7-Benz[c] acridinemethanols as tetracyclic analogs of the 2-phenyl-4-quinolinemethanol antimalarials

A series of new 7-benz[c]acridinemethanols and 5,6-dihydro-7-benz[c]acridinemethanols was prepared as rigid, tetracyclic analogs of the antimalarial 2-phenyl-4-quinolinemethanols. Condensation of 5,7-dichloroisatin with 6-chloro-, 7-chloro-, and 6,7-dichloro-1-tetralone furnished halogenated 5,6-dihydro-7-benz[c]acridinecarboxylic acids, which were transformed into the corresponding acid chlorides, acyl malonates, α-bromomethyl ketones, and epoxides. Fully aromatic members of the series obtained via dehydrogenation of the 5,6-dihydro acids were likewise converted into epoxides via the acylmalonate route. Although all the epoxides studied proved to be exceptionally resistant to ring-opening by di-n-butylamine, probably on account of steric effects, they could be cleaved readily with piperidine or morpholine. Nmr spectra of the resulting amino alcohols suggest that these compounds exist in a single preferred conformation stabilized by internal O-H····N hydrogen bonding, and that free rotation about the side chain C-C bond does not occur at room temperature.     

Nitrotyrosine-modified proteins and oxidative stress induced by diesel exhaust particles

Protein tyrosine nitration is a post-translational modification that occurs under conditions of oxidative stress and may play a role in the pathogenesis of diseases such as asthma. Through their ability to generate reactive oxygen species in macrophages and epithelial cells, particulate pollutants, such as diesel exhaust particles (DEPs), may lead to a worsening of the asthmatic condition. In this study, we looked for evidence of oxidative modification of proteins in RAW 264.7 cell line treated with DEP chemicals. We show that the induction of oxidative stress is accompanied by 53 newly expressed proteins which are suppressed by a thiol antioxidant, N-acetylcysteine. These include antioxidant enzymes, pro-inflammatory components, and products of intermediary metabolism. In addition, inducible nitric oxide synthase (iNOS) was identified as a biologically relevant oxidative stress protein that is induced concurrent with increased NO production and protein tyrosine-nitration in DEP-exposed RAW 264.7 cells. Utilizing two-dimensional gel electrophoresis, anti-nitrotyrosine immunoblotting, and mass spectrometry led to the identification of an additional ten nitrotyrosine modified proteins, including oxidative stress proteins involved in intermediary metabolism (e.g., GAPDH and enolase), antioxidant defense (e.g., MnSOD) and inhibition of proteosomal activity (e.g., Hsp 90alpha). These oxidative proteins may serve as markers for oxidative stress generation in vivo.     

Capto-dative Substituent Effects in Syntheses with Radicals and Radicophiles [New synthetic methods (32)]

The 100 yers old Wurster's salts have long been recognized as compounds with redical cations. Their unusual stabilization derives partly form capto-dative (cd) substitution. This principle is now discussed as one factor of radical stabilization and it is applied to simple methine derivatives. cd-Substitution has synthetically useful applications: cd-substituents on a carbon atom allow its selective dehydrodimerization. Olefines with geminal and thus cross-conjugated cd-substituents are “radicophilic” and permit twofold carbon radical addition. cd-Substituted olefines are useful antioxidants, polymerization inhibitors and are promising agents in the control of biological radical reactions. Generally, many reactions of cd-substituted molecules appear to involve radicals.     

Coupling of a Rydberg electron capture ion source with a quadrupole mass filter

The coupling of a Rydberg electron capture ion source with a Nermag R10-10H quadrupole mass filter is described. Details are given of the addition to this instrument of a creation cell for atoms excited in Rydberg states. Within the Nermag ion source, such atoms allow attachment of electrons of well-defined thermal energy. SF(6) was used for optimization of the main experimental parameters (gas pressures and voltages applied to the electrodes). The procedure by which Rydberg electron attachment was confirmed is described. A polychlorobiphenyl compound was used to illustrate the performance of this ionization technique. Ion formation was observed in the absence of fragmentation.     

Effect of radial distribution functions and poisson reparatition of reactants on the analysis of reactions involving long distance energy transfer

Starting from a uniform distribution and knowing the space dependent rate constant, it is possible to express the fluorescence quenching effect. In the case of long distance energy transfer (Forster), we show that the introduction of radial distribution functions and of non-uniform repartition of quenchers has only small effects on the kinetics of such reactions.

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. (Forster) , .

