A Photoswitchable Agonist for the Histamine H3 Receptor,a Prototypic Family A G‐Protein‐Coupled Receptor

Spatiotemporal control over biochemical signaling processes involving G protein‐coupled receptors (GPCRs) is highly desired for dissecting their complex intracellular signaling. We developed sixteen photoswitchable ligands for the human histamine H₃ receptor (hH₃R). Upon illumination, key compound 65 decreases its affinity for the hH₃R by 8.5‐fold and its potency in hH₃R‐mediated G_i protein activation by over 20‐fold, with the trans and cis isomer both acting as full agonist. In real‐time two‐electrode voltage clamp experiments in Xenopus oocytes, 65 shows rapid light‐induced modulation of hH₃R activity. Ligand 65 shows good binding selectivity amongst the histamine receptor subfamily and has good photolytic stability. In all, 65 (VUF15000) is the first photoswitchable GPCR agonist confirmed to be modulated through its affinity and potency upon photoswitching while maintaining its intrinsic activity, rendering it a new chemical biology tool for spatiotemporal control of GPCR activation.     

A Photoswitchable Agonist for the Histamine H3 Receptor,a Prototypic Family A G‐Protein‐Coupled Receptor

Spatiotemporal control over biochemical signaling processes involving G protein‐coupled receptors (GPCRs) is highly desired for dissecting their complex intracellular signaling. We developed sixteen photoswitchable ligands for the human histamine H₃ receptor (hH₃R). Upon illumination, key compound 65 decreases its affinity for the hH₃R by 8.5‐fold and its potency in hH₃R‐mediated G_i protein activation by over 20‐fold, with the trans and cis isomer both acting as full agonist. In real‐time two‐electrode voltage clamp experiments in Xenopus oocytes, 65 shows rapid light‐induced modulation of hH₃R activity. Ligand 65 shows good binding selectivity amongst the histamine receptor subfamily and has good photolytic stability. In all, 65 (VUF15000) is the first photoswitchable GPCR agonist confirmed to be modulated through its affinity and potency upon photoswitching while maintaining its intrinsic activity, rendering it a new chemical biology tool for spatiotemporal control of GPCR activation.     

Discovery of Potential,Dual-Active Histamine H3 Receptor Ligands with Combined Antioxidant Properties

In an attempt to find new dual acting histamine H₃ receptor (H₃R) ligands, we designed a series of compounds, structurally based on previously described in our group, a highly active and selective human histamine H₃ receptor (hH₃R) ligand KSK63. As a result, 15 obtained compounds show moderate hH₃R affinity, the best being the compound 17 (hH₃R K_i = 518 nM). Docking to the histamine H₃R homology model revealed two possible binding modes, with key interactions retained in both cases. In an attempt to find possible dual acting ligands, selected compounds were tested for antioxidant properties. Compound 16 (hH₃R K_i = 592 nM) showed the strongest antioxidant properties at the concentration of 10⁻⁴ mol/L. It significantly reduced the amount of free radicals presenting 50–60% of ascorbic acid activity in the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, as well as showed antioxidative properties in the ferric reducing antioxidant power (FRAP) assay. Despite the yet unknown antioxidation mechanism and moderate hH₃R affinity, 16 (QD13) constitutes a starting point for the search of potential dual acting H₃R ligands-promising tools for the treatment of neurological disorders associated with increased neuronal oxidative stress.     

Adsorption of molecular hydrogen on inorganometallic complexes B<Subscript>2</Subscript>H<Subscript>4</Subscript>M (M=Li,Be, Sc,Ti, V)

Molecular interaction between hydrogen molecules and B₂H₄M (M=Li, Be, Sc, Ti, V) complexes has been studied using the DFT method (M06 functional) and 6-311++G** basis set. The hydrogen uptake capacity of the complexes considered is higher than the target set by the US Department of Energy (5.5 wt% by 2020). The metal atom bound strongly to the B₂H₄ substrate. Adsorption of molecular hydrogen on Be-, Ti-, and V-decorated complexes is thermodynamically possible for all the pressures and temperatures considered whereas it is unfavorable for Li-decorated complexes for all the pressure and temperatures. For the Sc-doped complexes, adsorption of molecular hydrogen is favorable below 330 K and entire pressure range considered. All the H₂ adsorbed complexes are kinetically stable. For all the complexes, the interaction between the inorganometallic complexes and the H₂ molecules adsorbed is attractive whereas that between adsorbed H₂ molecules is repulsive. We have also performed molecular dynamics simulations to confirm the same number of H₂ molecule adsorption from the simulations and DFT calculations.     

