Perchloric Acid–Silica (HClO4⋅SiO2)‐Catalyzed Synthesis of 14‐Alkyl‐ or 14‐Aryl‐14H‐dibenzo[a,j]xanthenes and N‐[(2‐Hydroxynaphthalen‐1‐yl)methyl]amides

The synthesis of 14‐aryl‐ or 14‐alkyl‐14H‐dibenzo[a,j]xanthenes 3 involving the treatment of naphthalen‐2‐ol ( 1 ) with arenecarboxaldehydes or alkanals 2 in the presence of HClO₄?SiO₂ as a heterogeneous catalyst was achieved (Table 1), and this reaction was extended to the preparation of N‐[(2‐hydroxynaphthalen‐1‐yl)methyl]amides 5 by a three‐component reaction with urea ( 4a ) or an amide 4b – d as a third reactant (Table 2).     

THE PHOTOSENSITIZERS BENZOPHENOXAZINE and THIAZINES: COMPREHENSIVE INVESTIGATION OF PHOTOPHYSICAL and PHOTOCHEMICAL PROPERTIES

Eight differently substituted title dye compounds have been investigated regarding intersystem crossing, triplet state, fluorescence and singlet excited state pKa properties. In general, non-halogenated oxazines and thiazines as well as a mono bromooxazine show very low triplet quantum yields, phi tau (less than 0.03) and relatively long triplet lifetimes (approximately 40 microseconds) in acidic methanol. The phi tau data correlate well with known singlet oxygen yields. In basic methanol no triplet transient is observed but a significant yield of a ground state transient protonated (base dye) form is produced with a short lifetime, approximately 400 ns. Fluorescence can be seen simultaneously from both the excited base and the protonated base dye forms in basic methanol. For iodinated oxazine or thiazines, the triplet yield increases and can be as high as 0.5 (diiodo case) in acidic methanol. The triplet lifetimes are further shortened to approximately 10 microseconds compared to the non-iodinated derivatives above. The triplet yields of the iodo compounds are higher or equal to known singlet oxygen yields. In basic methanol triplet yields up to 0.2 can be seen, the triplet lifetime are shortened still further to 1 microsecond but no observable protonated form is produced (in distinction to the non-iodinated cases). Consideration is given to the correlation of triplet and singlet oxygen yields, ground and excited pKa properties, spin-orbit coupling and internal conversion properties, solvent effects, and phototherapeutic activity of these dyes.     

Platinum complexes of diazo ligands. Studies of regioselective aromatic ring amination, oxidative halogen addition and reductive halogen elimination reactions

2-(Arylazo)pyridine ligands, L1a-1c react with the salt K2[PtCl4] to give the mononuclear complexes [PtCl2(L1)](1), which readily react with ArNH2 to yield the monochloro complexes of type [PtCl(L2)](HL2= 2-[(2-(arylamino)phenyl)azo]pyridine)(2) via regioselective ortho-amine fusion at the pendent aryl ring of coordinated L1. Oxidative addition of the electrophiles Y2(Y = Cl, Br, I) to the square-planar platinum(II) complex, has led to syntheses of the corresponding octahedral platinum(IV) complexes, [PtY3(L2)](3) in high yields. Ascorbate ion reductions of the platinum(IV) complexes, , resulted in reductive halogen elimination to revert to the platinum(II) complexes almost quantitatively. Isolation of products and X-ray structure determination of the representative complexes followed all these chemical reactions. In crystal packing, the compound [PtCl2(L1c)](1c) forms dimeric units with a Pt...Pt distance of 3.699(1) A. In contrast, the crystal packing of 2b revealed that the molecules are arranged in an antiparallel fashion to form a noncovalent 1D chain to accommodate pi(aryl)-pi(pyridyl) and Pt-pi(aryl) interactions. Notably, the oxidation of [Pt(II)Cl(L2a)](2a) by I2 produced a mixed halide complex [Pt(IV)ClI2(L2a)](5), which, in turn, is reduced by ascorbate ion to produce [Pt(II)I(L2a)] with the elimination of ClI. All the platinum(II) complexes are brown, the platinum(IV) complexes, on the other hand, are green. Low-energy visible range transitions in the complexes of the extended ligand [L2]- are ascribed to ligand basedpi-pi* transitions. Cyclic voltammetric behaviour of the complexes is reported.     

Designed helical peptides inhibit an intramembrane protease

gamma-Secretase cleaves the transmembrane domain of the amyloid precursor protein, a process implicated in the pathogenesis of Alzheimer's disease, and this enzyme is a founding member of an emerging class of intramembrane proteases. Modeling and mutagenesis suggest a helical conformation for the substrate transmembrane domain upon initial interaction with the protease. Moreover, biochemical evidence supports the presence of an initial docking site for substrate on gamma-secretase that is distinct from the active site, a property predicted to be generally true of intramembrane proteases. Here we show that short peptides designed to adopt a helical conformation in solution are inhibitors of gamma-secretase in both cells and enzyme preparations. Helical peptides with all d-amino acids are the most potent inhibitors and represent potential therapeutic leads. Subtle modifications that disrupt helicity also substantially reduce potency, suggesting that this conformation is critical for effective inhibition. Fluorescence lifetime imaging in intact cells demonstrates that helical peptides disrupt binding between substrate and protease, whereas an active site-directed inhibitor does not. These findings are consistent with helical peptides interacting with the initial substrate docking site of gamma-secretase, suggesting a general strategy for the development of potent and specific inhibitors of intramembrane proteases.     

