Structurally homogeneous and heterogeneous synthetic combinatorial libraries

Summary We have designed and synthesized structurally homogeneous and heterogeneous nonpeptide libraries. Structurally homogeneous libraries are characterized by the presence of one common structural unit, a scaffold, in all library compounds (e.g. cyclopentane, cyclohexane, diketopiperazine, thiazolidine). In structurally heterogeneous libraries different organic reactions (acylation, etherification, reductive amination, nucleophilic displacement) were applied to connect bifunctional building blocks unrelated in structure (aromatic hydroxy acids, aromatic hydroxy aldehydes, amino alcohols, diamines, and amino acids). The focus of this communication is to document the use of bifunctional building blocks for the design and synthesis of structurally heterogeneous libraries ofN-(alkoxy acyl)amino acids, N,N-bis-(alkoxy acyl)diamino acids,N-acylamino ethers,N-(alkoxy acyl)amino alcohols,N-alkylamino ethers, andN-(alkoxy aryl)diamines.Abbreviations AcOH acetic acid - DCE dichloroethane - DCM dichloromethane - DEAD diethyl azodicarboxylate - DIAD diisopropyl azodicarboxylate - DIC diisopropyl carbodiimide - DIEA diisopropylethylamine - DMAP dimethylaminopyridine - DMF dimethylformamide - Fmoc fluorenylmethyloxycarbonyl - HOBt N-hydroxybenzotriazole - MeCN acetonitrile - MeOH methanol - NaOH sodium hydroxide - PEG/PS polyethylene-grafted copolystyrene - PPh₃ triphenylphosphine - t-Bu tert- butyl - TFA trifluoroacetic acid - TG TentaGel - THE tetrahydrofuran     

Rationally designed non-peptides: Variously substituted piperazine libraries for the discovery of bradykinin antagonists and other G-protein-coupled receptor ligands

Summary Molecular modeling studies of potent decapeptide bradykinin antagonists suggested the de novo design of peptide mimetics based on a 1,2,3,4-tetrasubstituted 1,4-piperazin-6-one scaffold. These de novo-designed antagonists exhibited only modest potency (IC₅₀ 55 M) on a cloned human B₂ receptor and antagonist activity in an in vitro human-cell functional assay. The success of these structures led to the creation of prototype libraries based on variously substituted 1,4-piperazine scaffolds, which allowed a rapid and general search of pharmacophores attached to a piperazine scaffold. The parent piperazinedione structures and fully reduced piperazine libraries differ from recently reported diketopiperazine libraries in the use of diverse nonnatural amino acids, on-resin-submonomer synthesis to provide more diverse N-substituted structures, and the adaptation of simultaneous ring closure and resin cleavage to drive the formation of highly hindered amide bonds. Using this chemistry, a rationally directed non-peptide library of approximately 2500 N,N-disubstituted piperazines and piperazinediones was synthesized and screened for ligand affinity on bradykinin, neurokinin, and opioid receptors. A number of lead structures were identified. Notably, a bradykinin antagonist lead, CP-2458, with good receptor selectivity and antagonist activity in human-cell assays was identified and is undergoing optimization by traditional and combinatorial methods.Abbreviations BK bradykinin - Boc tert-butoxycarbonyl - Cbz carboxybenzyl - DMF dimethylformamide - DMSO dimethylsulfoxide - Fmoc fluorenylmethoxycarbonyl - HBTU O-benzotriazol-l-yl-N,N,N,N-tetramethyluronium hexafluorophosphate - HPLC high-performance liquid chromatography - MALDI-MS matrix assisted laser desorption ionization-mass spectrometry - PyBroP bromo-tris-pyrrolydino-phosphonium hexafluorophosphate - RDDA rationally directed diverse analogs - TFA trifluoroacetic acid     

