Solid Lipid Nanoparticles (SLNs): Preparation and Properties of Calix[4]resorcinarene Derived Systems.

Solid Lipid Nanoparticles (SLNs) have been prepared fromc-2,c-8,c-14,c-20-tetraundecyl-4,6,10,12,16,18,22,24-octahydroxyresorc[4]areneas colloidal suspensions. Photon Correlation Spectroscopy studies revealed aparticle hydrodynamic diameter of 150 nm. Non-contact mode Atomic ForceMicroscopy allows observation of the particles as slightly flattened sphericalobjects of 236 (±40) nm diameter and 145 (±40) nm height. Thestudy of the preparation parameters showed that shear force does not affectthe hydrodynamic size of the SLNs. In contrast, the viscosity and the pH ofthe aqueous phase, the amphiphile concentration in the organic phase and thevolume of organic phase used, all lead to variation in the size of the particles.In term of post preparation parameters only the ionic strength has been shownto affect significantly the particle size; while the pH of the storing solution,microwave, ultrasonic and thermal treatments do not. Short and long-termstability studies have been performed to measure the effect of the ionic strengthon the stability of the particles. The use of carbohydrate cryoprotectants does notallow re-dispersion of the colloidal suspension after freeze-drying.     

Steric control in the oligomerisation of phosphazane dimers; towards new phosphorus-nitrogen macrocycles

The reaction of [ClP(mu-NtBu)]2 (1) with H2O (1 : 2 equivalents) in the presence of excess Et3N gives the new chain compound [(mu-O)[P(mu-NtBu)2P(H)=O]2] (3), consisting of two P2N2 rings linked by a mu-O atom and terminating in P(V)(H)=O groups. A similar chain species is obtained from the reaction of the lithiate of [(tBuNH)P(mu-NtBu)2P(H)=O] (5) with [ClP(mu-NtBu)2P(NHtBu)] (2), the product being [(mu-O)[P(mu-NtBu)2P(NHtBu)]2] (6). Compounds 3 and 6 are the first examples of O-bridged chain phosphazanes and potential precursors to new phosphorus-nitrogen macrocycles. The syntheses and X-ray structures of 3, 5 and 6 are reported.     

Methyl 4‐(2‐chloro‐5‐nitro­phenyl)‐2,7,7‐tri­methyl‐5‐oxo‐1,4,5,6,7,8‐hexa­hydro­quinoline‐3‐carboxyl­ate

The title compound, C₂₀H₂₁ClN₂O₅, has potential calcium modulatory properties. The 1,4‐di­hydro­pyridine ring has the usual shallow boat conformation. The 2‐chloro‐5‐nitro­phenyl ring is oriented such that the chloro substituent is in a synperiplanar orientation with respect to the 1,4‐di­hydro­pyridine ring plane, while the nitro substituent sits over the 1,4‐di­hydro­pyridine ring. The cyclo­hexenone ring has a conformation that is approximately half‐way between that of an envelope and that of a half‐chair. The mol­ecules are linked into chains by intermolecular N—H⋯O hydrogen bonds.     

Pincer-porphyrin hybrids

[reaction: see text] Starting from tetrakis(3,5-bis(bromomethyl)phenyl)porphyrin, pincer-porphyrin hybrid molecules (tetrakis(ECE-pincer)porphyrin; E = N, P, S) based on a tetraphenylporphyrin skeleton have been prepared in high yields. These multi-ligand site compounds could be selectively metalated at their peripheries, which was shown by X-ray crystallography.     

Metallation effects on the thermal interconversion of atropisomers of di(orthomethylarene)-substituted porphyrins

A new series of meso-substituted diaryl free-base and metalloporphyrins have been prepared. Each arene has been substituted with both a methyl group in the ortho position and a formyl group in the meta position. Rotation of the arene units is prevented at room temperature due to the steric restrictions imposed by the flanking methyl groups at the porphyrin beta-pyrrolic positions on the methyl groups at the ortho position on the meso-substituted arene unit. This allowed the alpha alpha and alpha beta atropisomers of this porphyrin to be separated and characterised. X-Ray crystallographic determination of the structure of the free-base porphyrin revealed a very flat porphyrin core. Metallation resulted in the isolation and characterisation of the nickel, zinc and copper derivatives. The assignments of the alpha alpha and alpha beta isomers are confirmed by X-ray crystallographic determination of the structures of the Cu(II) analogues. The copper alpha alpha structure exhibits a very twisted porphyrin core, the copper alpha beta structure is also distorted, but to a lesser degree. The activation energy for rotation has been calculated for each of the 2H, Ni and Zn derivatives. The energy required to rotate the arene ring increases in the order Ni < Zn approximately 2H. No significant difference in the free energy of rotation was observed between experiments carried out with the alpha alpha and small alpha beta isomers.     

