Introducing 77Se NMR Spectroscopy to Analyzing Galectin -Ligand Interaction.

Their emerging nature as multifunctional effectors explains the large interest to monitor glycan binding to galectins and to define bound-state conformer(s) of their ligands in solution. Basically, NMR spectroscopy facilitates respective experiments. Towards developing new and even better approaches for these purposes, extending the range of exploitable isotopes beyond 1H, 13C, and 15N offers promising perspectives. Having therefore prepared selenodigalactoside and revealed its bioactivity as galectin ligand, monitoring of its binding by 77Se NMR spectroscopy at a practical level becomes possible by setting up a 2D 1H, 77Se CPMG-HSQBMC experiment including CPMG-INEPT long-range transfer. This first step into applying 77Se as sensor for galectin binding substantiates its potential for screening relative to inhibitory potencies in compound mixtures and for achieving sophisticated epitope mapping. The documented strategic combination of synthetic carbohydrate chemistry and NMR spectroscopy prompts to envision to work with isotopically pure 77Se-containing ß-galactosides and to build on the gained experience with 77Se by adding 19F as second sensor in doubly labeled glycosides.

A low-temperature dynamic 1 H, 13 C, and 77 Se NMR study of 2,2'-selenodicyclohexanol.

2,2'-Selenodicyclohexanol 1 was shown to exist as two (all-trans-achiral and all-trans-chiral) stereoisomers with all C-Se and C-OH bonds in equatorial orientations. When the temperature is lowered, the 1 H, 13 C, and 77 Se NMR spectra exhibit a strongly one-sided dynamic process, which involves sterically hindered rotation about the C-Se bond. Structures, free energy differences of the rotamers ΔG°, and the rotational barrier were determined and confirmed by quantum chemical calculations at the M06-2X/6-311++G**, M06-2X/cc-pVTZ, and MP2/6-311+G** levels of theory.

Hydration of selenolate moiety: Ab initio investigation of properties of O-H⋯Se(-) hydrogen bonds in CH3 Se(-)⋯(H2 O)n clusters.

This work is devoted to investigations of the influence of O-H···Se(-) hydrogen bonds on the electronic shells of selenolate R-Se(-) fragment (R═CH3 ). The geometric, energetic and nuclear magnetic resonance (NMR) spectral parameters for various conformers of CH3 Se(-)⋯(H2 O)n clusters with n = 0-6 were calculated at CCSD/aug-cc-pVDZ level of theory. For selenolate anion CH3 Se(-) solvation free energy was calculated, and for water media it is equal to -71.41 kcal/mol. For O-H···Se(-) hydrogen bonds the proportionality coefficients between QTAIM parameters at (3; -1) bond critical point and the strength of an individual hydrogen bond ∆E were proposed. It was shown, that despite a relative weakness of O-H···Se(-) hydrogen bonds, the outer electronic shell of the selenium atom changes significantly upon formation of each hydrogen bond. This, in turn, cause the dramatic change of NMR parameters of selenium nuclei.

Galectin-Glycan Interactions: Guidelines for Monitoring by 77 Se NMR Spectroscopy, and Solvent (H2 O/D2 O) Impact on Binding.

Functional pairing between cellular glycoconjugates and tissue lectins like galectins has wide (patho)physiological significance. Their study is facilitated by nonhydrolysable derivatives of the natural O-glycans, such as S- and Se-glycosides. The latter enable extensive analyses by specific 77 Se NMR spectroscopy, but still remain underexplored. By using the example of selenodigalactoside (SeDG) and the human galectin-1 and -3, we have evaluated diverse 77 Se NMR detection methods and propose selective 1 H,77 Se heteronuclear Hartmann-Hahn transfer for efficient use in competitive NMR screening against a selenoglycoside spy ligand. By fluorescence anisotropy, circular dichroism, and isothermal titration calorimetry (ITC), we show that the affinity and thermodynamics of SeDG binding by galectins are similar to thiodigalactoside (TDG) and N-acetyllactosamine (LacNAc), confirming that Se substitution has no major impact. ITC data in D2 O versus H2 O are similar for TDG and LacNAc binding by both galectins, but a solvent effect, indicating solvent rearrangement at the binding site, is hinted at for SeDG and clearly observed for LacNAc dimers with extended chain length.