Synthesis and characterization of some novel triphenylarsenic(V) derivatives of monofunctional bidentate 2,2‐disubstituted benzothiazoline ligands

A series of triphenylarsenic(V) derivatives Ph₃As(OPrⁱ)[SC₆H₄N:C(R)CH₂C(O)R′] have been synthesized by the reactions of triphenylarsenic(V)‐ isoproproxide, Ph₃As(OPrⁱ)₂ with the corresponding 2,2‐disubstituted benzothiazolines of the type (where R = CH₃, R′ = CH₃( 1 ); R = CH₃, R′ = C₆H₅( 2 ); R = CH₃, R′ = 4‐CH₃C₆H₄( 3 ); R = CH₃, R′ = 4‐ClC₆H₄( 4 ); and R = CF₃, R′ = C₆H₅( 5 )) in equimolar ratio in refluxing benzene solution. Molecular weight measurements of these complexes show their monomeric nature in solution. Characterization of these compounds using elemental analyses, molecular weight measurements, and spectral studies (IR as well as NMR (¹H and ¹³C)) shows the monofunctional bidentate nature of the ligands and a hexacoordination around the central arsenic atom in these organoarsenic(V) derivatives. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:76–80, 2007; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20233     

Synthesis,structural characterization,and ethylene polymerization behavior of (arylimido)vanadium(V) complexes bearing tridentate Schiff base ligands

A series of novel (arylimido)vanadium(V) complexes bearing tridentate salicylaldiminato chelating ligands, V(N‐2,6‐Me₂C₆H₃)Cl₂[(O‐2‐^tBu‐4‐R‐C₆H₃)CH?ND] (R = H, D = 2‐CH₃O? C₆H₄ ( 2a ); 2‐CH₃S? C₆H₄ ( 2b ); 2‐Ph₂P? C₆H₄ ( 2c ); 8‐C₉H₆N (quinoline) ( 2d ); CH₂C₅H₄N ( 2e ); R = ^tBu, D = 2‐Ph₂P? C₆H₄ ( 2f )), were prepared from V(NAr)Cl₃ by reacting with 1.0 equiv of the ligands in the presence of triethylamine in tetrahydrofuran. These complexes were characterized by ¹H, ¹³C, ³¹P, and ⁵¹V NMR spectra and elemental analysis. The structures of 2c and 2f were further confirmed by X‐ray crystallographic analysis. These (arylimido)vanadium(V) complexes are effective catalyst precursors for ethylene polymerization in the presence of Et₂AlCl as a cocatalyst and ethyl trichloroacetate as a reactivating agent. Complex 2c with a ? PPh₂ group in the sidearm was found to exhibit an exceptional activity up to 133800 kg polyethylene/mol_V h for ethylene polymerization at 75 °C, which is one of the highest activities displayed by homogeneous vanadium(V) catalysts at high temperature. Moreover, high molecular weight polymers with unimodal molecular weight distribution can be obtained, indicating the single site behavior of these catalysts. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2633‐2642     

Organo group VB chemistry: Part VI. On the electric dipole moments of some substituted tertiary phenylphosphines, -arsines, -stibines and -bismuthines

The dipole moments of the following series of tertiary substituted aryl-group VB compounds were measured: (a) (C₆H₅)₃M and (XC₆H₄)₃M with M = P, As, Sb, Bi and X = 4-F, 4-Cl, 4-CH₃, 3-F, 3-Cl; and (b) (3-XC₆H₄)_3?n PR_n with R = C₆H₅, 4-FC₆H₄ and X = F, Cl. These experimental molecular moments are discussed as a consistent set of data that allows the calculation, within the framework of the vectorial additive method, of suitable group moments, bond moments and configurational parameters.     

