Bis(3-endo-camphoryl)phosphinic acid, a non-racemic helical supramolecular host with aquapores

Bis(3-endo-camphoryl)phosphinic acid (1) was prepared by the reaction of the lithium enolate of D-(+)-camphor and phosphorous trichloride followed by an oxidative work up. Compound 1 crystallizes from wet toluene as monohydrate 1·H2O, which was investigated by X-ray crystallography. Molecules of 1 are associated by strong hydrogen bonds giving rise to the formation of a supramolecular helix. The interior channel of the helix is filled by a one-dimensional (1D) string of water molecules that are also associated by hydrogen bonding. The 1D string adopts a twisted zigzag conformation. Although the hydrogen bond networks are not cross-linked both the screw of the helix and the twist of the 1D string of water molecules are left-handed (M) and controlled by the chiral camphoryl residues situated on the exterior of the helix. The overall supramolecular structure is strongly reminiscent of aquaporin-1, a significant membrane-channel protein responsible for the transport of water into the cells.

Organogermanium Compounds and Methods for their Use

The invention provides a method for enantioselectively reducing a prochiral carbon centred radical having one or more electron donor groups attached directly to the central prochiral carbon atom of the radical, and/or attached to a carbon atom within 1 to 4 atoms of the central prochiral carbon atom, comprising treating said radical with a chiral non-racemic organogermanium hydride in the presence of a Lewis acid. The invention also provides a novel class of chiral non-racemic organogermanium hydrides and a method of preparing chiral non-racemic organogermanium compounds.

Approaches to the synthesis of peptide substituted frameworks

The 1,3 dipolar cycloaddition between carbonyl ylids (generated from cyclobutene epoxides flanked by esters) and norbornyl alkenes – the ACE reaction – offers a facile method for the construction of polynorbornyl molecular frameworks. This reaction has, as described in this dissertation, underpinned the construction of molecular frameworks that have peptides and amino acids attached. Such highly rigid peptide-frameworks are of use in the field of peptidomimetics; the template molecule governs the final positioning of any attached groups such that a precise arrangement of amino acids can be achieved without the need to construct entire proteins. In the course of any ACE reaction the ester flanked cyclobutene epoxide is transformed to a 1,3 dipole, the esters serve to stablise this reactive intermediate and are as a consequence incorporated in the reaction product. Modification of these esters provides pseudo-equatorial points for peptide attachment. These methyl esters were replaced with tert-butyl esters to provide pseudo-axial attachment points that could be selectively addressed. The optimal strategy for peptide-framework construction involved direct condensation of carboxyl protected amino acids to bicyclo[2.2.1]hept-5-ene-2-endo-carboxylic acid as well as condensation of amino acids to cyclobutene epoxides derived from this acid. The ACE reaction of (±) bicycloheptene-2-endo-carboxylic acid derivatives with cyclobutene epoxides synthesised from such racemic acid derivatives provided a mixture of enantiomers and meso compounds. In order to control the position of the attachment points – and hence the final location of the attached peptides – the ACE reaction required chiral starting materials. Accordingly, all peptidoframeworks were derived from the chiral (2S)-(-)-bicycloheptene carboxylic acid. The ACE reaction of this (S)-norbornene with the (S)-epoxide provided a peptide framework in which the attached amino acids were positioned pseudo-axially. Deprotection of the amino acid allowed peptide chain building in the pseudo-axial direction. Using this strategy a framework with an alanine residue and a triglycine peptide was synthesised. By combining this strategy with the ter-butyl ester variant a framework with pseudo-axial alanine and pseudo-equatorial glycine residues was manufactured.

Investigations of Tris(2,2'-bipyridyl)ruthenium(II) as a chirally selective chemiluminescence reagent

Enantiomers of Tris(2,2'-bipyridyl)ruthenium(II) were selectively resolved and utilised in chiral kinetic studies. Instrumentation was designed and built for the collection of kinetic data from their chemiluminescence reactions. After testing the kinetic profiles of various enantiomerically pure analyte reagent combinations, results proved to be inconclusive and further testing is still required.

Setting the foundation for molecular nuts and bolts

The thesis outlines effective methods of designing and constructing chiral nano-porous materials. These materials may facilitate cheaper and large-scale production of chiral molecules, such as pharmaceuticals and bioactives. Computer models of target materials correlated well with laboratory experiments and effective synthetic strategies for manufacture were developed.

