Polymeric prodrugs of mitomycin C

Poly-[N-(2-hydroxyethyl)-L-glutamine] (PHEG) prodrugs of the cytotoxic agent Mitomycin C were synthesized using peptidyl spacers to link the drug to the polymeric carrier. The influence on the length and detailed structure of the oligopeptide on the rate of drug release was investigated in buffer, in the presence of lysosomal enzymes (tritosomes, cathepsin B and D) and metalloprotease type IV collagenase. It was observed that tetra- and hexapeptide based conjugates generally release Mitomycin C (MMC) more effectively than tripeptide derivatives. The gly-phe-ala-leu conjugate released MMC very rapidly both in presence of lysosomal enzymes and collagenase IV. Only in the presence of the aspartic protease cathepsin D, the gly-phe-leu-gly-phe-leu derivative turned out to be a better substrate. In vivo studies against C26 solid tumour bearing mice suggest that PHEG-spacer-MMC conjugates act as prodrugs of MMC: antitumour efficacy of the macromolecular prodrugs was better than free MMC both in inhibition of tumour growth and increasing survival.     

Inhibitory Role of Berberine,an Isoquinoline Alkaloid,on NLRP3 Inflammasome Activation for the Treatment of Inflammatory Diseases

The pyrin domain-containing multiprotein complex NLRP3 inflammasome, consisting of the NLRP3 protein, ASC adaptor, and procaspase-1, plays a vital role in the pathophysiology of several inflammatory disorders, including neurological and metabolic disorders, chronic inflammatory diseases, and cancer. Several phytochemicals act as promising anti-inflammatory agents and are usually regarded to have potential applications as complementary or alternative therapeutic agents against chronic inflammatory disorders. Various in vitro and in vivo studies have reported the anti-inflammatory role of berberine (BRB), an organic heteropentacyclic phytochemical and natural isoquinoline, in inhibiting NLRP3 inflammasome-dependent inflammation against many disorders. This review summarizes the mechanism and regulation of NLRP3 inflammasome activation and its involvement in inflammatory diseases, and discusses the current scientific evidence on the repressive role of BRB on NLRP3 inflammasome pathways along with the possible mechanism(s) and their potential in counteracting various inflammatory diseases.     

Copper-bispidine coordination chemistry: syntheses,structures, solution properties,and oxygenation reactivity

Copper(I) and copper(II) complexes of two mononucleating and four dinucleating tetradentate ligands with a bispidine backbone (2,4-substituted (2-pyridyl or 4-methyl-2-pyridyl) 3,7-diazabicyclo[3.3.1]nonanone) have been prepared and analyzed structurally, spectroscopically, and electrochemically. The structures of the copper chromophores are square pyramidal, except for two copper(I) compounds which are four-coordinate with one noncoordinated pyridine. The other copper(I) structures have the two pyridine donors, the co-ligand (NCCH(3)), and one of the tertiary amines (N3) in-plane with the copper center and the other amine (N7) coordinated axially (Cu-N3 > Cu-N7, approximately 2.25 A vs 2.20 A). The copper(II) compounds with pyridine donors have a similar structure, but the axial amine has a weaker bond to the copper(II) center (Cu-N3 < Cu-N7, approximately 2.03 A vs 2.30 A). The structures with methylated pyridine donors are also square pyramidal with the co-ligands (Cl(-) or NCCH(3)) in-plane. With NCCH(3) the same structural type as for the other copper(II) complexes is observed, and with the bulkier Cl(-) the co-ligand is trans to N7, leading to a square pyramidal structure with the pyridine donors rotated out of the basal plane and only a small difference between axial and in-plane amines (2.15, 2.12 A). These structural differences, enforced by the rigid bispidine backbone, lead to large variations in spectroscopic and electrochemical properties and reactivities. Oxygenation of the copper(I) complexes with pyridine-substituted bispidine ligands leads to relatively stable mu-peroxo-dicopper(II) complexes; with a preorganization of the dicopper chromophores, by linking the two donor sets, these peroxo compounds are stable at room temperature for up to 1 h. The stabilization of the peroxo complexes is to a large extent attributed to the square pyramidal coordination geometry with the substrate bound in the basal plane, a structural motif enforced by the rigid bispidine backbone. The stabilities and structural properties are also seen to correlate with the spectroscopic (UV-vis and Raman) and electrochemical properties.     