A Serendipitous Rendezvous with a Four‐Center Two‐Electron Bonded Intermediate in the Aerial Oxidation of Hydrazine

Oxidation by dioxygen has a rich repertoire of mechanistic intricacies. Herein, we report a hitherto unknown paradigm of dioxygen activation reaction which propagates through a four center two electron (4c–2e) bound species. Using static DFT and ab initio quantum chemical techniques we have unraveled the oxidation pathway for hydrazine and its methylated analogues by dioxygen which involves formation of this unconventional 4c–2e bonded species en route to the oxidation products. Inconvertible evidence in favor of such an unprecedented dioxygen activation route is provided by capturing the events of formation of the 4c–2e species in aqueous phase for hydrazine and its congeners and the experimentally observed products from the respective 4c–2e species, like H₂O₂ and N₂H₂, diazene in the case of hydrazine using Car–Parrinello molecular dynamics simulations.     

Molecular and Silica‐Supported Mo and W d0 Imido‐Methoxybenzylidene Complexes: Structure and Metathesis Activity

5‐Coordinated methoxybenzylidene complexes M(=NAr)(=CH?C₆H₄?o‐OMe)(O^tBu_F3)₂ (Ar=2,6‐ⁱPr₂C₆H₃; ^tBu_F3=CMe₂(CF₃)) of Mo ( 1m_Mo ) and W ( 1m_W ) were synthesized by cross‐metathesis from the corresponding neophylidene/neopentylidene precursors and o‐methoxystyrene. 1m_Mo and 1m_W were grafted onto the surface of silica partially dehydroxylated at 700 °C to give well‐defined silica‐supported alkylidenes (≡SiO)M(=NAr)(=CH?C₆H₄?o‐OMe)(O^tBu_F3) (M=Mo ( 1_Mo ), W ( 1_W )). Supported methoxybenzylidene complexes were tested in metathesis of cis‐4‐nonene, 1‐nonene, and ethyl oleate, and compared to their molecular precursors and supported classical analogs (≡SiO)M(=NAr)(=CHCMe₂R)(O^tBu_F3) (M=Mo, R=Ph ( 2_Mo ), M=W, R=Me ( 2_W )). Both grafted complexes 1_Mo and 1_W show significantly better performance as compared to their molecular precursors 1m_Mo and 1m_W but are less efficient than the classical 4‐coordinated alkylidenes 2_Mo and 2_W . Noteworthy, both 1_Mo and 1_W can reach equilibrium conversion in metathesis of cis‐4‐nonene at catalyst loadings as low as 50 ppm.     

Verification of DFT-predicted hydrogen storage capacity of VC3H3 complex using molecular dynamics simulations

Density functional theory (DFT) and Fourth‐order Möller–Plesset (MP4) perturbation theory calculations are performed to examine the possibility of hydrogen storage in V‐capped VC₃H₃ complex. Stability of bare and H₂ molecules adsorbed V‐capped VC₃H₃ complex is verified using DFT and MP4 method. Thermo‐chemistry calculations are carried out to estimate the Gibbs free corrected averaged H₂ adsorption energy which reveals whether H₂ adsorption on V‐capped VC₃H₃ complex is energetically favorable, at different temperatures. We use different exchange and correlation functionals employed in DFT to see their effect on H₂ adsorption energy. Molecular dynamic (MD) simulations are performed to confirm whether this complex adsorbs H₂ molecules at a finite temperature. We elucidate the correlation between H₂ adsorption energy obtained from density functional calculations and retaining number of H₂ molecules on VC₃H₃ complex during MDs simulations at various temperatures. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011     

Highly active and thermo-stable iminopyridyl vanadium oxychloride catalyzed isoprene polymerization

