine, and iodine) variously interact with the receptor loops C-D interfacial niche via H-bonding and/or hydrophobic interactions.     

How do halogen bonds (S–O⋯I,N–O⋯I and C–O⋯I) and halogen–halogen contacts (C–I⋯I–C,C–F⋯F–C) subsist in crystal structures? A quantum chemical insight

Thirteen X-ray crystal structures containing various non-covalent interactions such as halogen bonds, halogen–halogen contacts and hydrogen bonds (I?N, I?F, I?I, F?F, I?H and F?H) were considered and investigated using the DFT-D3 method (B97D/def2-QZVP). The interaction energies were calculated at MO62X/def2-QZVP and MP2/aug-cc-pvDZ level of theories. The higher interaction and dispersion energies (2nd crystal) of ?9.58 kcal mol^?1 and ?7.10 kcal mol^?1 observed for 1,4-di-iodotetrafluorobenzene bis [bis (2-phenylethyl) sulfoxide] structure indicates the most stable geometrical arrangement in the crystal packing. The electrostatic potential values calculated for all crystal structures have a positive σ-hole, which aids understanding of the nature of σ-hole bonds. The significance of the existence of halogen bonds in crystal packing environments was authenticated by replacing iodine atoms by bromine and chlorine atoms. Nucleus independent chemical shift analysis reported on the resonance contribution to the interaction energies of halogen bonds and halogen–halogen contacts. Hirshfeld surface analysis and topological analysis (atoms in molecules) were carried out to analyze the occurrence and strength of all non-covalent interactions. These analyses revealed that halogen bond interactions were more dominant than hydrogen bonding interactions in these crystal structures.

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Graphical Abstract Molecluar structure of 1,4-Di-iodotetrafluorobenzene bis(thianthrene 5-oxide) moelcule and its corresponding molecular electrostatic potential map for the view of σ-hole.

     

A theoretical study on the halogen bonding interactions of C6F5I with a series of group 10 metal monohalides

The halogen bonding interactions between C₆F₅I and a series of transition metal monohalides trans-[M(X)(2-C₅NF₄)-(PR₃)₂] (M = Ni, Pd, Pt; X = F, Cl, Br; R = Me, Cy) have been studied with quantum chemical calculations. Optimized geometries of the halogen bonding complexes indicate that angles C₁-I···X are basically linear (178–180°) and angles I···X-M mainly range from 90 to 150°. The strength of these metal-influenced halogen bonds alters with different metal centers, metal-bound halogen atoms and the substitutes on phosphine ligands. Electrostatic potential and natural bond orbital analysis show that both of the electrostatic and orbital interactions make a contribution to the formation of halogen bonds, while the electrostatic term plays a dominant role. AIM analysis suggests that, for trans-[M(F)(2-C₅NF₄)-(PR₃)₂] (M = Ni, Pd, Pt) monomers, the formed halogen bonding complexes are stabilized by local concentration of the charge of intermediate character, while for the metal monomers containing chlorine and bromine, a typical closed-shell interaction exist. These results prove that the structures and geometries of these halogen bonding complexes can be tuned by changing the halogen atoms and metal centers, which may provide useful information for the design and synthesis of new functional materials.

DspA from Strongylocentrotus purpuratus: The first biochemically characterized haloalkane dehalogenase of non-microbial origin

Haloalkane dehalogenases are known as bacterial enzymes cleaving a carbon–halogen bond in halogenated compounds. Here we report the first biochemically characterized non-microbial haloalkane dehalogenase DspA from Strongylocentrotus purpuratus. The enzyme shows a preference for terminally brominated hydrocarbons and enantioselectivity towards β-brominated alkanes. Moreover, we identified other putative haloalkane dehalogenases of eukaryotic origin, representing targets for future experiments to discover dehalogenases with novel catalytic properties.     

Structure of the Escherichia coli phosphonate binding protein PhnD and rationally optimized phosphonate biosensors

The phnD gene of Escherichia coli encodes the periplasmic binding protein of the phosphonate (Pn) uptake and utilization pathway. We have crystallized and determined structures of E. coli PhnD (EcPhnD) in the absence of ligand and in complex with the environmentally abundant 2-aminoethylphosphonate (2AEP). Similar to other bacterial periplasmic binding proteins, 2AEP binds near the center of mass of EcPhnD in a cleft formed between two lobes. Comparison of the open, unliganded structure with the closed 2AEP-bound structure shows that the two lobes pivot around a hinge by ∼ 70° between the two states. Extensive hydrogen bonding and electrostatic interactions stabilize 2AEP, which binds to EcPhnD with low nanomolar affinity. These structures provide insight into Pn uptake by bacteria and facilitated the rational design of high signal-to-noise Pn biosensors based on both coupled small-molecule dyes and autocatalytic fluorescent proteins.     