Determining the excited‐state substituent constants of furyl and thienyl groups

Six series of styrene derivatives XCH═CHArY (total of 65) containing the styrene parent molecular skeleton were synthesized (here, Y is OMe, Me, H, F, Cl, CF₃, CN, and NO₂, and X is 2‐furyl, 3‐furyl, 2′‐methyl‐2‐furyl, 2‐thienyl, 3‐thienyl, and 2′‐methyl‐2‐theniyl). Their ultraviolet absorption spectra were measured in anhydrous ethanol, and their wavelength of absorption maximum λ_max was recorded. For the wavenumber ν_max (cm^?1, ν_max = 1/λ_max) of the obtained λ_max, a quantitative correlation analysis was performed, and 6 excited‐state substituent constants of groups X were obtained by means of curve‐fitting method. Taking the ν_max values of total 90 compounds of styrene derivatives as a data set (including 25 compounds from reference and 65 compounds of this work), a quantitative correlation analysis was performed, and the reliability of the obtained was verified. In addition, 12 samples of disubstituted Schiff bases (XCH═NArY) involving the above groups X were synthesized, and their ν_max values were recorded. Using these 12 ν_max together with the 14 ν_max values of Schiff bases taken from reference (total of 26 compounds), it was further verified that the values are reliable by means of quantitative correlation method.     

Magnetostriction of REBa2Cu3O7-δ

The magnetostriction (MS) of REBa₂Cu₃O_7– (RE=Y, Nd, Eu, Gd, Ho, Er, Yb) is reported as a function of magnetic field and temperature forH<5 T and 1.5H>1 T. The MS is much larger when the rare earth carries a magnetic moment, as usual, but the volume MS observed with moment carrying REBa₂Cu₃O_7– is larger than that of nonsuperconducting intermetalics. This effect is explained by the shielding currents which are induced by the 4f magnetic moments in the superconducting CuO-lattice. The thermal expansion of GdBa₂Cu₃O_7– shows a large peak at the ordering temperature of 2.2 K in both the superconducting and the nonsuperconducting samples.     

Substituent effect on the UV spectra of p‐disubstituted compounds XPh(CHCHPh)nY (n = 0, 1, 2)

Three parameters, , and , are developed to express the substituent effect and the effect of the parent molecular structure of p‐disubstituted compounds XPh(CH?CHPh)_nY (n = 0, 1, 2). The investigated result shows a good correlation between the UV absorption wavenumbers (υ_max) and the three parameters for a diverse set of title compounds, and the correlation equation can be used to predict the UV absorption energy of compounds with the mentioned structure. This approach provides a new insight for the quantitative structure‐property relationship (QSPR) correlation of the UV absorption energy of p‐disubstituted homologues. Copyright © 2010 John Wiley & Sons, Ltd.     

Dynamic short-range order observed in the (Zn)[Fe2]O4 spinel by neutron diffraction, μSR,and Mössbauer experiments

Using neutron diffraction (ND), muon-spin rotation/relaxation (SR), and⁵⁷Fe-Mössbauer spectroscopy (MS) we have investigated magnetic properties of the normal spinel (Zn)[Fe₂]O₄. In compounds which are slowly cooled from 1200°C to room temperature inversion is below detection limits. AtT _N = 10.5 K the spinel exhibits long-range antiferromagnetic order (LRO). The transition as seen in thermal-scan spectra by MS is very sharp. However, ND andSR experiments show that already at temperatures of 10T _N a short-range antiferromagnetic ordering (SRO) develops which extends through 70% of the sample volume just aboveT _N . BelowT _N SRO and LRO coexist. At 4.2 K still 25% of the sample is short-range ordered. The regions over which the SRO extends have a size of 3 nm. Their fluctuation rates are in the GHz range. Modern ab initio cluster calculations successfully describe the magnetic hyperfine fields as well as the electric field gradient (EFG) tensor at the Fe sites. Covalency of the Fe-O and Zn-O bonds is important. The physical origin of the regions exhibiting SRO, however, remains unresolved at this point.     

Spectral effects of intramolecular interaction in the chloranhydrides of unsaturated phosphorus acids

Measurements have been made of the integral Raman line strength of unsaturated phosphorus acids; it is concluded that the phosphorus-bearing group interacts with the-electron system of the aromatic radical in the excited state. It is found that the -PCl₂, -P(O)Cl₂ and -P(S) · Cl₂ will show acceptor behavior in the conjugated system when interacting with donor substituents. The role of the vacant orbitals of the chlorine attached to the phosphorus is discussed.Translated from Izvestiya Vysshikh Uchebnykh Zavedenii Fizika, No. 11, pp. 25–28, November, 1972.     