Stereoregular polymerizations are of high importance, which disclosing the relationships between microstructures and physical properties of polymers. In this contribution, a series of iminopyridyl vanadium oxychloride complexes V1 – V8 (R = H, R¹ = CH₂Ph for V1 ; R = H, R¹ = CHPh₂ for V2 ; R = H, R¹ = octamyl for V3 ; R = H, R¹ = Ph for V4 ; R = H, R¹ = 4-OMe-C₆H₄ for V5 ; R = H, R¹ = 4-CF₃ C₆H₄ for V6 ; R = H, R¹ = 2,4,6-Ph₃ C₆H₂ for V7 and R = Me, R¹ = Ph for V8 ) have been prepared, and were investigated for their catalytic capacity of isoprene polymerization. A single crystal structure of V7′ was reported, which was reduced from V(v) to V(iv) in the oxidation state of vanadium central atom. The catalytic activity was up to 408 kg (mol V)⁻¹ hr⁻¹, when V4 was used. The catalyst V6 was found to be highly thermo-stable with excellent activity even at 100°C. Most importantly, resultant polymers mainly possessed cis-1,4 units (up to 75%) with 25% side-chain 3,4 functional group, which is particularly important component to enhance the application of these synthetic rubbers.     

Olefin polymerization and copolymerization by complexes bearing [ONNO]‐Type salan ligands: Effect of ligand structure and metal type (titanium,zirconium, and vanadium)

A series of novel titanium(IV) complexes bearing tetradentate [ONNO] salan type ligands: [Ti{2,2′‐(OC₆H₃‐5‐t‐Bu)₂‐NHRNH}Cl₂] (Lig¹TiCl₂: R = C₂H₄; Lig²TiCl₂: R = C₄H₈; Lig³TiCl₂: R = C₆H₁₂) and [Ti{2,2′‐(OC₆H₂‐3,5‐di‐t‐Bu)₂‐NHC₆H₁₂NH}Cl₂] (Lig⁴TiCl₂) were synthesized and used in the (co)polymerization of olefins. Vanadium and zirconium complexes: [ M{2,2′‐(OC₆H₃‐3,5‐di‐t‐Bu)₂‐NHC₆H₁₂NH}Cl₂] (Lig⁴VCl₂: M = V; Lig⁴ZrCl₂: M = Zr) were also synthesized for comparative investigations. All the complexes turned out active in 1‐octene polymerization after activation by MAO and/or Al(i‐Bu)₃/[Ph₃C][B(C₆F₅)₄]. The catalytic performance of titanium complexes was strictly dependent on their structures and it improves for the increasing length of the aliphatic linkage between nitrogen atoms (Lig¹TiCl₂ << Lig²TiCl₂ < Lig³TiCl₂) and declines after adding additional tert‐Bu group on the aromatic rings (Lig³TiCl₂ < Lig⁴TiCl₂). The activity of all titanium complexes in ethylene polymerization was moderate and the properties of polyethylene was dependent on the ligand structure, cocatalyst type, and reaction conditions. The Et₂AlCl‐activated complexes gave polymers with lover molecular weights and bimodal distribution, whereas ultra‐high molecular weight PE (up to 3588 kg mol^?1) and narrow MWD was formed for MAO as a cocatalyst. Vanadium complex yielded PE with the highest productivity (1925.3 kg mol_v^?1), with high molecular weight (1986 kg mol^?1) and with very narrow molecular weight distribution (1.5). Copolymerization tests showed that titanium complexes yielded ethylene/1‐octene copolymers, whereas vanadium catalysts produced product mixtures. © 2014 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2014 , 52, 2111–2123     

Quantum chemistry investigation of electronic structure and NMR spectral characteristics for fluorides of dialkylamidosulfoxylic acids and related compounds

The parent (H₂N? S? F) and N,N‐dialkyl‐substituted fluorides of amidosulfoxylic acid (R₂N? S? F, R?Me or R₂N?Morph) as well as the related compounds X? S? F (X?CH₃, OH, F, SiH₃, PH₂, SH, Cl) have been investigated with quantum chemical calculations at the ab initio (MP2) level of approximation. The geometries, electronic structures, molecular orbital (MO) energies and NMR chemical shift values have been calculated to evaluate the role and extent of the polarization and delocalization effects in forming of the high‐field fluorine NMR resonances within the series of interest. The δF magnitudes for all investigated fluorides of amidosulfoxylic acid as well as the δN value calculated for Me₂N? S? F are in the good agreement with the ¹⁹F and ¹⁴N NMR chemical shift values measured experimentally. For the parent compounds, H₂N? S? F and H₂N? SO₂? F, the orientation of principal axes of the magnetic shielding tensors and the corresponding principal σ_ii values along these axes have been qualitatively interpreted basing on the analysis of the MO interactions in the presence of the rotating magnetic field. Copyright © 2009 John Wiley & Sons, Ltd.     

