Sigma-pi Interaction Research Articles

Imperatorin alleviates cancer cachexia and prevents muscle wasting via directly inhibiting STAT3

Skeletal muscle wasting is the most remarkable phenotypic feature of cancer cachexia that increases the risk of morbidity and mortality. Imperatorin (IMP), a main bioactive component of Angelica dahurica Radix, has been reported to possess several pharmacological effects including potential anti-colitis, anti-arthritis and anti-tumor activities. In this work, we demonstrated that IMP is a promising agent for the treatment of muscle wasting in cancer cachexia. IMP (5−20 μM) dose-dependently attenuated TCM-induced C2C12 myotube atrophy and prevented the induction of E3 ubiquitin ligases muscle RING-finger containing protein-1 (MuRF1) and muscle atrophy Fbox protein (Atrogin-1/MAFbx). Moreove, IMP administration significantly improved chief features of cancer cachexia in vivo, with significant prevention of the loss of body weight and deleterious wasting of multiple tissues, including skeletal muscle, fat and kidney and decreased expression of MuRF1 and Atrogin-1 in cachectic muscles. Cellular signaling pathway analysis showed that IMP selectively inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3) in vitro and in vivo, and surface plasmon resonance (SPR) affinity experiments further demonstrated IMP bound to STAT3 in a concentration-dependent resonance manner. Molecular docking results revealed that IMP binds to the SH2 domain of STAT3, forming a hydrogen bond interaction with Arg-609, and a Sigma-Pi interaction with Lys-591. Mechanism analysis demonstrated that STAT3 overexpression markedly weakens the improvements of IMP on myotube atrophy and muscle wasting of cancer cachexia, indicating that STAT3 mediated the therapeutic effect of IMP. All these favorable results indicated that IMP is a new potential therapeutic candidate for cancer cachexia.

In silico identification of novel antagonists and binding insights by structural and functional analyses of guanylate kinase of Leishmania donovani and interaction with inhibitors

Guanylate kinase (GK; EC 2.7.4.8) is an important enzyme which catalyzed the ATP-dependent phosphorylation of GMP (guanosine monophosphate) into GDP (guanosine diphosphate) for survival of parasites; this suggests that it is a good target for design inhibitor(s). Knowledge of 3D structure of GKLdv is essential for elucidating interaction studies with the inhibitors and compared with substrate binding pattern in both the built model and template structures. The final reliable model of GKLdv has revealed α/β type protein with a G-X2-G-X-G-K that has a catalytic conserved domain in both template and model structure. The core domain consists of a central five-stranded parallel β-sheet (β5, β6, β3 and β4) whereas model has both α1-α10 and β1-β9 and active sites consist of flexible loop (FL1 to FL3). The superimposition structure of main-chain atoms of the GK model with closely homologue of GK (1EX7, chain A), has revealed better alignment and its root mean square deviation (RMSD) (43% similarity) is 0.602Ǻ. The virtual screening result has suggested that the binding pocket interacts with 5GP (5′-guanylic acid) with exhibited higher score in both GOLD and LigandFit scores and involve in amino acid interaction (H-bonding) are Arg40, Try80, Tyr52, Ser36, Glu71, and Asp102. The reported antileishmanial diospyrin (IC₅₀-7.2μM) has also exhibited higher binding activities (Dock score - 49.314 and Fitness score - 52.69) with frequently involved amino acids are Arg45, Glu102, Tyr35, Tyr54, Ser38, Tyr82, Ile103, Asp104, Lys106, Lys18, Pro13 and Ser14. The sigma pi interaction between Ile103 with diospyrin ring has revealed greater stable complex after molecular dynamic simulation studies. The best scoring compounds need for further validation in-vitro test.

Design and synthesis of novel 2-pyrazoline-1-ethanone derivatives as selective MAO inhibitors

Thirty seven novel 2-pyrazoline-1-ethanone derivatives were designed, synthesized and evaluated as selective hMAO inhibitors. Among them, compounds 7h (IC50=2.40μM) and 12c (IC50=2.00μM) exhibited best inhibitory activity and selectivity against hMAO-A, surpassing that of the positive control Clorgyline (IC50=2.76μM). Based on selective activity of hMAO-A, SAR analysis showed that the order of N1 substituent contribution was bromo (3)>piperidinyl (4)>morpholinyl (5)>imidazolyl (6), and compounds with electron-withdrawing substituents (-F, -Cl) at C3 or C5 phenyl ring of 2-pyrazoline nucleus dedicated stronger MAO-A inhibitory activity. Molecular docking showed that compounds 7h and 12c were nicely bound to hMAO-A via two hydrogen bonds (SER209, GLU216), one Pi–Pi interaction and three hydrogen bonds (SER209, GLU216, TYR69), one Sigma–Pi interaction, respectively. In addition, the substituent at C3 position of 2-pyrazoline with the N1 acetyl has little effect on MAO-A inhibitory activity. These data support further studies to assess rational design of more efficiently selective hMAO inhibitors in the future.