The link between the ionization potential and heat of formation for organic homologous compounds

Based on the relationship between the heat of formation and the change of valence electronic energy in the formation of a compound from its component atoms, and combined with the relationship between the first ionization potential and the average valence electronic energy, the direct link of ionization potential, Ip, with the heat of formation, ΔH⁰_f, was deduced for organic homologous compounds, that is, where N_ve,m is the number of valence electrons in molecule, SVEE_x is the sum of valence electronic energy of isolated atoms forming the molecule, the term expresses the initial‐state effect of the molecule, and the symbol R_m represents its final‐state effect (polarizability effect). The above equation was confirmed by the correlations between the ionization potentials and the heat of formation of alkanes, alkenes, monosubstituted alkanes RY (Y = OH, NH₂, SH, Cl, Br, and I), in which all the expressions have good correlations with correlation coefficients more than 0.9990. With the obtained correlation equations, the ionization potentials of some monosubstituted alkanes were predicted from their experimental heats of formation. The result provides a new insight into the intercorrelation between the ionization potential and the heat of formation for organic homologous compounds. Copyright © 2007 John Wiley & Sons, Ltd.     

Magnetostriction of several high-T c superconductors

We report on magnetostriction measurements of superconducting and nonsuperconducting YBa₂Cu₃O_7– and of two Bi samples with the nominal compositions Bi₂CaSr₂Cu₂O _x and Bi_0.8Pb_0.2Sr_0.8CaCu_1.5O _x . Both types of high temperature superconductors show a nearly identical strongly hysteretic field dependence of the magnetostriction (MS) (l/l+(2–6)*10^–6 at 5 T and 1.5 K). In both cases the MS is a linear function of field in the region 1–5 T, which we explain by striction due to surface currents. Between 1.5 and 35 K the hysteresis of the MS decreases strongly with increasing temperature, which implies a decrease of the pinning force. The MS of quenched nonsuperconducting YBa₂Cu₃O_7– is at least two orders of magnitude smaller than that of the superconductor.     

Intramolecular energy transfer in compounds with two 1-pyrenoate groups separated by methylene spacers

Steady-state fluorescence anisotropy (r) and fluorescence lifetime () measurements have been used to study the efficiency of nonradiative singlet energy transfer as a function of alkane size in 1-pyrenecarboxylic acid alkanediyl esters (as a function ofm in Py-COO-(CH₂) _m -OOC-Py, where Py denotes pyrene substituted in the 1-position, andm=2–6). Experiments were performed in media of different viscosity, , obtained by changing the temperature (from –20 to 40°C) of dilute solutions in ethylene glycol and by examination of the compounds in a solid matrix of poly(methyl methacrylate) (PMMA) at ambient temperature. The Py-COO-(CH₂)_m-OOC-Py exhibit intramolecular excimer emission in ethylene glycol at these temperatures, but the intensity of this emission is much lower than when these compounds are placed in common solvents of lower . The values of indicate that excitation hopping or intramolecular energy transfer takes place between the chromophores attached to the ends of the alkane bridges. Values ofr obtained by the extrapolationsT/0 orT/0 in ethylene glycol, as well as the values obtained in the rigid matrix of PMMA, show very little dependence onm. A theoretical conformational analysis, using the rotational isomeric state (RIS) model, was also performed. The combination of the experimental results forr in the media of high with the theoretical (RIS) analysis produces an estimated value of 21 ±2 Å for the Förster radius in Py-COO-(CH₂)_m-OOC-Py.     

Contribution ofd-like states to magnesium,aluminium and phosphorusL-emission bands of MgO,Al2O3 and AlPO4

We have measured the MgL-, AlL- and PL-emission bands of MgO, -Al₂O₃ and AlPO₄, respectively. For MgO and Al₂O₃ the electronic structure and the X-ray emission bands have been calculated. In spite of different crystal structure and chemical composition of these compounds the cationL-emission bands are very similar. We have found that for the interpretation of theL-emission bands of these compounds the cation 3d-like electrons are crucial.     