Efficacy of bromochlorodimethylhydantoin againstLegionella pneumophila in industrial cooling water

Summary Free residual chlorine and bromine can be generated in water from bromochlorodimethylhydantoin (BCDMH). Efficacy of chlorine from inorganic sources has been studied extensively, but there is much less information on the efficacy of bromine againstL. pneumophila; only a few efficacy studies of organically-derived. halogen appear in the literature and the results from different studies conflict or are difficult to interpret. This paper describes the efficacy of halogen from BCDMH against planktonic, pure cultureL. pneumophila in an industrial cooling water. There was no difference in efficacy between halogen derived from organic or inorganic sources in controlled laboratory experiments. Effective doses in laboratory studies cannot be translated directly to field applications because of significant differences in the microbiology. However, the data suggest that disinfection (>99.9% reduction in viability within 10 min) of planktonic, pure cultureL. pneumophila can be achieved with about 1 ppm free residual halogen (expressed as chlorine) from BCDMH in a typical industrial cooling water.     

Synthesis and in vitro binding of N,N-dialkyl-2-phenylindol-3-yl-glyoxylamides for the peripheral benzodiazepine binding sites

A series of N,N-dialkyl-2-phenylindol-3-ylglyoxylamides bearing the halogens iodine and bromine were synthesised and their binding affinity for the peripheral benzodiazepine binding sites (PBBS) in rat kidney mitochondrial membranes was evaluated using [(3)H]PK11195. Central benzodiazepine receptor (CBR) affinities were also evaluated in rat cortices using [(3)H]flumazenil to determine their selectivity for PBBS over CBR. The tested compounds had PBBS binding affinities (IC(50)) ranging from 7.86 to 618 nM, with all compounds showing high selectivity over the CBR (CBR IC(50) > 5000 nM). Among the 12 compounds tested, those with a diethylamide group were the most potent. The highest affinity iodinated PBBS ligand, N,N-diethyl-[5-chloro-2-(4-iodophenyl)indol-3-yl]glyoxylamide, was radiolabelled with iodine-123. This high affinity and selective radioligand may be useful for imaging neurodegeneration, inflammation and tumours using single photon emission computed tomography.     

A new chitooligosaccharide specific lectin from snake gourd (Trichosanthes anguina) phloem exudate. Purification, physico-chemical characterization and thermodynamics of saccharide binding

A new lectin has been purified to homogeneity from the phloem exudate of snake gourd (Trichosanthes anguina) by affinity chromatography on chitin. The snake gourd phloem lectin (SGPL) specifically binds chitooligosaccharides and their inhibitory potency increased with increase in size. PAGE and SDS-PAGE studies indicate that SGPL is a heterodimer, in which the two subunits (48 and 53 kDa) are joined by disulfide bonds. Consistent with this, electrospray-ionization mass spectrum yielded the exact mass of the protein as 104,621.8 Daltons. CD studies showed that SGPL contains about 9% α-helix, 39% β-sheet, 20% β-turns and 32% unordered structures and that saccharide binding does not significantly affect its secondary and tertiary structures. Titration calorimetric studies indicate that the dimeric lectin binds two ligand molecules [(GlcNAc)_3–6] with association constants determined at 25 °C being 1.7 × 10⁵ and 3.6 × 10⁵ M⁻¹, for chitotriose and chitohexaose, respectively. Binding of all the chitooligosaccharides is governed by enthalpic forces, whereas the contribution from binding entropies was unfavorable. These results suggest that the SGPL-saccharide interaction is stabilized by hydrogen bonding and van der Waals’ interactions. Enthalpy–entropy compensation was observed for the SGPL-chitooligosaccharide interaction, suggesting that water molecules play a key role in the binding process.     

The structure, properties, and nature of unconventional π halogen bond in the complexes of Al 4 2- and halohydrocarbons

Quantum chemical calculations have been performed to study the all-metal π halogen bonding in Al(4)(2-)···halohydrocarbon complexes. The result shows the existence of the all-metal π halogen bond in the complexes. There are three interaction modes (top, corner, and side) between Al(4)(2-) and halohydrocarbon. The interaction energy of this interaction varies from a positive value to -90.54 kJ mol(-1) in Al(4)(2-)···I-ethyne-s complex. The interaction strength is affected greatly by the hybridization of C atom and follows the order of C(sp(3)) < C(sp(2)) < C(sp) in most complexes. The methyl group in the halogen donor plays a negative contribution to the formation of halogen bond. The halogen bonding becomes stronger for the heavier halogen atom. The effect of binding site on the strength of halogen bond is related with the nature of halogen atom. The complexes have been analyzed with electrostatic potential, NICS, ELF, NBO, and AIM.     