New coumarin derivatives: Design, synthesis and use as inhibitors of hMAO

A series new 2H-chromene-3-carboxamides (4a–4i) and S-2H-chromene-3-carbothioates (5j–5t) were synthesized and evaluated as monoamine oxidase A and B inhibitors. Among them, compound 5k (IC50=0.21μM, IC50 iproniazid=7.65μM) showed the most activity and higher MAO-B selectivity (189.2-fold vs 1-fold) with respect to the MAO-A isoform. The need to clarify at a 3D level some important molecular aspects of discussed SAR, we undertaked a number of docking simulations to better assess. The steric effect was analyzed interms of both posing and scoring by investigating the nature of the binding interactions. The docking results of active compound 5k with hMAO-B complex indicated that conserved residue ILE 199 was important for ligand binding via Sigma–Pi interaction.

Kinetics and mechanism of the interaction of nitric oxide with pentacyanoferrate(II). Formation and dissociation of [Fe(CN)5NO]3 -.

The interaction of NO with [Fe(CN)(5)H(2)O](3)(-) (generated by aquation of the corresponding ammine complex) to produce [Fe(CN)(5)NO](3)(-) was studied by UV-vis spectrophotometry. The reaction product is the well characterized nitrosyl complex, described as a low-spin Fe(II) bound to the NO radical. The experiments were performed in the pH range 4-10, at different concentrations of NO, temperatures and pressures. The rate law was first-order in each of the reactants, with the specific complex-formation rate constant, k(f)( )()= 250 +/- 10 M(-)(1) s(-)(1) (25.4 degrees C, I = 0.1 M, pH 7.0), DeltaH(f)() = 70 +/- 1 kJ mol(-)(1), DeltaS(f)() = +34 +/- 4 J K(-)(1) mol(-)(1), and DeltaV(f)() = +17.4 +/- 0.3 cm(3) mol(-)(1). These values support a dissociative mechanism, with rate-controlling dissociation of coordinated water, and subsequent fast coordination of NO. The complex-formation process depends on pH, indicating that the initial product [Fe(CN)(5)NO](3)(-) is unstable, with a faster decomposition rate at lower pH. The decomposition process is associated with release of cyanide, further reaction of NO with [Fe(CN)(4)NO](2)(-), and formation of nitroprusside and other unknown products. The decomposition can be prevented by addition of free cyanide to the solutions, enabling a study of the dissociation process of NO from [Fe(CN)(5)NO](3)(-). Cyanide also acts as a scavenger for the [Fe(CN)(5)](3)(-) intermediate, giving [Fe(CN)(6)](4)(-) as a final product. From the first-order behavior, the dissociation rate constant was obtained as k(d) = (1.58 +/- 0.06) x 10(-)(5) s(-)(1) at 25.0 degrees C, I = 0.1 M, and pH 10.2. Activation parameters were found to be DeltaH(d)() = 106.4 +/- 0.8 kJ mol(-)(1), DeltaS(d)() = +20 +/- 2 J K(-)(1) mol(-)(1), and DeltaV(d)() = +7.1 +/- 0.2 cm(3) mol(-)(1), which are all in line with a dissociative mechanism. The low value of k(d) as compared to values for the release of other ligands L from [Fe(II)(CN)(5)L](n)()(-) suggests a moderate to strong sigma-pi interaction of NO with the iron(II) center. It is concluded that the release of NO from nitroprusside in biological media does not originate from [Fe(CN)(5)NO](3)(-) produced on reduction of nitroprusside but probably proceeds through the release of cyanide and further reactions of the [Fe(CN)(4)NO](2)(-) ion.