Ring‐opening polymerization of cyclic esters promoted by phosphido‐diphosphine pincer group 3 complexes

Phosphido‐diphosphine Group 3 metal complexes 1–4 [(o‐C₆H₄PR₂)₂P‐M(CH₂SiMe₃)₂; R = Ph, 1 : M = Y, 2 : M = Sc; R = iPr, 3 : M = Y, 4 : M = Sc] are very efficient catalysts for the ring‐opening polymerization (ROP) of cyclic esters such as ε‐caprolactone (ε‐CL), L ‐lactide, and δ‐valerolactone under mild polymerization conditions. In the ROP of ε‐CL, complexes 1–4 promote quantitative conversion of high amount of monomer (up to 3000 equiv) with very high turnover frequencies (TOF) (～4 × 10⁴ mol_CL/mol_I h) showing a catalytic activity among the highest reported in the literature. The immortal and living ROP of ε‐CL and L ‐lactide is feasible by combining complexes 1–4 with 5 equiv of 2‐propanol. Polymers with controlled molecular parameters (M_n, end groups) and low polydispersities (M_w/M_n = 1.05–1.09) are formed as a result of fast alkoxide/alcohol exchange. In the ROP of δ‐valerolactone, complexes 1–4 showed the same activity observed for lactide (L ‐ and D ,L ‐lactide) producing high molecular weight polymers with narrow distribution of molar masses. Complexes 1–4 also promote the ROP of rac‐β butyrolactone affording atactic low molecular weight poly(hydroxybutyrate) bearing unsaturated end groups probably generated by elimination reactions. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

G-Protein-Coupled Receptor–Membrane Interactions Depend on the Receptor Activation State

G-protein-coupled receptors (GPCRs) are the largest family of human membrane proteins and serve as primary targets of approximately one-third of currently marketed drugs. In particular, adenosine A₁ receptor (A₁AR) is an important therapeutic target for treating cardiac ischemia–reperfusion injuries, neuropathic pain, and renal diseases. As a prototypical GPCR, the A₁AR is located within a phospholipid membrane bilayer and transmits cellular signals by changing between different conformational states. It is important to elucidate the lipid–protein interactions in order to understand the functional mechanism of GPCRs. Here, all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) method were performed on both the inactive (antagonist bound) and active (agonist and G-protein bound) A₁AR, which was embedded in a 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) lipid bilayer. In the GaMD simulations, the membrane lipids played a key role in stabilizing different conformational states of the A₁AR. Our simulations further identified important regions of the receptor that interacted distinctly with the lipids in highly correlated manner. Activation of the A₁AR led to differential dynamics in the upper and lower leaflets of the lipid bilayer. In summary, GaMD enhanced simulations have revealed strongly coupled dynamics of the GPCR and lipids that depend on the receptor activation state. © 2019 Wiley Periodicals, Inc.     

Synthesis,characterization and toxicity of new heterobimetallic complexes of platinum(II) and palladium(II)

Heterobimetallic complexes of the type [M(C₆H₆N₂)₂(M′)₂(R)₄]Cl₂ have been synthesized by the direct reaction of [M(C₆H₈N₂)₂]Cl₂ with Group 4 or 14 organometallic dichlorides Ph₂M′Cl₂,Me₂M′Cl₂ or Cp₂M″Cl₂ in 1:2 molar ratio in MeOH (M = Pd or Pt, M′ = Si or Sn and M″ = Ti or Zr). The compounds were characterized by elemental analysis, molecular weight determination, electronic, ¹H NMR and IR spectra, magnetic susceptibilities and conductivity measurements. These studies showed that the compounds are monomers and dimagnetic in nature, with a square‐planar geometry around palladium and platinum metals. Both the free ligands and their metal complexes were screened for antimicrobial activity on different species of pathogenic fungi and bacteria and were found active in this respect.Copyright © 2001 John Wiley & Sons, Ltd.     

