Effects of nucleobase metalation on frontier molecular orbitals: potential implications for pi-stacking interactions with tryptophan

Biochemical recognition processes mediated through pi-stacking interactions are a potential target for rational drug synthesis. A combination of electrostatic, hydrophobic, solvation, charge-transfer, induction, and dispersion interactions has been used to account for the three-dimensional arrangements observed in such motifs. A principal example involves the interaction of purine and pyrimidine rings of nucleic acids with aromatic amino-acid residues such as tryptophan, phenylalanine, and tyrosine. Protonation, alkylation, or coordination of a metal ion such as Pd(II) or Pt(II) to a nucleobase strengthens this interaction by lowering the energy of the lowest unoccupied molecular orbital (LUMO) of the modified nucleobase and improving overlap with the highest occupied molecular orbital (HOMO) in N-acetyl tryptophan. The relative energy difference between the frontier orbitals of isolated molecules, obtained using Density Functional Theory (DFT), is explored as a predictive tool for the strength of the pi-stacking interaction of the nucleobase/tryptophan pair. From the optimized structures of these species, evaluation of the donor-acceptor HOMO-LUMO gap (Deltaepsilon d-->a) suggests that this parameter is a promising predictor of pi-stacking strength for the donor-acceptor pairs presented in this study. The analysis correlates well with experimental association constants, measured by fluorescence spectroscopy, of metallated and alkylated nucleobases with tryptophan in comparison to free nucleobases.     

Effects of geometric isomerism and anions on the kinetics and mechanism of the stepwise formation of long-range DNA interstrand cross-links by dinuclear platinum antitumor complexes

Reported herein is a detailed study of the kinetics and mechanism of formation of a 1,4-GG interstrand cross-link by the dinuclear platinum anticancer compound [15N][{cis-PtCl(NH3)2}2{mu-NH2(CH2)6NH2}]2+ (1,1/c,c (1)). The reaction of [15N]1 with 5'-{d(ATATGTACATAT)2} (I) has been studied by [1H,15N] HSQC NMR spectroscopy in the presence of different concentrations of phosphate. In contrast with the geometric trans isomer (1,1/t,t), there was no evidence for an electrostatic preassociation of 1,1/c,c with the polyanionic DNA surface, and the pseudo-first-order rate constant for the aquation of [(15)N]1 was actually slightly higher (rather than lower) than that in the absence of DNA. When phosphate is absent, the overall rate of formation of the cross-link is quite similar for the two geometric isomers, occurring slightly faster for 1,1/t,t. A major difference in the DNA binding pathways is the observation of phosphate-bound intermediates only in the case of 1,1/c,c. 15 mM phosphate causes a dramatic slowing in the overall rate of formation of DNA interstrand cross-links due to both the slow formation and slow closure of the phosphate-bound monofunctional adduct. A comparison of the molecular models of the bifunctional adducts of the two isomers shows that helical distortion is minimal and globally the structures of the 1,4 interstrand cross-links are quite similar. The effect of carrier ligand was investigated by similar studies of the ethylenediamine derivative [15N]1-en. A pKa value of 5.43 was determined for the [15N]1,1/c,c-en diaquated species. The rate of reaction of [15N]1-en with duplex I is similar to that of 1,1/c,c and the overall conformation of the final adduct appears to be similar. The significance of these results to the development of "second-generation" polynuclear platinum clinical candidates based on the 1,1/c,c chelate (dach) series is discussed.     

Zinc metalloproteins as medicinal targets

Zinc bioinorganic chemistry has emphasized the role of the metal ion on the structure and function of the protein. There is, more recently, an increasing appreciation of the role of zinc proteins in a variety of human diseases. This critical review, aimed at both bioinorganic and medicinal chemists, shows how apparently widely-diverging diseases share the common mechanistic approaches of targeting the essential function of the metal ion to inhibit activity. Protein structure and function is briefly summarized in the context of its clinical relevance. The status of current and potential inhibitors is discussed along with the prospects for future developments (162 references).     

Investigation of polar organic solvents compatible with Corona Charged Aerosol Detection and their use for the determination of sugars by hydrophilic interaction liquid chromatography

A range of organic solvents (ethanol, isopropanol and acetone) has been investigated as alternatives to acetonitrile and methanol when used in conjunction with Corona Charged Aerosol Detection (Corona CAD). These solvents have been evaluated with regard to their effect on the response of the Corona CAD. Three dimensional response surfaces were constructed using raw data showing the relationship between detector response, analyte concentration and percentage of organic solvent in the mobile phase, using sucralose or quinine as the test analyte. The detector response was non-linear in terms of analyte concentration for all solvents tested. However, detector response varied in an approximately linear manner with percentage of organic solvent over the range 0–40% for ethanol or isopropanol and 0–80% for acetone and methanol. The chromatographic performance of the various solvents when used as aqueous–organic mobile phases was evaluated for isocratic and gradient separations of sugars and sugar alcohols by hydrophilic interaction liquid chromatography (HILIC) using an Asahipak NH2P-504E column coupled with Corona CAD detection. It was found that whilst acetonitrile provided the highest column efficiencies and lowest detection limits of the solvents studied, acetone also performed well and could be used to resolve the same number of analytes as was possible with acetonitrile. Typical efficiencies and detection limits of 5330 plates m⁻¹ and 1.25 μg mL⁻¹, respectively, were achieved when acetone was used as the organic modifier. Acetone was utilised successfully as an organic modifier in the HILIC separation of carbohydrates in a beer sample and also for a partially digested dextran sample.     