An analysis of side chain interactions and pair correlations within antiparallel β-sheets : the differences between backbone hydrogen-bonded and non-hydrogen-bonded residue pairs

Cross-strand pair correlations are calculated for residue pairs in antiparallel β-sheet for two cases: pairs whose backbone atoms are hydrogen bonded together (H-bonded site) and pairs which are not (non-H-bonded site). The statistics show that this distinction is important. When glycine is located on the edge of a sheet, it shows a 3:1 preference for the H-bonded site. Thestrongest observed correlations are for pairs of disulfide-bonded cystines, many of which adopt a close-packed conformation with each cystine in a spiral conformation of opposite chirality to its partner. It is likely that these pairs are a signature for the family of small, cystine-rich proteins. Most other strong positive and negative correlations involve charged and polar residues. It appears that electrostatic compatibility is the strongest factor affecting pair correlation. Significant correlations are observed for β- and γ-branched residues inthe non-H-bonded site. An examination of the structures showsa directionality in side chain packing. There is a correlation between (1) the directionality in the packing interactions of non-H-bonded β- and γ-branched residue pairs, (2) the handedness of the observed enantiomers of chiral β-branched side chains, and (3) the handedness of the twist of β-sheet. These findings have implications for the formation of β-sheets during protein folding and the mechanism by which the sheet becomes twisted

The synthesis and evaluation of novel, C2-symmetric organocatalysts

This thesis presents the synthesis and evaluation of a series of C2-symmetric, diprolinamide based organocatalysts. These catalysts were designed to investigate the effect that catalyst bridge length imparted on activity and chiral selectivity through catalytic site cooperation. Evaluation of these compounds led to the postulation of a novel “chiral pocket” transition state that will aid in the design of future catalysts.

Direct observation of oxidative stress on the cell wall of Saccharomyces cerevisiae strains with atomic force microscopy

We imaged pores on the surface of the cell wall of three different industrial strains of Saccharomyces cerevisiae using atomic force microscopy. The pores could be enlarged using 10 mM diamide, an SH residue oxidant that attacks surface proteins. We found that two strains showed signs of oxidative damage via changes in density and diameter of the surface pores. We found that the German strain was resistant to diamide induced oxidative damage, even when the concentration of the oxidant was increased to 50 mM. The normal pore size found on the cell walls of American strains had diameters of about 200nm. Under conditions of oxidative stress the diameters changed to 400nm.This method may prove to be a useful rapid screening process (45-60 min) to determine which strains are oxidative resistant, as well as being able to screen for groups of yeast that are sensitive to oxidative stress. This rapid screening tool may have direct applications in molecular biology (transference of the genes to inside of living cells) and biotechnology (biotransformations reactions to produce chiral synthons in organic chemistry.

Pareamento BCS em um Líquido de Luttinger em 1D

In this work we investigate the effect of a BCS-type pairing term for free spinless fermions, with a propensity to form a condensate of pairs in a 1+1 dimension. Using the of bosonization technique we explore the possible condition of existence of quasiparticles in a superconducting state. Although there is no spontaneous breaking of chiral symmetry the propagator of one-particle fermion is massive and, in fact, resembles the one-particle Green s function of conventional quasiparticles

Semipreparative enantioseparation of methamidophos by HPLC-UV and preliminary in vitro study of butyrylcholinesterase inhibition

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Reduction of enantioselectivity in the kinetic disposition and metabolism of verapamil in rats exposed to toluene

Toluene and verapamil are subject to extensive oxidative metabolism mediated by CYP enzymes, and their interaction can be stereoselective. In the present study we investigated the influence of toluene inhalation on the enantioselective kinetic disposition of verapamil and its metabolite, norverapamil, in rats. Male Wistar rats (n = 6 per group) received a single dose of racemic verapamil (10 mg/kg) orally at the fifth day of nose-only toluene or air (control group) inhalation for 6 h/day (25, 50, and 100 ppm). Serial blood samples were collected from the tail up to 6 h after verapamil administration. The plasma concentrations of verapamil and norverapamil enantiomers were analyzed by LC-MS/MS by using a Chiralpak AD column. Toluene inhalation did not influence the kinetic disposition of verapamil or norverapamil enantiomers (p > 0.05, Kruskal-Wallis test) in rats. The pharmacokinetics of verapamil was enantioselective in the control group, with a higher plasma proportion of the S-verapamil (AUC 250.8 versus 120.4 ng.h.mL(-1); p <= 0.05, Wilcoxon test) and S-norverapamil (AUC 72.3 versus 52.3 ng.h.mL(-1); p <= 0.05, Wilcoxon test). Nose-only exposure to toluene at 25, 50, or 100 ppm resulted in a lack of enantioselectivity for both verapamil and norverapamil. The study demonstrates the importance of the application of enantioselective methods in studies on the interaction between solvents and chiral drugs.