Quantum chemical calculations of 77 Se and 125 Te nuclear magnetic resonance spectral parameters and their structural applications.

An accurate quantum chemical (QC) modeling of 77 Se and 125 Te nuclear magnetic resonance (NMR) spectra is deeply involved in the NMR structural assignment for selenium and tellurium compounds that are of utmost importance both in organic and inorganic chemistry nowadays due to their huge application potential in many fields, like biology, medicine, and metallurgy. The main interest of this review is focused on the progress in QC computations of 77 Se and 125 Te NMR chemical shifts and indirect spin-spin coupling constants involving these nuclei. Different computational methodologies that have been used to simulate the NMR spectra of selenium and tellurium compounds since the middle of the 1990s are discussed with a strong emphasis on their accuracy. A special accent is placed on the calculations resorting to the relativistic methodologies, because taking into account the relativistic effects appreciably influences the precision of NMR calculations of selenium and, especially, tellurium compounds. Stereochemical applications of quantum chemical calculations of 77 Se and 125 Te NMR parameters are discussed so as to exemplify the importance of integrated approach of experimental and computational NMR techniques.

Titanocene Selenide Sulfides Revisited: Formation, Stabilities, and NMR Spectroscopic Properties.

[TiCp2S5] (phase A), [TiCp2Se5] (phase F), and five solid solutions of mixed titanocene selenide sulfides [TiCp2SexS5-x] (Cp = C5H5-) with the initial Se:S ranging from 1:4 to 4:1 (phases B⁻E) were prepared by reduction of elemental sulfur or selenium or their mixtures by lithium triethylhydridoborate in thf followed by the treatment with titanocene dichloride [TiCp2Cl2]. Their 77Se and 13C NMR spectra were recorded from the CS2 solution. The definite assignment of the 77Se NMR spectra was based on the PBE0/def2-TZVPP calculations of the 77Se chemical shifts and is supported by 13C NMR spectra of the samples. The following complexes in varying ratios were identified in the CS2 solutions of the phases B⁻E: [TiCp2Se5] (51), [TiCp2Se4S] (41), [TiCp2Se3S2] (31), [TiCp2SSe3S] (36), [TiCp2SSe2S2] (25), [TiCp2SSeS3] (12), and [TiCp2S5] (01). The disorder scheme in the chalcogen atom positions of the phases B⁻E observed upon crystal structure determinations is consistent with the spectral assignment. The enthalpies of formation calculated for all twenty [TiCp2SexS5-x] (x = 0⁻5) at DLPNO-CCSD(T)/CBS level including corrections for core-valence correlation and scalar relativistic, as well as spin-orbit coupling contributions indicated that within a given chemical composition, the isomers of most favourable enthalpy of formation were those, which were observed by 77Se and 13C NMR spectroscopy.

Efficient Synthesis of 1,4-Bis-heteroatom-substituted Tetraselanylbenzenes via 1,4-Dilithiation of Hexaselanylbenzene and Investigation on Their Electronic Properties.

We successfully synthesized mono- and bis-substituted polyselanylbenzenes 3 and 5 via mono- and dilithiation of hexakis(phenylselanyl)benzene (1), respectively. Introduction of various heteroatom functionalities into hexaselanylbenzene changed the electronic properties dependent on the σ-symmetric circular orbitals that were formed by the interactions between neighboring heteroatoms. In the cyclic voltammetry and theoretical studies on bis-heteroatom-substituted benzenes 5, the extent of the interactions in the circular orbitals with σ-symmetry affected the stability of the cationic species of 5. This study would give insight into the molecular design for new σ-delocalized systems and inspire the development of tuning electronic properties of benzene derivatives by σ-type orbital interactions derived from heteroatom functionalities.