     

Inhibition of folylpolyglutamate synthetase by substrate analogues with an ornithine side chain

N^α-[4-[[(4-Aminopteridin-6-yl)methyl]amino]benzoyl]-L-ornithine (dAPA-Orn) was synthesized, and its ability to inhibit folylpolyglutamate synthetase from mouse liver was compared with that of the corresponding 2,4-diamino analogue APA-Orn. Also compared were the inhibitory activities of the deaza analogues 5-deazaAPA-Orn, 8-deazaAPA-Orn, and 5,8-dideazaAPA-Orn, as well as those of N^α-pteroyl-L-ornithine (PteOrn) and its deaza analogues 5-deazaPteOrn and 5,8-dideazaPteOrn. The inhibition constant K_i of dAPA-Orn was 7-fold greater than that of APA-Orn, indicating that the 2-amino group plays a role in binding to the active site. The binding affinity of the 2,4-diamino compounds increased in the order 5-deazaAPA < APA-Orn <5,8-dideazaAPA-Orn < 8-deazaAPA-Orn, and that of the 2-amino-4(3H)-oxo compounds increased in the order 5-deazaPteOrn < PteOrn < 5,8-dideazaPteOrn. The most potent inhibitor of both groups was 8-deazaAPA-Orn, with a K_i of 0.018 μM, coresponding to an 8-fold and 15-fold increase in affinity relative to APA-Orn and 5-deazaAPA-Orn, respectively. The results suggest (a) that the binding of Orn-containing folylpolyglutamate synthetase inhibitors is affected to a greater degree by replacement of N⁸ by a carbon atom than it is by the corresponding change at N⁵, (b) that the effect of carbon for nitrogen replacement is greater in the 2,4-diamino derivatives than in the 2-amino-4(3H)-oxo compounds, and (c) that the 2,4-diamines are the better inhibitors. Comparison of the K_i values of the Orn-containing inhibitors with the K_m values of the corresponding glutamate-containing substrates revealed that K_m/K_i ratio can vary as much as 100-fold depending on the nature of the heterocyclic moiety, suggesting that caution should be exercised in using K_m values of known substrates to predict K_i values of putative inhibitors.     

Computation of LCAO wave functions for ground states of polymers and solids

The LCAO form of the Hartree–Fock method is discussed in its application to crystals. General formulae are given for obtaining Fourier coefficient of electronic density (in direct space) as well as of the band structure (in momentum space). Finally, it is shown that in its LCAO form, Slater–Hartree–Fock equations are very simple and that this method is of interest for numerical applications. Special integrals occurring in this formalism are evaluated for a Gaussian basis in the last part of this paper.     

QUENCHING OF SINGLET OXYGEN BY SENSITIZER IN DYE-SENSITIZED PHOTOOXYGENATION*

Abstract— A general method for the determination of the extent of the singlet oxygen (¹O₂) quenching by sensitizer in the dye-sensitized photooxygenation of olefins is used in the case of rose bengal (RB) in methanol and oil-soluble chlorophyll (M) in benzene with 2-methyl-2-pentene and tetramethylethylene as acceptors. Unlike RB, M which contains only a low percentage of pure chlorophyll (Chi), quenches ¹O₂. It is shown that this very cheap mixture can be used for kinetic studies and that the chemical quenching of ¹O₂ by M is very weak with respect to the physical quenching. The upper limit for the rate constants of physical and chemical quenching of ¹O₂ by Chi is estimated.     

A new tri-orthogonal strategy for peptide cyclization

A solid phase tri-orthogonal protection/cleavage strategy that uses acidic, basic, and neutral conditions is described. Strategically protected alpha-azido-gamma-9-fluorenylmethyl-L-glutamate (1) and alpha-azido-epsilon-N-Fmoc-L-lysine (2) were incorporated into growing peptides on Wang resin using a novel azide protection strategy. These residues, separated by 1-3 monomers, were deprotected at the side chains and cyclized via lactam formation. The N-terminus was further functionalized to extend the chain. This method represents a straightforward protocol for peptide cyclization on solid support.     

alpha-(2,6)-Sialyltransferase-catalyzed sialylations of conformationally constrained oligosaccharides

It is demonstrated that conformationally restricted oligosaccharides can act as acceptors for glycosyltransferases. Correlation of the conformational properties of N-acetyl lactosamine (Galbeta(1-4)GlcNAc, LacNAc) and several preorganized derivatives with the corresponding apparent kinetic parameters of rat liver alpha-(2,6)-sialyltransferase-catalyzed sialylations revealed that this enzyme recognizes LacNAc in a low energy conformation. Furthermore, small variations in the conformational properties of the acceptors resulted in large differences in catalytic efficiency. Collectively, our data suggest that preorganization of acceptors in conformations that are favorable for recognition by a transferase may improve catalytic efficiencies.