Capillary electrophoretic separation of dicarboxylic acids in atmospheric aerosol particles

2,3-Pyrazinedicarboxylic acid (PZDA), 2,6-pyridinedicarboxylic acid (PDA) and 2,3-pyridinedicarboxylic acid (QUIN) solutions were studied as background electrolytes (BGEs) in the capillary electrophoretic analysis of dicarboxylic acids in aerosol particles with indirect UV detection. The BGEs were selected on the basis of similarity in structure with the analytes so that mobilities would be compatible. Optimised pH values for PZDA, PDA and QUIN solutions were 10.6, 11.0 and 10.2, respectively. Myristyltrimethylammonium hydroxide and myristyltrimethylammonium bromide were added to reverse the electroosmotic flow in the solutions in the direction of anode to enable fast anion detection. Separation was obtained for nine dicarboxylic acids (C₂–C₁₀) differing in the number of CH₂ groups in their skeleton. The electrophoretic mobilities were determined to lie in the range 3.0×10⁻⁴–7.0×10⁻⁴ cm² V⁻¹ s⁻¹. The relative standard deviations (RSDs) for the absolute migration times of the analytes were mostly less than 0.5% (n=6) in PZDA solution. In PDA solution the within-day and day-to-day RSD values for migration were less than 1% and between 2 and 4%, respectively. Peak heights and areas mostly deviated between 1 and 15% in both PZDA and PDA solutions. Detection limits ranged between 1 and 5 mg/l. Methods were applied to the analysis of dicarboxylic acids isolated from aerosol particles.     

Constructor graph description of hydrogen bonding in a supra­molecular assembly of N,N′‐bis­(2‐hydr­oxy‐1‐methyl­ethyl)phthalamide

Hydrogen bonds of four types (N—H⋯O=C, N—H⋯OH, O—H⋯O=C and O—H⋯OH) connect mol­ecules of the title compound, C₁₄H₂₀N₂O₄, in the crystal into sheets folded into a zigzag pattern. The inter­molecular inter­actions are discussed in terms of the first‐ through fourth‐level graph sets, and a constructor graph helps visualize the supra­molecular assembly.     

Cyanogen isocyanate and dicyanoether: ab initio studies of geometries and electronic structures

Complete geometry optimizations, employing a minimal STO-3G basis set, have been applied to the recently-prepared cyanogen isocyanate [NCNCO] and to the isomeric dicyanoether [NCOCN]. Cyanogen isocyanate is found to be a rather flexible molecule with the computed barrier to inversion about the central nitrogen being ~5 k cal mol^?1. In addition, the inversion motion is found to be coupled to the bending of the NCN and OCN linkages away from colinearity. On the other hand, dicyanoether is predicted to be a fairly rigid molecule, with no important inversion motions. Both molecules are predicted to have planar trans bent equilibrium structures similar to that found for the simpler HNCO-HOCN isomers. Cyanogen isocyanate is predicted to be the more stable isomer. Electronic structures of these molecules are discussed in the light of the results of a Mulliken population analysis.     

Synthese und Charakterisierung der 8 isomeren,im Ring B mono- bzw. dihydroxylierten Royleanone

Synthesis and Characterization of the 8 Stereoisomeric Royleanones with One or Two Hydroxy Groups in Ring B The partial syntheses of 6α, 7α-dihydroxyroyleanone ( 6a ), 6α, 7β-dihydroxyroyleanone ( 7a ) and 6β, 7β-dihydroxyroyleanone ( 9a ) are described. Thus, all in ring B mono- and dihydroxylated royleanones are now known (see [2–11]), being fully characterized by extensive spectroscopic, chiroptic and chromatographic (HPLC.) methods. An opening of the epoxyroyleanone 11a yields cis- and trans-diols together with their corresponding mono- and di-O-acetyl derivatives. We postulate a reversible addition of the acetate ion at C(8) of the quinone system, followed by a neighbouring group participation of this O-acetyl group.