Immune recognition,antigen design,and catalytic antibody production

Catalytic antibodies have been developed by experimental approaches exploiting the analogy between antibody-antigen and enzyme-substrate interaction. Haptens have been prepared to model the electrostatic or geometric attributes of a reaction’s transition state and to induce combining sites having appropriate catalytic residues. The relative merits of these design strategies may be gleaned from the apparent activities and efficiencies of the respective catalysts. The implications of screening strategies on the kinetic characteristics of the resulting abzymes are also considered. Combining-site hypermutation provides the variation in the antibody repertoire from which high-affinity clones are selected. The same mechanism can also lead to a subset of antibodies with reduced hapten affinity, but improved catalytic activity. This possibility has not been adequately characterized, but is suggested by a number of considerations. These include the unexplained efficiency and diversity of mechanisms utilized by various antibody catalysts, and the observed catalytic activity of antibodies found in autoimmune serum. This article attempts to assess critically the evidence for rational design of catalytic activity in antibodies. Correlations among abzymes and their relevant models could lead to revised or novel strategies for producing better catalysts.     

Novel 17 substituted pregnadiene derivatives as 5 alpha-reductase inhibitors and their binding affinity for the androgen receptor

The in vitro antiandrogenic activity of four new progesterone derivatives: 4, 5, 6 and 7 (8 is a known compound) was determined. These compounds were evaluated as 5alpha-reductase inhibitors as well as by their capacity to bind to the androgen receptor in gonadectomized hamster prostate. The IC(50) value was determined using increasing concentrations of 4, 5, 6, 7 and 8 in the presence of [(3)H]T and the microsomal fraction of the hamster prostate containing the 5alpha-reductase enzyme. In this paper we also demonstrated the effect of increasing concentrations of the novel steroids upon [(3)H]DHT binding to the androgen receptors from hamster prostate which produces competition for the androgen receptor sites. The in vitro studies showed that steroids 4, 5, 6, 7 and 8 had an inhibitory activity for the 5alpha-reductase with IC(50) of: 4 (0.17 microM), 5 (0.19 microM), 6 (1 microM), 7 (4.2 microM), and 8 (2.7 microM). On the other hand, the IC(50) value for compounds 4, 5, 6, 7, 8 and DHT showed the following order of affinity for the androgen receptor: 6>7>5>DHT. Surprisingly compounds 4 and 8 did not bind to the androgen receptor. The overall data indicate that all synthesized compounds are inhibitors for the enzyme 5alpha-reductase present in the hamster prostate. In contrast, compounds 5, 6 and 7, which have a cyclohexyl group in the side chain showed a high affinity for the androgen receptor.     

Generation and coupling of [Mn(dmpe)2(C triple bond CR)(C triple bond C)]* radicals producing redox-active C4-bridged rigid-rod complexes

The symmetric d(5) trans-bis-alkynyl complexes [Mn(dmpe)(2)(C triple bond CSiR(3))(2)] (R = Me, 1 a; Et, 1 b; Ph, 1 c) (dmpe = 1,2-bis(dimethylphosphino)ethane) have been prepared by the reaction of [Mn(dmpe)(2)Br(2)] with two equivalents of the corresponding acetylide LiC triple bond CSiR(3). The reactions of species 1 with [Cp(2)Fe][PF(6)] yield the corresponding d(4) complexes [Mn(dmpe)(2)(C triple bond CSiR(3))(2)][PF(6)] (R = Me, 2 a; Et, 2 b; Ph, 2 c). These complexes react with NBu(4)F (TBAF) at -10 degrees C to give the desilylated parent acetylide compound [Mn(dmpe)(2)(C triple bond CH)(2)][PF(6)] (6), which is stable only in solution at below 0 degrees C. The asymmetrically substituted trans-bis-alkynyl complexes [Mn(dmpe)(2)(C triple bond CSiR(3))(C triple bond CH)][PF(6)] (R = Me, 7 a; Et, 7 b) related to 6 have been prepared by the reaction of the vinylidene compounds [Mn(dmpe)(2)(C triple bond CSiR(3))(C=CH(2))] (R = Me, 5 a; Et, 5 b) with two equivalents of [Cp(2)Fe][PF(6)] and one equivalent of quinuclidine. The conversion of [Mn(C(5)H(4)Me)(dmpe)I] with Me(3)SiC triple bond CSnMe(3) and dmpe afforded the trans-iodide-alkynyl d(5) complex [Mn(dmpe)(2)(C triple bond CSiMe(3))I] (9). Complex 9 proved to be unstable with regard to ligand disproportionation reactions and could therefore not be oxidized to a unique Mn(III) product, which prevented its further use in acetylide coupling reactions. Compounds 2 react at room temperature with one equivalent of TBAF to form the mixed-valent species [[Mn(dmpe)(2)(C triple bond CH)](2)(micro-C(4))][PF(6)] (11) by C-C coupling of [Mn(dmpe)(2)(C triple bond CH)(C triple bond C*)] radicals generated by deprotonation of 6. In a similar way, the mixed-valent complex [[Mn(dmpe)(2)(C triple bond CSiMe(3))](2)(micro-C(4))][PF(6)] [12](+) is obtained by the reaction of 7 a with one equivalent of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). The relatively long-lived radical intermediate [Mn(dmpe)(2)(C triple bond CH)(C triple bond C*)] could be trapped as the Mn(I) complex [Mn(dmpe)(2)(C triple bond CH)(triple bond C-CO(2))] (14) by addition of an excess of TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) to the reaction mixtures of species 2 and TBAF. The neutral dinuclear Mn(II)/Mn(II) compounds [[Mn(dmpe)(2)(C triple bond CR(3))](2)(micro-C(4))] (R = H, 11; R = SiMe(3), 12) are produced by the reduction of [11](+) and [12](+), respectively, with [FeCp(C(6)Me(6))]. [11](+) and [12](+) can also be oxidized with [Cp(2)Fe][PF(6)] to produce the dicationic Mn(III)/Mn(III) species [[Mn(dmpe)(2)(C triple bond CR(3))](2)(micro-C(4))][PF(6)](2) (R = H, [11](2+); R = SiMe(3), [12](2+)). Both redox processes are fully reversible. The dinuclear compounds have been characterized by NMR, IR, UV/Vis, and Raman spectroscopies, CV, and magnetic susceptibilities, as well as elemental analyses. X-ray diffraction studies have been performed on complexes 4 b, 7 b, 9, [12](+), [12](2+), and 14.     