Classical/Non-classical Polyoxometalate Hybrids.

Two polyanions [SeI V2 PdII4 WVI14 O56 H]11- and [SeI V4 PdII4 WVI28 O108 H12 ]12- are the first hybrid polyoxometalates in which classical (Group 5/6 metal based) and non-classical (late transition-metal based) polyoxometalate units are joined. Requiring no supporting groups, this co-condensation of polyoxotungstate and isopolyoxopalladate constituents also provides a logical link between POM-PdII coordination complexes and the young subclass of polyoxopalladates. Solid-state, solution, and gas-phase studies suggest interesting specific reactivities for these hybrids and point to several potential derivatives and functionalization strategies.

Four-component relativistic DFT calculations of (77) Se NMR chemical shifts: A gateway to a reliable computational scheme for the medium-sized organoselenium molecules.

A versatile high-accuracy computational scheme for the (77) Se nuclear magnetic resonance (NMR) chemical shifts of the medium-sized organoselenium compounds is suggested within a framework of a full four-component relativistic density functional theory (DFT). The main accuracy factors (DFT functionals, relativistic geometry, vibrational corrections, and solvent effects) are addressed. The best result is achieved with NMR-oriented KT2 functional of Keal-Tozer characterized by a fairly small error of only 30 ppm for the span of about 1700 ppm (<2%).

MP2 calculation of (77) Se NMR chemical shifts taking into account relativistic corrections.

The main factors affecting the accuracy and computational cost of the Second-order Möller-Plesset perturbation theory (MP2) calculation of (77) Se NMR chemical shifts (methods and basis sets, relativistic corrections, and solvent effects) are addressed with a special emphasis on relativistic effects. For the latter, paramagnetic contribution (390-466 ppm) dominates over diamagnetic term (192-198 ppm) resulting in a total shielding relativistic correction of about 230-260 ppm (some 15% of the total values of selenium absolute shielding constants). Diamagnetic term is practically constant, while paramagnetic contribution spans over 70-80 ppm. In the (77) Se NMR chemical shifts scale, relativistic corrections are about 20-30 ppm (some 5% of the total values of selenium chemical shifts). Solvent effects evaluated within the polarizable continuum solvation model are of the same order of magnitude as relativistic corrections (about 5%). For the practical calculations of (77) Se NMR chemical shifts of the medium-sized organoselenium compounds, the most efficient computational protocols employing relativistic Dyall's basis sets and taking into account relativistic and solvent corrections are suggested. The best result is characterized by a mean absolute error of 17 ppm for the span of (77) Se NMR chemical shifts reaching 2500 ppm resulting in a mean absolute percentage error of 0.7%.

Stereochemical behavior of geminal and vicinal 77Se-13C spin-spin coupling constants studied at the SOPPA(CC2) level taking into account relativistic corrections.

A systematic theoretical study of geminal and vicinal (77)Se-(13)C spin-spin coupling constants in the series of the open-chain selenides and selenium-containing heterocycles revealed that relativistic effects play an essential role in the selenium-carbon coupling mechanism, especially when the coupling pathway includes a triple bond, contributing to about 10-15% of their total values and noticeably improving the agreement of the calculated couplings with experiment. Both geminal and vicinal (77)Se-(13)C spin-spin coupling constants show marked stereochemical behavior as documented by their calculated dihedral angle dependence that could be used as a practical guide in stereochemical studies of organoselenium compounds.

SEAL by NMR: glyco-based selenium-labeled affinity ligands detected by NMR spectroscopy.