Diastereoselective formation of glycoluril dimers: isomerization mechanism and implications for cucurbit[n]uril synthesis

Cucurbit[6]uril (CB[6]) is a macrocyclic compound, prepared in one pot from glycoluril and formaldehyde, whose molecular recognition properties have made it the object of intense study. Studies of the mechanism of CB[n] formation, which might provide insights that allow the tailor-made synthesis of CB[n] homologues and derivatives, have been hampered by the complex structure of CB[n]. By reducing the complexity of the reaction to the formation of S-shaped (12S-18S) and C-shaped (12C-18C) methylene bridged glycoluril dimers, we have been able to probe the fundamental steps of the mechanism of CB[n] synthesis to a level that has not been possible previously. For example, we present strong evidence that the mechanism of CB[n] synthesis proceeds via the intermediacy of both S-shaped and C-shaped dimers. The first experimental determination of the relative free energies of the S-shaped and C-shaped dimers indicates a thermodynamic preference (1.55-3.25 kcal mol(-)(1)) for the C-shaped diastereomer. This thermodynamic preference is not because of self-association, solvation, or template effects. Furthermore, labeling experiments have allowed us to elucidate the mechanism of this acid-catalyzed equilibrium between the S-shaped and C-shaped diastereomers. The equilibration is an intramolecular process that proceeds with high diastereoselectivity and retention of configuration. On the basis of the broad implications of these results for CB[n] synthesis, we suggest new synthetic strategies that may allow for the improved preparation of CB[n] (n > 8) and CB[n] derivatives from functionalized glycolurils.     

Internalization and processing of the EGF receptor in the induction of DNA synthesis in cultured fibroblasts: the endocytic activation hypothesis.

The addition of EGF to cultured murine 3T3 cells produces a decrease in EGF binding activity with concomitant internalization and degradation of the initially bound EGF. When the EGF receptor on cultured 3T3 cells is affinity labeled with high specific activity 125I-EGF, and the fate of the affinity labeled EGF-receptor complex determined, the loss in binding activity was accounted for by receptor internalization and subsequent proteolytic processing of the EGF receptor molecules in the lysosomes. Studies of the effects of EGF concentration on EGF binding by cells, EGF-induced receptor internalization and EGF-induced stimulation of 3H-thymidine uptake into cellular DNA show that there is a direct correlation between EGF-induced receptor internalization and EGF-induced stimulation of DNA synthesis, but not between EGF binding and EGF-induced stimulation of DNA synthesis. This correlation is lost at high EGF concentrations, where stimulation of DNA synthesis is suboptimal. Optimal stimulation of DNA synthesis requires a minimum of 6 h of incubation of EGF with cells, and the suboptimal stimulation of DNA synthesis at high EGF concentration is intensified when the period of incubation of EGF with cells is less than 6 h. These data are consistent with a model of hormone signal transmission by Endocytic Activation, wherein the activation of EGF-induced processes requires constant EGF-induced internalization of receptor for a requisite 6-8 h period as an obligatory step in production of "second messenger" in the action of this hormone.     

Studies on the kinetics and mechanism of dissociation of copper(II) and nickel(II) complexes of the macrocyclic ligand 1, 5, 9, 13-tetraaza-2, 4, 4, 10, 12, 12-hexamethyl-cyclohexadecane-1, 9-diene in perchloric acid media

Summary Acid catalysed dissociation of the copper(II) and nickel(II) complexes (ML²⁺ of the quadridentate macrocyclic ligand 1, 5, 9, 13-tetraaza-2, 4, 4, 10, 12, 12-hexamethyl-cyclohexadecane-1, 9-diene (L) has been studied spectrophotometrically. Both complexes dissociate quite slowly with the observed pseudo-first order rate constants (k_obs) showing acid dependence; for the nickel(II) complex (k_obs)=k_O+k_H[H⁺], the k_o path is however absent with the copper(II) complex. At 60°C (I=0.1M) the k_H values areca 10^–4 M^–1 s^–1 for both complexes; k _H ^Cu /k _H ^Ni =ca. 3.9, comparable to some other square-planar complexes of these metal ions. The rate difference is primarily due to H values [copper(II) complex, 29.4±0.5 kJ mol^–1; nickel(II) complex, 35.6±1.5 kJ mol^–1] with highly negative S values [for copper(II), –215.5 ±6.1 JK^–1 mol^–1 and for nickel(II), –208.1 ±5.6 JK^–1 mol^–1] which are much higher than the entropy of solvation of Ni²⁺ (ca. –160 JK^–1 mol^–1) and Cu²⁺ (ca. –99 JK^–1 mol^–1) ions; significant solvation of the released metal ions and the ligand is indicated.     