Analysis by metadynamics simulation of binding pathway of influenza virus M2 channel blockers

M2 protein of influenza A virus is a proton channel spanning the viral envelope. Activity of this proton channel is required for uncoating of viral particles and equilibrating the pH across the trans Golgi apparatus, which prevents conformational change in hemagglutinin. Amantadine, an anti‐influenza A virus drug, inhibits M2 proton channel activity by binding to the channel pore; however, most currently circulating influenza A viruses are amantadine‐resistant. The most prevalent resistant mutation is a substitution from Ser31 to Asn31 in M2. Further atomistic analysis of ligand‐M2 complexes is needed to provide new approaches for the design of novel M2 channel blockers. Here, the free energy profiles of the binding kinetics of M2 channel blockers were examined by well‐tempered metadynamics simulations and it was found that amantadine first binds to Asp24 of S31 M2 and forms a metastable conformation. In contrast, the free energy profiles of adamantyl bromothiophene dual inhibitor with either S31 M2 or N31 M2 are broad funnel‐shaped curves, suggesting that adamantyl bromothiophene does not form metastable complexes with M2. The trajectory of well‐tempered metadynamics simulations revealed that steric hindrance between adamantyl bromothiophene and S31 M2 interrupts formation of a metastable conformation at Asp24 and that a halogen bond between the bromine atom and N31 is responsible for pulling down the ligand to the channel pore of N31 M2 in the absence of a metastable state. Binding pathways of M2 channel blockers to M2 are here proposed on the basis of these findings; they may provide new approaches to designing further M2 channel blockers.     

植物中的CDPK/SnRK蛋白激酶家族

在植物中至少存在五类蛋白激酶,这五类都属于CDPK/SnRK家族,它们的结构中含有EF手型结构或者与其相互作用的蛋白质中包含着EF手型结构。CDPK和CCaMKs在C-端都包含EF手型结构,在与钙离子结合后而被激活。SnRK3s结合蛋白包含着三个EF手型,其中一些被钙离子激活。植物两类其它的蛋白激酶家族成员-CaMK和CRK,与钙调素相结合。本文将阐述这些蛋白激酶结构、活性调节以及参与钙信号传递的潜能。     

Effects of single nucleotide changes on the binding and activity of RNA aptamers to human papillomavirus 16 E7 oncoprotein

ATP:Cobalamin adenosyltransferases catalyze the transfer a 5′-deoxyadenosyl moiety from ATP to cob(I)alamin in the synthesis of the Co–C bond of coenzyme B₁₂. There are three types of adenosyltransferases, CobA, PduO and EutT. Among these adenosyltransferases, the PduO-type adenosyltransferases is the most widely distributed enzyme. Structural comparisons between apo BcPduO and BcPduO in complex with MgATP revealed that the N-terminal strands of both structures were ordered, which is in contrast with the most previously available PduO-type adenosyltransferase structures. Furthermore, unlike other reported structures, apo BcPduO was bound to additional dioxane molecules causing a side chain conformational change at the Tyr30 residue, which is an important residue that mediates hydrogen bonding with ATP molecules upon binding of cobalamin to the active site. This study provides more structural information into the role of active site residues on substrate binding.     

An overview about the impact of hinge region towards the anticancer binding affinity of the Ck2 ligands: a quantum chemical analysis

Abstract

Casein kinase 2 (CK2) is extremely preserved and universally uttered serine/threonine kinase, vital for cellular feasibility. The present study aimed to analyse the binding strength of CK2 ligands specifically in the hinge region, as it is aware that most of the existing drugs are targeted to bind the hinge of the corresponding protein. The analysis will give a clear picture about the role of hinge region with ligand, which will be useful for scientist community in drug designing. To predict the binding strength of CK2 ligands, the role of halogen bond, hydrogen bond interaction at the hinge region was depicted in detail through interaction energy calculations at M062Z/def2-QZVP level of theory. Highest occupied molecular orbital (HOMO) map plotted for CK2 ligands gives a clear pictorial representation of orbitals, which induce for interaction. Ligand properties discussed in detail through Lipinski’s five rules predict that almost all the ligands satisfy the rule, except 3KXG, which violates Lipinski’s two rules, i.e. molecular mass exceeds 500?Da, i.e. 512.61?Da, and Log P value is high of 5.09. The natural bond orbital analysis deliberates that the hydrogen/halogen bonds figuring out within the complexes are observed to have moderate stabilization energy, but those hydrogen/halogen bonds that exist with close contacts have high stabilization energy. Overall, this computational work will give an understandable depiction for modelling anticancer ligands along the hinge region in CK2 protein; also, it will give a new path for the choice of side chains on the ligand.

Communicated by Ramaswamy H. Sarma