We report a method for the screening of interactions between proteins and selenium-labeled carbohydrate ligands. SEAL by NMR is demonstrated with selenoglycosides binding to lectins where the selenium nucleus serves as an NMR-active handle and reports on binding through (77)Se NMR spectroscopy. In terms of overall sensitivity, this nucleus is comparable to (13)C NMR, while the NMR spectral width is ten times larger, yielding little overlap in (77)Se NMR spectroscopy, even for similar compounds. The studied ligands are singly selenated bioisosteres of methyl glycosides for which straightforward preparation methods are at hand and libraries can readily be generated. The strength of the approach lies in its simplicity, sensitivity to binding events, the tolerance to additives and the possibility of having several ligands in the assay. This study extends the increasing potential of selenium in structure biology and medicinal chemistry. We anticipate that SEAL by NMR will be a beneficial tool for the development of selenium-based bioactive compounds, such as glycomimetic drug candidates.

Relativistic effects in the one-bond spin-spin coupling constants involving selenium.

One-bond spin-spin coupling constants involving selenium of seven different types, (1) J(Se,X), X = (1) H, (13) C, (15) N, (19) F, (29) Si, (31) P, and (77) Se, were calculated in the series of 14 representative compounds at the SOPPA(CCSD) level taking into account relativistic corrections evaluated both at the RPA and DFT levels of theory in comparison with experiment. Relativistic corrections were found to play a major role in the calculation of (1) J(Se,X) reaching as much as almost 170% of the total value of (1) J(Se,Se) and up to 60-70% for the rest of (1) J(Se,X). Scalar relativistic effects (Darwin and mass-velocity corrections) by far dominate over spin-orbit coupling in the total relativistic effects for all (1) J(Se,X). Taking into account relativistic corrections at both random phase approximation and density functional theory levels essentially improves the agreement of theoretical results with experiment. The most 'relativistic' (1) J(Se,Se) demonstrates a marked Karplus-type dihedral angle dependence with respect to the mutual orientation of the selenium lone pairs providing a powerful tool for stereochemical analysis of selenoorganic compounds.

Transformation of a wobble 2-thiouridine to 2-selenouridine via S-geranyl-2-thiouridine as a possible cellular pathway.

The newly discovered S-geranylated 2-thiouridines (geS2U) (Dumelin et al., 2012) and 2-selenouridines (Se2U) were recently shown to be synthesized by a single enzyme (selenouridine synthase, SelU) through two distinct pathways using the same 2-thiouridine substrate (S2U); however, no clear catalytic mechanism was proposed. We suggest that S-geranyl-2-thiouridine is an intermediate of the SelU-catalyzed conversion of S2U to Se2U. The successful chemical transformation of S2U→geS2U→Se2U is demonstrated here as an initial approximation of the intracellular pathway. The structure of Se2U was confirmed by spectroscopic methods, which included, for the first time, (77)Se NMR data (δ 354ppm).

Full four-component relativistic calculations of the one-bond 77Se-13C spin-spin coupling constants in the series of selenium heterocycles and their parent open-chain selenides.

Four-component relativistic calculations of (77)Se-(13)C spin-spin coupling constants have been performed in the series of selenium heterocycles and their parent open-chain selenides. It has been found that relativistic effects play an essential role in the selenium-carbon coupling mechanism and could result in a contribution of as much as 15-25% of the total values of the one-bond selenium-carbon spin-spin coupling constants. In the overall contribution of the relativistic effects to the total values of (1)J(Se,C), the scalar relativistic corrections (negative in sign) by far dominate over the spin-orbit ones (positive in sign), the latter being of less than 5%, as compared to the former (ca 20%). A combination of nonrelativistic second-order polarization propagator approach (CC2) with the four-component relativistic density functional theory scheme is recommended as a versatile tool for the calculation of (1)J(Se,C). Solvent effects in the values of (1)J(Se,C) calculated within the polarizable continuum model for the solvents with different dielectric constants (ε 2.2-78.4) are next to negligible decreasing negative (1)J(Se,C) in absolute value by only about 1 Hz. The use of the locally dense basis set approach applied herewith for the calculation of (77)Se-(13)C spin-spin coupling constants is fully justified resulting in a dramatic decrease in computational cost with only 0.1-0.2-Hz loss of accuracy.