Orientation of ordered structures of cytosine and cytidine -monophosphate adsorbed at Au(110)/liquid interfaces

It is demonstrated using reflection anisotropy spectroscopy that the adsorption of cytosine and cytidine -monophosphate at the Au(110) 1 x 2/electrolyte interface gives rise to ordered structures in which the base is oriented vertical to the surface and parallel to the [110] axis of the Au(110) plane.     

Stereoselective [4 + 1] annulation reactions with silyl vinylketenes derived from Fischer carbene complexes

Stable silyl vinylketenes were prepared via the thermal reaction of Fischer carbene complexes with triisopropylsilyl- or tert-butyldimethylsilyl-substituted alkynes. The ability of these silyl vinylketenes to participate with carbenoid reagents in [4 + 1] annulation reactions was investigated. The best results were obtained with diazomethane and substituted diazomethane reagents, which provided cyclopentenone products in excellent yields and essentially complete stereoselectivity.     

Reducing conjugacy in the full diffeomorphism group of ℝ to conjugacy in the subgroup of orientation-preserving maps

Let Diffeo = Diffeo(ℝ) denote the group of infinitely differentiable diffeomorphisms of the real line ℝ, under the operation of composition, and let Diffeo⁺ be the subgroup of diffeomorphisms of degree +1, i.e., orientation-preserving diffeomorphisms. We show how to reduce the problem of determining whether or not two given elements f, g ∈ Diffeo are conjugate in Diffeo to associated conjugacy problems in the subgroup Diffeo⁺. The main result concerns the case when f and g have degree −1, and specifies (in an explicit and verifiable way) precisely what must be added to the assumption that their (compositional) squares are conjugate in Diffeo⁺, in order to ensure that f is conjugated to g by an element of Diffeo⁺. The methods involve formal power series and results of Kopell on centralisers in the diffeomorphism group of a half-open interval. Bibliography: 4 titles. Published in Zapiski Nauchnykh Seminarov POMI, Vol. 360, 2008, pp. 231–237.     

Directional integration on unstructured meshes via supermesh construction

Unstructured meshes are in widespread use throughout computational physics, but calculating diagnostics of simulations on such meshes can be challenging. For example, in geophysical fluid dynamics, it is frequently desirable to compute directional integrals such as vertical integrals and zonal averages; however, it is difficult to compute these on meshes with no inherent spatial structure. This is widely regarded as an obstacle to the adoption of unstructured mesh numerical modelling in this field. In this paper, we describe an algorithm by which one can exactly compute such directional integrals on arbitrarily unstructured meshes. This is achieved via the solution of a problem of computational geometry, constructing the supermesh of two meshes. We demonstrate the utility of this approach by applying it to a classical geophysical fluid dynamics system: the thermally driven rotating annulus. This addresses an important objection to the more widespread use of unstructured mesh modelling.     

Germanium microsphere high-Q resonator

In this Letter, the fabrication and characterization of a microsphere resonator from the semiconductor germanium is demonstrated. Whispering gallery modes are excited in a 46 μm diameter germanium microsphere resonator using evanescent coupling from a tapered silica optical fiber with a waist diameter of 2 μm. Resonances with Q factors as high as 3.8×10(4) at wavelengths near 2 μm are observed. Because of their ultrahigh optical nonlinearities and extremely broad transparency window, germanium microsphere resonators offer the potential for optical processing devices, in particular at long wavelengths, such as around 2 μm.     

Diboraperylene Diborinic Acid Self-Assembly on Ag(111)—Kagome Flat Band Localized States Imaged by Scanning Tunneling Microscopy and Spectroscopy

Replacement of sp²-hybridized carbon in polycyclic aromatic hydrocarbons (PAHs) by boron affords electron-deficient π-scaffolds due to the vacant p_z-orbital of three-coordinate boron with the potential for pronounced electronic interactions with electron-rich metal surfaces. Using a diboraperylene diborinic acid derivative as precursor and a controlled on-surface non-covalent synthesis approach, we report on a self-assembled chiral supramolecular kagome network on an Ag(111) surface stabilized by intermolecular hydrogen-bonding interactions at low temperature. Scanning tunneling microscopy (STM) and spectroscopy (STS) reveal a flat band at ca. 0.33 eV above the Fermi level which is localized at the molecule center, in good agreement with tight-binding model calculations of flat bands characteristic for kagome lattices.