Study of conformational stability of polycarbonitrile-polyazine copolymers

In a previous study we showed that the trans-polycarbonitrile polymer presents a strong deviation from the planarity suggesting that this conformation does not correspond to the most stable structure of the system. These non-planarity can affect significantly the electronic properties of the polymer. On the other hand the polyazine derivative, a conjugated polymer, a nitrogen containing analog of the polyacetylene, that can be considered the head-to-head polymer of the imine repeat unit, is a planar conjugated system with very small sigma-pi interaction. In this work we report a comparative study of the electronic structures and the electrical conduction properties of the polycarbonitrile-polyazine copolymers. Our results indicate that the planarity of the copolymers depends on the competition among carbonitrile-azine segments size and can lead to a conductive system.

An ESR study of the [16]annulene anion radical. A thermally accessible excited electronic state

An ESR study of the [16]annulene anion radical is reported. The hyperfine splitting is observed to be temperature dependent. This temperature dependence arises from two sources. One, the sigma-pi interaction parameter, Q H, is a function of temperature. Two, the spin-density distribution within the molecule is also dependent upon temperature. Analysis of the temperature dependence of the spin-density distribution shows that the observed changes are consistent with the following model: one, a molecular symmetry of D 4 h ; two, a ground state with symmetry classification A 1 u ; three, an excited electronic state, 1140(±120) cm −1 above the ground state with symmetry classification of A 2 u . The sigma-pi interaction parameter, Q, for the [16]annulene anion radical is observed to be as strongly dependent upon temperature as those reported for benzene anion and cycloheptatrienyl radicals. The magnetic resonance parameters observed for the [16]annulene are discussed in terms of those observed for some selected near-orbitally degenerate free radicals.

Nonempirical Calculations on Excited States: The Formaldehyde Molecule

A series of calculations on the excited states of formaldehyde using excitation operator techniques are presented. As in ethylene, the effect of σ–π interaction on the “π→π*”(1A1) excitation is rather large, decreasing the calculated excitation energy from 14.89 to 12.03 eV and the oscillator strength from 1.01 to 0.30. The coupling has little effect on the corresponding triplet state (3A1). The next higher approximation reduces the excitation energy to 11.22 eV and the oscillator strength to 0.21. The effect of the coupling on the “n→π*”(1,3A2) excitations is not as large as that for the A11 state, lowering the excitation energies for both the singlet and triplet by ∼0.5 eV. Similar results were obtained for the “σ→π*”(1,3B1) excitations. Trends are observed in calculations on corresponding states in ethylene and formaldehyde. Numerous one-electron properties are claculated for the excited states. The results are in moderate agreement with experiment; a major source of error probably arises from the use of an unoptimized, minimum basis set LCAO(STO)–MO–SCF wavefunction.

Sigma and Pi Electronic Reorganization in Acetylene

Accurate SCF—LCAO—MO wavefunctions have been computed for acetylene neutral ground state, singly excited π→π* states, and for the acetylene anion and cation. A limited basis set of Slater orbitals was used, the carbon 2s, 2pπ, and 2pσ orbital exponents were independently optimized for each state, and hydrogen 1s for the ground state. All integrals were computed accurately. For the ground state the C2p±1 optimized orbital (ξ=1.59) is very different from the C2pσ optimized orbital (ξ=2.03) with the result that the Π cloud does not penetrate the Σ cloud as greatly as would be predicted by Slater or best-atom AO. However, the penetration remains sizeable (Fig. 2). The ground-state energy − 76.678 a.u. (1 a.u.=27.2098 eV) is improved by 0.134 a.u. over McLean's best-atom calculations, but is 0.176 a.u. poorer than McLean's Hartree—Fock calculations. Reorganizations of the sigma and pi electronic shells with change in state of the pi system are computed to be large. A gain or loss of a pi electron is accompanied by a sigma energy change of 0.2 a.u. partially due to deformation of the C2s AO and partially due to sigma polarization away from the H atoms in the cation and vice versa in the anion. The large reorganization in the pi distribution is illustrated by the 2pπ exponents: cation 1.68, anion 1.45, ground state 1.59. The total reorganization energy in acetylene (−0.033 a.u. G state→cation; −0.069 a.u. G state→anion) is only 6% of the largest reorganization term: the change in sigma—pi interaction (0.586 and 1.262 a.u., respectively). The success of conventional pi-electron theory then basically depends on cancellation of the sigma and pi reorganization energy terms with the change in the sigma—pi interaction. The Hijcore parameters are found to be nearly independent of pi density providing justification for pi-electron approaches which adjust the pi atomic orbitals according to pi density.