Biochemical, histopathological and clinical evaluation of delayed effects caused by methamidophos isoforms and TOCP in hens: Ameliorative effects using control of calcium homeostasis

This work evaluated the potential of the isoforms of methamidophos to cause organophosphorus-induced delayed neuropathy (OPIDN) in hens. In addition to inhibition of neuropathy target esterase (NTE) and acetylcholinesterase (AChE), calpain activation, spinal cord lesions and clinical signs were assessed. The isoforms (+)-, (+/-)- and (-)-methamidophos were administered at 50 mg/kg orally; tri-ortho-cresyl phosphate (TOCP) was administered (500 mg/kg, po) as positive control for delayed neuropathy. The TOCP hens showed greater than 80% and approximately 20% inhibition of NTE and AChE in hen brain, respectively. Among the isoforms of methamidophos, only the (+)-methamidophos was capable of inhibiting NTE activity (approximately 60%) with statistically significant difference compared to the control group. Calpain activity in brain increased by 40% in TOCP hens compared to the control group when measured 24h after dosing and remained high (18% over control) 21 days after dosing. Hens that received (+)-methamidophos had calpain activity 12% greater than controls. The histopathological findings and clinical signs corroborated the biochemical results that indicated the potential of the (+)-methamidophos to be the isoform responsible for OPIDN induction. Protection against OPIDN was examined using a treatment of 2 doses of nimodipine (1 mg/kg, i.m.) and one dose of calcium gluconate (5 mg/kg, iv.). The treatment decreased the effect of OPIDN-inducing TOCP and (+)-methamidophos on calpain activity, spinal cord lesions and clinical signs. (C) 2012 Elsevier B.V. All rights reserved.

Comparative in vitro study of the inhibition of human and hen esterases by methamidophos enantiomers

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Structural aspects of the fermion-boson mapping in two-dimensional gauge and anomalous gauge theories with massive fermions

Using a synthesis of the functional integral and operator approaches we discuss the fermion-buson mapping and the role played by the Bose field algebra in the Hilbert space of two-dimensional gauge and anomalous gauge field theories with massive fermions. In QED, with quartic self-interaction among massive fermions, the use of an auxiliary vector field introduces a redundant Bose field algebra that should not be considered as an element of the intrinsic algebraic structure defining the model. In anomalous chiral QED, with massive fermions the effect of the chiral anomaly leads to the appearance in the mass operator of a spurious Bose field combination. This phase factor carries no fermion selection rule and the expected absence of Theta-vacuum in the anomalous model is displayed from the operator solution. Even in the anomalous model with massive Fermi fields, the introduction of the Wess-Zumino field replicates the theory, changing neither its algebraic content nor its physical content. (C) 2002 Elsevier B.V. (USA).

Multiflavor soldering

In two dimensions the simple addition of two chiral bosons of opposite chiralities does not lead to a full massless scalar field. Similarly, in three dimensions the addition of two Maxwell-Chern-Simons fields of opposite helicities +/- 1 will not produce a parity invariant Maxwell-Proca theory. An interference term between the opposite chiralities (helicities) states is required in order to obtain the expected result. The so-called soldering procedure provides the missing interference Lagrangian in both 2D and 3D cases. In two dimensions such interference term allows to fuse two chiral fermionic determinants into, a non-chiral one. In a recent work we have generalized this procedure by allowing the appearance of an extra parameter which takes two possible values and leads to two different soldered Lagrangians. Here we apply this generalized soldering in a bosonic theory which has appeared in a partial bosonization of the 3D gauged Thirring model with N flavors. The multiplicity of flavors allow new types of solderings and help us to understand the connection between different perturbative approaches to bosonization in 3D. In particular, we obtain an interference term which takes us from a multiflavor Niaxwell-Chern-Simons theory to a pair of self-dual and anti-self-dual theories when we combine together both fermionic determinants of +1/2 and -1/2 helicity fermions. An important role is played by a set of pure non-interacting Chern-Simons fields which amount to a normalization factor in the fermionic determinants and act like spectators in the original theory but play an active role in the soldering procedure. Our results suggest that the generalized soldering could be used to provide dual theories in both 2D and 3D cases. (c) 2007 Elsevier B.V. All rights reserved.