Histone deacetylase inhibitors: structure-based modeling and isoform-selectivity prediction

An enhanced version of comparative binding energy (COMBINE) analysis, named COMBINEr, based on both ligand-based and structure-based alignments has been used to build several 3-D QSAR models for the eleven human zinc-based histone deacetylases (HDACs). When faced with an abundance of data from diverse structure-activity sources, choosing the best paradigm for an integrative analysis is difficult. A common example from studies on enzyme-inhibitors is the abundance of crystal structures characterized by diverse ligands complexed with different enzyme isoforms. A novel comprehensive tool for data mining on such inhomogeneous set of structure-activity data was developed based on the original approach of Ortiz, Gago, and Wade, and applied to predict HDAC inhibitors' isoform selectivity. The COMBINEr approach (apart from the AMBER programs) has been developed to use only software freely available to academics.     

Parity doubling and SU(2)LxSU(2)R restoration in the hadron spectrum

We construct the most general nonlinear representation of chiral SU(2)LxSU(2)R broken down spontaneously to the isospin SU(2), on a pair of hadrons of same spin and isospin and opposite parity. We show that any such representation is equivalent, through a hadron field transformation, to two irreducible representations on two hadrons of opposite parity with different masses and axial-vector couplings. This implies that chiral symmetry realized in the Nambu-Goldstone mode does not predict the existence of degenerate multiplets of hadrons of opposite parity nor any relations between their couplings or masses.     

Enantioselective guest exchange in a chiral resorcin[4]arene cavity

Gas-phase proton-bound complexes between a chiral resorcin[4]arene and some representative amino acids, that is, L- and D-alanine or L- and D-serine, were generated in the source of a Fourier transform ion cyclotron resonance mass spectrometer. Gas-phase exchange of the amino acid from the diastereomeric complexes with the enantiomers of 2-butylamine exhibits a significant enantioselectivity, which depends not only upon the configuration of the leaving guest but also on that of the incoming amine. These findings, coupled with molecular dynamic calculations, point to the observed gas-phase enantioselectivity as determined by the effects of the resorcin[4]arene chiral cavity upon the diastereomeric exchange transition structures.     

Studies on the oxidation of Cu complexes of quadridentate Schiff bases derived from salicylaldehyde or ortho-aminophenol

The oxidation of various [CuL] (where L are the dianions of quadridentate Schiff bases derived from salicylaldehyde, and 1,2-diaminoethane, namely 2,2′-[1,2-ethanediylbis(nitrilomethylidene)diphenatol], salen, its 1,3-propane homologue, saltn, or from glyoxal and ortho-aminphenol, namely 2,2′-[(ethanediimine)diphenato], glyaph, as well as some of their analogues) has been studied by cyclic voltammetry. Anodic sweeps show one, or two, usually irreversible, oxidation peaks originated by the presence of Cu^II, since neither LH₂ nor [ZnL] are oxidized under the same conditions. The oxidations of the 5-NO₂-substituted derivatives are reversible at high scan rate (1 V s⁻¹). The oxidation potentials of the complexes with substituents at the aromatic rings suggest that the electronic influence of such substituents are transmitted to the metal centre via the phenato, rather than the azomethine groups. The glyaph and saltn derivatives are oxidized at potentials higher than the corresponding salen complexes. Electronic and ESR spectroscopy studies on [CuL] samples, oxidized with a H₂O₂/H₅IO₆ mixture, suggest that the initially formed [Cu^IIIL]⁺ rapidly decomposes to Cu^II species, presumably through [Cu(II)0L ·]⁺ intermediates. Some poorly stable complexes of the formula [CuL]HSO₄·2H₂O have been isolated.     

Exceptional gas-phase enantioselectivity of chiral tetramide macrocycles

Diastereomeric proton-bound complexes between some phenylalanine derivatives (A) and chiral tetramide macrocycles (M) exhibit an uncommon enantioselectivity when reacting with the enantiomers of 2-aminobutanes in the gas phase (B). The measured enantioselectivity depends mainly on two distinct factors: (i) the configuration of the A guest; and (ii) the structure and the relative stability of isomeric [MHA]+ complexes. No significant effects of the B configuration are observed. The diastereomeric [MHA]+ complexes with A = 1-naphthylalanine ethyl ester exhibit the largest enantioselectivity factor ever measured in the gas phase (khomo/khetero = 0.046). The origin of such an exceptional enantioselectivity is mainly attributed to the relative stability of the diastereomeric [MHA]+ complexes, as demonstrated by the comparison of the kinetic results with those from collision-induced dissociation of the trimeric [M2HA]+ adducts and with computational evidence.     

PHOTOREACTION OF PSORALEN DERIVATIVES WITH STRUCTURALLY ORGANIZED DNA

Abstract— The DNA-photobinding process of a number of psoralen derivatives has been investigated using different nucleic acid structures, such as double helical DNA, nucleosomes, and chromatin under various ionic strength conditions. Important differences were observed using "free" vs organised DNA as the target macromolecule, which are related to conformational, stereochemical, ionic and competition effects. The furocoumarin chemical nature also plays a role; in particular, charged compounds are shown to be more reactive than uncharged analogues with free DNA at low salt concentration, whereas a levelling off in photobinding efficiency occurs on increasing ionic strength and nucleic acid complexity. These results allow an explanation for the photobiological effects of the examined psoralens.     

On the simple connectedness of hyperplane complements in dual polar spaces

Let Δ be a dual polar space of rank n≥4, H be a hyperplane of Δ and Γ?Δ?H be the complement of H in Δ. We shall prove that, if all lines of Δ have more than 3 points, then Γ is simply connected. Then we show how this theorem can be exploited to prove that certain families of hyperplanes of dual polar spaces, or all hyperplanes of certain dual polar spaces, arise from embeddings.