Oxygen−17 Hyperfine Splitting Constants in the ESR Spectra of p-Semiquinones—17O

Oxygen−17 hyperfine splitting constants have been determined for a number of semiquinones—17O. The results were correlated with the spin density distribution in the radicals. It was found that the splitting constants aO can be very well fitted to an expression of the form, aO=QOC O ρO+QCO O ρC, where ρO and ρC are pπ spin densities on the oxygen and carbon atoms of the carbonyl group, and the Q's are sigma—pi interaction constants. QOC O is about −40 G, but the analysis does not allow the value of QCOO to be determined, although its magnitude is certainly much less than that of QOC O. These interaction constants are discussed in terms of the general theory of Karplus and Fraenkel. Solvent effects on aO were observed, especially in going from apropic to hydrogen-bonding solvents and are discussed in terms of radical—solvent interaction at the carbonyl oxygen. In the Appendixes molecular orbital parameters for oxygen and chlorine are derived from the analysis of proton hyperfine splitting constants in simple and chloro-substituted semiquinones.

Sigma-Pi Interaction Accompanied by Stereoselection

Abstract A simple molecular orbital theoretical treatment of the sigma-pi interaction caused by chemical reactions of planar-conjugated systems has been developed. The problem of the streo-selection of the two alternative directions of configuration altering due to the hybridization change at the centers of interaction has been considered by means of a simple perturbation treatment. Two theoretical indices, which represent the conjugation stabilization by way of the sigma-pi and reagent-pi interactions, have been introduced for this purpose. The theoretical results are consistent with the results of experience so far accumulated in various organic reactions, such as additions, eliminations, substitutions, and rearrangements, of conjugated molecules.

Paramagnetic Resonance of Alkyl Nitroxides

Methods of preparation and the electron paramagnetic resonance spectra are given for the three prototype alkyl nitroxide free radicals: H2NO, CH3(H)NO, and (CH3)2NO. The sigma—pi interaction theory of Karplus and Fraenkel for 13C, which has been applied extensively to 14N hyperfine splitting, is examined critically by the application of linear regression to 41 14N-containing free radicals. Three different sets of 14N sigma—pi interaction parameters are found which reproduce the experimental 14N coupling constants to an equally high degree of accuracy. Consequently, the prediction of experimental coupling constants within the order of magnitude of solvent effects (5%—10%), should not be considered a satisfactory test of a set of theoretical 14N interaction parameters, since the parameter values can fall within a wide range and still fulfill the test requirement. The parameter SN does not appear to play an important role in the sigma—pi interaction of these radicals.

Sigma-pi interaction constants (EPR) of nitrogen in sp2 hybridization

Sigma-pi interaction constants (EPR) of nitrogen in sp2 hybridization

Spin-Density Distribution in Nitrile Anion Radicals

Molecular-orbital calculations of the pi-electron spin densities in a series of aromatic and aliphatic nitrile anion radicals have been performed using the Hückel—LCAO method and the approximate configuration-interaction correction of McLachlan. Coulomb and resonance integrals for the nitrile group were estimated by comparing calculated spin densities with proton and carbon-13 hyperfine splittings obtained from electron-spin resonance measurements. The predicted spin densities were in generally good agreement with the experimental results, but for some of the compounds it is impossible to get an exact fit between theory and experiment within the framework of the simple valence-theory calculations if the sigma—pi interaction parameters relating splittings to spin densities are taken as fixed quantities. Semiempirical treatments of the N14 and C13 splittings in the cyano groups give excellent correlations of the experimental splittings with the calculated spin densities, and estimates have been made of some of the sigma—pi interaction parameters relating to the N14 splitting. Polarographic half-wave potentials have also been compared with calculated pi-electron energies. A discussion is given of the relation between the spin densities predicted by the valencebond and molecular-orbital theories.