Surface modified ormosil nanoparticles

Organically modified silanes (ORMOSIL) such as vinyl triethoxysilane readily aggregate in the aqueous cores of reverse micelles where the triethoxysilane moieties are hydrolyzed to form a hydrated silica network and the vinyl groups protruded out from the surface of the nanoparticles toward the hydrophobic side of the micellar interface. These particles are spherical and the size distribution of the particles is relatively narrow, with an average diameter of 87 nm. Surface vinyl silica nanoparticles so formed have been oxidized to surface carboxylic silica nanoparticles, followed by chemical conjugation with polyethyleneglycol amine (PEG amine) through the ethyl-3-(3-dimethylaminopropyl) (EDCI) carbodiimide reaction. The characteristic surface groups have been identified by Fourier transform infrared spectroscopy, while the size and the morphology of the particles have been studied by dynamic light scattering and transmission electron microscopy. It has been found that about 80-85% of the carboxylic groups are PEGylated during the EDCI reaction.     

Kinetics and mechanisms of the reactions of thiosulphato-amine complexes of cobalt(III). Part I. Isomerization and base hydrolysis ofcis andtrans isomers of dithiosulphatobis(ethylenediamine) cobalt(III) ion in aqueous solution

Summary Investigations were carried out on the isomerization and base hydrolysis ofcis andtrans forms of dithiosulphatobis-(ethylenediamine)cobalt(III) ions. Thecis form isomerizes to thetrans form in neutral aqueous medium, rates being 1.15, 2.30 and 4.0×10^–5s^–1, respectively at 42, 50 and 58 °C. Thetrans complex isomerizes to thecis form in basic solution only, the rate varying with pH in a sigmoid pattern. In presence of OH^–, an acid-base equilibrium of the complex ion sets in, but only the basic form takes part in the isomerization reaction. Hydrolysis of thecis isomer proceeds through a base-dependent path only, but that of thetrans isomer proceeds both through base-dependent and base-independent paths. The mechanisms are associative in nature. Thetrans form reacts faster thancis in all cases.     

Ruthenium complexes of 2-[(4-(arylamino)phenyl)azo]pyridine formed via regioselective phenyl ring amination of coordinated 2-(phenylazo)pyridine: isolation of products,X-ray structure,and redox and optical properties

Aromatic ring amination reactions in the ruthenium complex of 2-(phenylazo)pyridine is described. The substitutionally inert cationic brown complex [Ru(pap)(3)](ClO(4))(2) (1) (pap = 2-(phenylazo)pyridine) reacts smoothly with aromatic amines neat and in the presence of air to produce cationic and intense blue complexes [Ru(HL(2))(3)](ClO(4))(2) (2) (HL(2) = 2-[(4-(arylamino)phenyl)azo]pyridine). These were purified on a preparative TLC plate. The X-ray structure of the new and representative complex 2c has been solved to characterize them. The results are compared with those of the starting complex, [Ru(pap)(3)](ClO(4))(2) (1). The transformation 1 --> 2 involves aromatic ring amination at the para carbon (with respect to the diazo function) of the pendant phenyl rings of all three coordinated pap ligands in 1. The transformation is stereoretentive, and the amination reaction is regioselective. The extended ligand HL(2) coordinates as a bidentate ligand and chelates to ruthenium(II) through the pyridine and one of the azo nitrogens. The amine nitrogen of this bears a hydrogen atom and remains uncoordinated. Similarly, the amination reaction on the mixed-ligand complex [Ru(pap)(bpy)(2)](ClO(4))(2) produces the blue complex [Ru(HL(2))(bpy)(2)](ClO(4))(2) (3) as anticipated. The reactions of [RuCl(2)(dmso)(4)] and [Ru(S)(2)(L)(2)](2+) (dmso = dimethyl sulfoxide, S = labile coordinated solvent, L = 2,2'-bipyridine (bpy) and pap) with the preformed HL(2) ligand have been explored. The structure of the representative complex [RuCl(2)(HL(2a))(2)] (5a) is reported. It has the chlorides in trans configuration while the pyridine as well as azo nitrogens are in cis geometry. Optical spectra and redox properties of the newly synthesized complexes are reported. All the ruthenium complexes of HL(2) are characterized by their intense blue solution colors. The lowest energy transitions in these complexes appear near 600 nm, which have been attributed to intraligand charge-transfer transitions. For example, the lowest energy visible range transition in [Ru(HL(2b))(3)](2+) appears at 602 nm and its intensity is 65 510 M(-1) cm(-1). All the tris chelates show multiple-step electron-transfer processes. In [Ru(HL(2))(3)](2+), six reductions waves constitute the complete electron-transfer series. The electrons are believed to be added successively to the three azo functions. In the mixed-ligand chelates [Ru(HL(2))(pap)(2)](2+) and [Ru(HL(2))(bpy)(2)](2+) the reductions due to HL(2), pap, and bpy are observed.