NMR-spektroskopische Untersuchungen an Fluoro-diaza-diphosphetidinen und Fluoro-λ5-monophosphazenen

N.M.R. Investigations of Fluorodiazadiphosphetidines and Fluoro-λ⁵-monophosphazenes The ¹⁹F and ³¹P n.m.r. data of 37 fluorodiazadiphosphetidines [RR′PF? NC₆H₄X]₂, and 62 fluoro-λ⁵-monophosphazenes, RR′PF=NC₆H₄X, are submitted. In the case of tetrafluorodiazadiphosphetidines, [RPF₂? NC₆H₄X]₂, an intramolecular exchange of the fluorine atoms at phosphorus has to be concluded from the n.m.r. data. The influence of the substituents R and X on the n.m.r. parameters is discussed using simple models of molecular structure.     

EQCM Study of Ru and RuO2 Surface Electrochemistry

The present study represents comparative analysis of voltammetric and microgravimetric behavior of active ruthenium (Ru), electrochemically passivated ruthenium (Ru/RuO₂) and thermally formed RuO₂ electrodes in the solutions of 0.5 M H₂SO₄ and 0.1 M KOH. It has been found that cycling the potential of active Ru electrode within E ranges 0 V–0.8 V and 0 V–1.2 V in 0.5 M H₂SO₄ and 0.1 M KOH solutions, respectively, leads to continuous electrode mass increase, while mass changes observed in alkaline medium are considerably smaller than those in acidic one. Microgravimetric response of active Ru electrode in 0.5 M H₂SO₄ within 0.2 V–0.8 V has revealed reversible character of anodic and cathodic processes. The experimentally found anodic mass gain and cathodic mass loss within 0.2–0.8 V make 2.2–2.7 g F^?1, instead of 17 g F^?1, which is the theoretically predicted value for Ru(OH)₃ formation according to equation: Ru+3H₂O?Ru(OH)₃+3H⁺+3e^?. In the case of Ru/RuO₂ electrode relatively small changes in mass have been found to accompany the anodic and cathodic processes within E range between 0.4 V and 1.2 V in the solution of 0.5 M H₂SO₄. Meanwhile cycling the potential of thermally formed RuO₂ electrode under the same conditions has lead to continuous decrease in electrode mass, which has been attributed to irreversible dehydration of RuO₂ layer. On the basis of microgravimetric and voltammetric study as well as the coulometric analysis of the results conclusions are presented regarding the nature of surface processes taking place on Ru and RuO₂ electrodes.     

Polythiolated complexes. Part 2(1). Palladium(II) and platinum(II) derivatives of polyfluorophenylthiolates

Summary The preparation and characterization of the new thiolate complexes [M(SR)₂(SEt₂)₂] (M=Pt, R=C₆F₅ orp-C₆HF₄) and [M(SR)₂]_n (M=Pd, R=C₆F₅,p-C₆HF₄ orp-C₆H₄F; M=Pt, R=p-C₆H₄F) is discussed. The tendency to form polymeric, rather than monomeric species, varies as follows: Pd>Pt; C₆H₄F>C₆HF₄> C₆F₅. [Pt(SC₆F₅)₂(SEt₂)₂] has atrans square planar coordination.     

Fluorooxoperoxo complexes of vanadium(V)

Substances crystallizing under various conditions from the MVO₃(MF, HF)H₂O₂H₂O (M = NH₄, K) systems have been characterized by elemental analysis, infrared and Raman spectra and X-ray powder patterns. Besides the known M₂[VO(O₂)₂F] complexes, complexes of two new types have been obtained: M₃[HV₂O₂(O₂)₃F₄·2H₂O and (NH₄)₃[V₂O₂(O₂)₄F]·nH₂O (n≈2). Vibrational spectra of new complexes are consistent with the presence of dimeric anions containing V(μ₂O₂)V and VFV bridges, respectively.