Acid-base and metal-ion-binding properties of 9-[2-(2-phosphonoethoxy)ethyl]adenine (PEEA), a relative of the antiviral nucleotide analogue 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA). An exercise on the quantification of isomeric complex equilibria in solution

The acidity constants of 3-fold protonated 9-[2-(2-phosphonoethoxy)ethyl]adenine, H3(PEEA)+, and of 2-fold protonated (2-phosphonoethoxy)ethane, H2(PEE), and the stability constants of the M(H;PEEA)+, M(PEEA), and M(PEE) complexes with M2+ = Mg2+, Ca2+, Sr2+, Ba2+, Mn2+, Co2+, Ni2+, Cu2+, Zn2+, or Cd2+ have been determined (potentiometric pH titrations; aqueous solution; 25 degrees C; I = 0.1 M, NaNO3). It is concluded that in the M(H;PEEA)+ species, the proton is at the phosphonate group and the metal ion at the adenine residue. The application of previously determined straight-line plots of log K(M(R-PO3))M versus pK(H(R-PO3))H for simple phosph(on)ate ligands, R-PO3(2-), where R represents a residue that does not affect metal-ion binding, proves that the M(PEEA) complexes of Co2+, Ni2+, Cu2+, Zn2+, and Cd2+ as well as the M(PEE) complexes of Co2+, Cu2+, and Zn2+ have larger stabilities than is expected for a sole phosphonate coordination of M2+. For the M2+ complexes without an enhanced stability (e.g., Mg2+ or Mn2+), it is concluded that M2+ binds in a monodentate fashion to the phosphonate group of the two ligands. Combination of all of the results allows the following conclusions: (i) The increased stability of the Co(PEE), Cu(PEE), Zn(PEE), and Co(PEEA) complexes is due to the formation of six-membered chelates involving the ether-oxygen atom of the aliphatic residue (-CH2-O-CH2CH2-PO3(2-)) of the ligands with formation degrees of about 15-30%. (ii) Cd(PEEA) forms a macrochelate with N7 of the adenine residue (formation degree about 30%); Ni(PEEA) has similar properties. (iii) With Zn(PEEA), both mentioned types of chelates are observed, that is, Zn(PEEA)(cl/O) and Zn(PEEA)(cl/N7), with formation degrees of about 13 and 41%, respectively; the remaining 46% is due to the "open" isomer Zn(PEEA)(op) in which the metal ion binds only to the PO3(2-) group. (iv) Most remarkable is Cu(PEEA) because a fourth isomer, Cu(PEEA)(cl/O/N3), is formed that contains a six-membered ring involving the ether oxygen next to the phosphonate group and also a seven-membered ring involving N3 of the adenine residue with a very significant formation degree of about 50%. Hence, PEEA(2-) is a truly ambivalent ligand, its properties being strongly dependent on the kind of metal ion involved. Comparisons with M2+ complexes formed by the dianions of 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA) and related ligands reveal that five-membered chelates involving an ether-oxygen atom are considerably more stable than the corresponding six-membered ones. This observation offers an explanation of why PMEA is a nucleotide analogue with excellent antiviral properties and PEEA is not.     