Spectroscopy of alkali atoms and molecules attached to liquid He clusters

Large helium clusters, ranging in size from a few hundred to several thousand atoms, are produced in a nozzle expansion. Combining this source with a pick-up scattering cell in which the clusters can be seeded with chromophores allows us to probe the influence of the helium environment on the atoms and molecules attached to the clusters. Using an alkali as chromophore we recorded laser induced fluorescence spectra of Na atoms and molecules attached to helium clusters. Apart from the spectrum of the Na monomer, we have found spectroscopic bands which can unambiguous be assigned to two bound Na atoms. The first of this bands is due to 1^{1 +} (A) 1¹ _g ⁺ (X) excitations of the covalently bound singlet Na₂ molecule while the second is due to 1³ _g ⁺ 1^{3 +} excitations for the van der Waals bound triplet Na₂ dimer. Both bands have been vibrationally resolved. Furthermore we found very large fluorescence intensities in the region 605–635 nm which are likely due to the excitation of a species containing three Na atoms attached to a helium cluster.     

The Dynamics of Intramolecular Excited State Relaxation of <Emphasis Type="Italic">N</Emphasis>-Anthryl Substituted Pyridinium Cations

N-(1-Anthryl)-2,4,6-trimethyl-pyridinium (I), N-(2-anthryl)-2,4,6-trimethyl-pyridinium (II) and 10-(1-anthryl)-1,2,3,4,5,6,7,8-octahydro-acridinium cations (III) with anomalously high fluorescence Stokes shift have been investigated. Fluorescence kinetics analysis at various temperatures showed that in the range 293–77 K, the radiative deactivation rate constants (k_f) increase by 5.5 to 30 times. The low-temperature time-resolved emission spectra of I–III were found to be consistent with the model: A A^* B^* where A^* is the local excited twisted form and B^* is the relaxed more planar, bent conformer of the molecule. The rate constants of the excited relaxed state formation (k₁) and back reaction (k_–1) of compounds studied were estimated.     

Mössbauer studies and magnetic properties of Ln2SrCu2O6 compounds

Mössbauer and magnetic susceptibility measurements were used to study the magnetic properties of Ln_1.9Sr_1.1Cu₂O₆ (Ln=Pr,Nd) and La₂SrCu₂O₆ materials. These compounds were prepared by solid-state reaction and crystallize in a tetragonal structure, space group I4/mmm with two formula units per unit cell. There is only one crystallographic site for Cu atoms, which form a double layer of CuO₅ pyramids. These compounds are not superconducting, but we show, using Mössbauer spectroscopy (MS) on iron doped samples and susceptibility measurements, that the Cu planes order antiferromagnetically. The hyperfine fields on iron nuclei at 4.2 K extend from 472 kOe for La₂SrCu₂O₆ to 501 kOe for Nd_1.9Sr_1.1Cu₂O₆. The ordering temperaturesT _N are: R20, 190, and 250 K for Ln=La, Pr and Nd, respectively.     

Gauge-invariant on-shellZ 2 in QED,QCD and the effective field theory of a static quark

We calculate theon-shell fermion wave-function renormalization constantZ ₂ of a general gauge theory, to two loops, inD dimensions and in an arbitrary covariant gauge, and find it to be gauge-invariant. In QED this is consistent with the dimensionally regularized version of the Johnson-Zumino relation: d logZ ₂/da ₀=i(2)^–D e ₀ ² d ^D k/k ⁴=0. In QCD it is, we believe, a new result, strongly suggestive of the cancellation of the gauge-dependent parts of non-abelian UV and IR anomalous dimensions to all orders. At the two-loop level, we find that the anomalous dimension _F of the fermion field in minimally subtracted QCD, withN _L light-quark flavours, differs from the corresponding anomalous dimension of the effective field theory of a static quark by the gauge-invariant amount