Electron Spin Resonance of Azulene Anion Radicals

The electron spin resonance spectra of the anion radicals of azulene, azulene-1,3-d2, 4,6,8-trimethylazulene, and 4,6,8-trimethylazulene-1,3-d2 have been examined. These hydrocarbons are nonalternant and have aromatic ring structures with C–C–C bond angles that depart from 120°. The radicals were generated electrolytically in N,N-dimethylformamide using tetra-n-propylammonium perchlorate as supporting electrolyte. Sigma-pi-interaction calculations of the parameter QCHH [in the relation aiH=QCHHρiπ between the isotropic proton hyperfine splitting (aiH) and pi-electron spin density (ρiπ)] have been performed as a function of the bond angles at the carbon atom bonded to the proton. These calculations indicate a strong dependence of this parameter on angle. By using recent x-ray data on azulene, predictions could be made of the Q's at the different positions in the radicals. In contrast, the proton splitting at a methyl-group substituent, determined by the parameter QCCH3H, is predicted to be independent of the bond angles at the carbon atom of the aromatic system. Calculations of the pi-electron spin density were made in both the simple Hückel and the McLachlan extended self-consistent field molecular-orbital theory approximations. These calculations were used with the experimental splitting constants to make a comparison with the predicted bond-angle variation of the sigma-pi interaction parameters (Q's). The McLachlan procedure gives much more satisfactory results than the Hückel calculations, but the agreement with experiment, involving use of the predicted dependence of QCHH on bond angle, is only approximate. The theoretical estimates of the variation of QCHH with bond angle, and of the constancy of QCCH3H, appear to be qualitatively correct. Applications of the theory for the change of QCHH with angle may in some instances necessitate taking into account bent bonds.

Theoretical Interpretation of Carbon-13 Hyperfine Interactions in Electron Spin Resonance Spectra

A quantitative theory of the isotropic electron-nuclear spin interactions of carbon 13 in pi-electron radicals is presented and applied to the hyperfine splittings observed in the electron spin resonance spectra of these substances. The splittings arise from sigma-pi interactions which polarize both the 1s and 2s electrons. The 1s-orbital spin polarization is shown to contribute a term of negative sign with a magnitude comparable to that from the 2s electrons. For an sp2 hybridized carbon atom that is bonded to three atoms, Xi (i=1, 2, 3), the hyperfine constant aC has the form aC=(SC+ ∑ i=13QCXiC)ρπ+ ∑ i=13QXiCCρiπ,where ρπ and ρiπ(i=1,2,3) are the pi-electron spin densities on atoms C and Xi, respectively. The contribution of the 1s electrons is determined by SC and that of the 2s electrons by the Q's, where QBCA is the sigma-pi parameter for the nucleus of atom A resulting from the interaction between the bond BC and the pi-electron spin density on atom B. Calculations for a planar CHC2 fragment model yield SC= —12.7 gauss, QCHC=19.5 gauss, QCC′C=14.4 gauss, and QC′CC= —13.9 gauss. The theory predicts both the magnitude and sign of the hyperfine splittings and is readily applied to a variety of compounds. Excellent agreement is obtained with the available experimental data. For the methyl radical, the measured C13 splitting is shown to be consistent with a planar model and limits the deviation from planarity to ≲5°. The theory provides a useful criterion for the validity of approximate wave functions that is illustrated by a comparison of various theoretical treatments for the naphthalene negative ion and triphenylmethyl. The sigma-pi interaction parameters are shown to depend on the bond length, the type of hybridization (including the angles between sigma bonds), and on the nature of the bonding atoms. For pi-electron systems, the results demonstrate that the magnitude of the sigma-pi exchange energy is a small fraction of the total energy. It is also noted that the proton parameter QCHH is somewhat larger in CHC2 than in CH3, which suggests a theoretical justification for some of the variation in the experimental ``QCHH'' required to fit measured proton splittings. The form of the theory is readily extended to the treatment of hyperfine splittings from nuclei other than C13.

A further study on the electronic structure and spectrum of ethylene

Calculations on the lower electronic states, ionization potential and electron affinity of ethylene are carried out by a semi-empirical ASMO method including configuration interaction. The carbon-carbon sigma bonding electrons are explicitly included. One-centre quantities for ethylene, ethylene negative ion and ethylene positive ion are evaluated from atomic valence-state energies, taking account of changes in effective nuclear charges of the corresponding states. Two-centre electronic repulsion integrals are determined by interpolation between theoretical values for distant nuclear separations and one-centre repulsion integrals obtained; two-centre core integrals are computed purely theoretically. Good agreement between calculated and observed values is obtained. Although preferential stabilization of the ion cannot be expected from sigma-pi configuration interaction, it is shown that the reorganization of the electronic sub-structure of the atom upon ionization plays a significant role.