On the symmetries of the Hubbard model: application to finite-size clusters

We evaluate the density of states of the Hubbard model at half filling on a four-site cluster with periodic boundary conditions. The results are obtained from an exact diagonalization study of the model, where theSU(2) symmetry, the Yang\(\widetilde{SU}(2)\) pseudospin symmetry and the translational invariance of the Hamiltonian are explicitly taken into account.     

Analysis of a stabilized finite element method for fluid flows through a porous interface

This work is devoted to the numerical simulation of an incompressible fluid through a porous interface, modeled as a macroscopic resistive interface term in the Stokes equations. We improve the results reported in [M.A. Fernández, J.-F. Gerbeau, V. Martin, Numerical simulation of blood flows through a porous interface, Math. Model. Num. Anal. (M2AN) 42 (6) (2008) 961–990], by showing that the standard Pressure Stabilized Petrov–Galerkin (PSPG) finite element method is stable, and optimally convergent, without the need for controlling the pressure jump across the interface.     

Olefin polymerization catalyzed by amide vanadium(IV) complexes: The stereo‐ and regiochemistry of propylene insertion

The reaction of VCl₃(THF)₃ with 1 equiv of the lithium salt of ligand ArNH(Me₂SiCH₂CH₂SiMe₂)NHAr or ArNH(SiMe₃) (Ar = 2,6‐Me₂C₆H₃) afforded the corresponding V(IV) amide complexes, [1,2‐CH₂CH₂(Me₂SiNAr)₂]VCl₂ ( 3 ) and (Me₃SiNAr)₂VCl₂ ( 4 ). The activation of 3 and 4 with the alkyl aluminum compound Al₂Et₃Cl₃ or AlEt₂Cl produced active ethylene polymerization catalysts exhibiting productivity values among the highest reported for vanadium amide based catalysts. Moreover, syndiotactic specific propylene polymerization was successfully conducted at ?40 °C in the presence of 3 /Al₂Et₃Cl₃ and 4 /Al₂Et₃Cl₃. Syndiotactic polypropylenes with moderate stereoregularity ([rr] = 0.66) and a concentration of regioirregular propylene of 6.9 mol % were obtained. Monomodal molecular weight distributions and polydispersity indices lower than 2 were observed in the polymerization runs carried out in heptane solutions. Thus, ethylene–propylene copolymers with propylene concentrations up to 45 mol % were synthesized and characterized by ¹³C NMR and thermal analysis. Good alternation and random distribution of the two monomers were actually obtained. Samples with elevated concentrations of propylene were completely amorphous, with a glass‐transition temperature of ?50 °C. The properties and structure of the copolymers produced with amide vanadium catalysts 3 and 4 were similar to those reported for ethylene–propylenes produced with industrial vanadium‐based catalysts, suggesting the presence of the same active catalyst species. © 2006 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 3279–3289, 2006     

Efficient access to 5-substituted thiazoles by a novel metallotropic rearrangement

A novel rearrangement process involving the migration of trimethylstannanyl or trimethylsilanyl groups around the thiazole ring provides access to either 2- or 5-metallated thiazoles by tuning the reaction conditions. The proposed mechanism, based on experimental evidence, is characterized by the catalytic role of thiazole bisadducts as metal-transfer agents.     

The Case for Inertia as a Vacuum Effect: A Reply to Woodward and Mahood

The possibility of an extrinsic origin for inertial reaction forces has recently seen increased attention in the physical literature. Among theories of extrinsic inertia, the two considered by the current work are (1) the hypothesis that inertia is a result of gravitational interactions and (2) the hypothesis that inertial reaction forces arise from the interaction of material particles with local fluctuations of the quantum vacuum. A recent article supporting the former and criticizing the latter is shown to contain substantial errors.     

Analysis of Calorimetric Curves Detected During the Polymorphic Transformation of Isotactic Polybutene-1

Multiple endotherms detected on heating melt-crystallized i-polybutene-1(PBu-1) are associated to the polymorphic transformation from the tetragonal (Form II) to the hexagonal modification (Form I). During this transformation, a progressive increase of the intensity of the high temperature endotherm, at the expenses of that pertaining to the low temperature one, is observed in DSC heating curves. Depending on molecular characteristics of the constituent chains and crystallization conditions, the two endotherms may exhibit some extent of superposition. In these cases, a reliable procedure to analyze the whole thermal curve must be found and adopted in order to follow the progress of the transformation in quantitative terms. The same set of thermal curves, detected after various ageing times of melt-crystallized i-PBu-1, has been analyzed according to four different approaches. Comparison of the results shows that, with the exception of the analysis based on the ‘partial area’ routine, available to most instruments, all methods lead to equivalent results. The simplest approach, based on the mass balance during structural transformation, should be preferred whenever constant overall degree of crystallinity can be assumed throughout the whole process. This revised version was published online in July 2006 with corrections to the Cover Date.