DFT study and NBO analysis of the mutual interconversion of cumulene compounds

The B3LYP/6‐31G* method was used to investigate the configurational properties of allene (1,2‐propadiene) ( 1 ), 1,2,3‐butatriene ( 2 ), 1,2,3,4‐pentateriene ( 3 ), 1,2,3,4,5‐hexapentaene ( 4 ), 1,2,3,4,5,6‐heptahexaene ( 5 ), 1,2,3,4,5,6,7‐octaheptaene ( 6 ), 1,2,3,4,5,6,7,8‐nonaoctaene ( 7 ), and 1,2,3,4,5,6,7,8,9‐decanonaene ( 9 ). The calculations at the B3LYP/6‐31G* level of theory showed that the mutual interconversion energy barrier in compounds 1 – 8 are: 209.73, 131.77, 120.34, 85.00, 80.91, 62.19, 55.56, and 46.83 kJ mol^?1, respectively. The results showed that the difference between the average C?C double bond lengths ( ) values in cumulene compounds 1 and 2 , is larger than those between 7 and 8 , which suggest that with large n (number of carbon atoms in cumulene chain), the values approach a limiting value. Accordingly, based on the plotted data, the extrapolation to n = ∞, gives nearly the same limiting (i. e., ). Also, NBO results revealed that the sum of π‐bond occupancies, , decrease from 1 to 8 , and inversely, the sum of π‐antibonding orbital occupancies, , increase from compound 1 to compound 8 . The decrease of values for compounds 1 – 8 , is found to follow the same trend as the barrier heights of mutual interconversion in compounds 1 – 8 , while the decrease of the barrier height of mutual interconversion in compounds 1 – 8 is found to follow the opposite trend as the increase in the number of carbon atom. Accordingly, besides the previously reported allylic resonant stabilization effect in the transition state structures, the results reveal that the values, , Δ(E_HOMO ? E_LUMO), and the C atom number could be considered as significant criteria for the mutual interconversion in cumulene compounds 1 – 8 . This work reports also useful predictive linear relationships between mutual interconversion energy barriers ( ) in cumulene compounds and the following four parameters: , , Δ(E_HOMO ? E_LUMO), and C_Number. Copyright © 2007 John Wiley & Sons, Ltd.     

Remarkable emissions in diprotonated 2,2′:6′,2″‐terpyridine derivatives

A series of new metal‐free blue emission compounds, i.e., diprotonated terpyH₂ClPF₆ ( 1 ), tterpyH₂ClPF₆ ( 2 ), ClterpyH₂ClPF₆ ( 3 ), and BterpyH₂(PF₆)₂ ( 4 ), were prepared and characterized by electrospray ionization mass spectrometry, UV–vis spectroscopy, and cyclic voltammetry (CV). Abbreviations used are terpy = 2,2′:6′,2″‐terpyridine, tterpy = 4′‐(4‐tolyl)‐2,2′:6′,2″‐terpyridine, Clterpy = 4′‐chloro‐2,2′:6′,2″‐terpyridine, and Bterpy = 4,4′,4″‐tert‐butyl‐2,2′:6′,2″‐terpyridine. The X‐ray crystal structures of the three new compounds 1, 2, and 4 were determined. Both protonated pyridine rings of the terpyridine derivatives are hydrogen bonded intermolecularly to the adjacent Cl^? ion in compounds 1 , 2, and 3 . The π–π* absorption bands in the UV region for 1, 2, 3, and 4 in acetonitrile were red‐shifted relative to those of the corresponding neutral compounds. All the compounds exhibited stronger emissions (around 400 nm) than their neutral counterparts. All the CVs for the diprotonated species, terpyH, tterpyH, ClterpyH, and BterpyH, showed the first reduction waves around ?0.6 V, which were more positive than those of the neutral ones. Density functional theory was applied to interpret the remarkable differences in the interaction of the Cl^? ion. The attachment of two protons to the two terminal Bterpy nitrogens in 4 elicits remarkable characteristics. Both positive charges on the nitrogens are delocalized over the conjugated pyridine systems and the tertiary carbonium ions are stabilized to lead to stronger emission (Φ = 0.35) than the corresponding neutral Bterpy (Φ = 0.045). CCDC 732045–732047 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif Copyright © 2010 John Wiley & Sons, Ltd.     

Study of the effect of the substitution of O by F,S, and Cl on the superconductivity of Y1Ba2Cu3O7−δ

We have studied the superconducting transitions of Y₁Ba₂Cu₃D _x O_7–x– samples where O has been replaced by D=F, S, or Cl andx=0.2-2. No single phase compounds were obtained forx>0.2. No dramatic increase inT _c was registered. Generally the results can be interpreted as a dilution of the highT _c 1 2 3 phase by other phases as the dopant concentration increases, ultimately suppressingT _c completely. Possibly there is an increase ofT _c for an intermediate dopant range,x, in the Cl series.