Methyl rotational tunneling dynamics of p-xylene confined in a crystalline zeolite host

The methyl rotational tunneling spectrum of p-xylene confined in nanoporous zeolite crystals has been measured by inelastic neutron scattering (INS) and proton nuclear magnetic resonance (NMR), and analyzed to extract the rotational potential energy surfaces characteristic of the methyl groups in the host-guest complex. The number and relative intensities of the tunneling peaks observed by INS indicate the presence of methyl-methyl coupling interactions in addition to the methyl-zeolite interactions. The INS tunneling spectra from the crystals (space group P2(1)2(1)2(1) with four crystallographically inequivalent methyl rotors) are quantitatively interpreted as a combination of transitions involving two coupled methyl rotors as well as a transition involving single-particle tunneling of a third inequivalent rotor, in a manner consistent with the observed tunneling energies and relative intensities. Together, the crystal structure and the absence of additional peaks in the INS spectra suggest that the tunneling of the fourth inequivalent rotor is strongly hindered and inaccessible to INS measurements. This is verified by proton NMR measurements of the spin-lattice relaxation time which reveal the tunneling characteristics of the fourth inequivalent rotor.     

Effect of the parent ligand on the photophysical properties of closely-coupled, binuclear ruthenium(II) tris(2,2'-bipyridine) complexes

The photophysical properties of closely-coupled, binuclear complexes formed by connecting two ruthenium(II) tris(2,2'-bipyridine) complexes via an alkynylene group differ significantly from those of the relevant mononuclear complex. In particular, the energy of the first triplet excited state is lowered relative to the parent complex, because of the presence of the alkynylene substituent, while the triplet lifetime is prolonged, in part, because of extended electron delocalization. We now report that the triplet lifetime is also affected by the nature of the spectator 2,2'-bipyridyl ligands. Thus, replacing the parent 2,2'-bipyridine ligands with the corresponding 4,4'-dinitro-substituted ligands serves to decrease the luminescence yield and lifetime. With the corresponding carboxylate ester, the luminescence yield and lifetime are increased. Perdeuteration of the parent 2,2'-bipyridine ligands also leads to a modest increase in the luminescence yield. Such observations are indicative of electronic coupling between the various metal-to-ligand, charge-transfer excited triplet states. Temperature dependence studies confirm that these excited states are closely spaced and thermally accessible at ambient temperature. For some of the binuclear complexes, the quantum yield for formation of the lowest-energy triplet state is significantly less than unity.     

Coordination of 9-ethylguanine to the mixed-ligand compound alpha-[Ru(azpy)(bpy)Cl2] (azpy = 2-phenylazopyridine and bpy = 2,2'-bipyridine). An unprecedented ligand positional shift, correlated to the cytotoxicity of this type of [RuL2Cl2] (with L = azpy or bpy) complex

The striking difference in cytotoxic activity between the inactive cis-[Ru(bpy)(2)Cl(2)] and the recently reported highly cytotoxic alpha-[Ru(azpy)(2)Cl(2)] (alpha indicating the isomer in which the coordinating Cl atoms, pyridine nitrogens, and azo nitrogens are in mutual cis, trans, cis orientation) encouraged the synthesis of the mixed-ligand compound cis-[Ru(azpy)(bpy)Cl(2)]. The synthesis and characterization of the only occurring isomer, i.e., alpha-[Ru(azpy)(bpy)Cl(2)], 1 (alpha denoting the isomer in which the Cl ligands are cis related to each other and the pyridine ring of azpy is trans to the pyridine ring of bpy), are described. The solid-state structure of 1 has been determined by X-ray structure analysis. The IC(50) values obtained for several human tumor cell lines have indicated that compound 1 shows mostly a low to moderate cytotoxicity. The binding of the DNA model base 9-ethylguanine (9-EtGua) to the hydrolyzed species of 1 has been studied and compared to DNA model base binding studies of cis-[Ru(bpy)(2)Cl(2)] and alpha-[Ru(azpy)(2)Cl(2)]. The completely hydrolyzed species of 1, i.e., alpha-[Ru(azpy)(bpy)(H(2)O)(2)](2+), has been reacted with 9-EtGua in water at room temperature for 24 h. This resulted in the monofunctional binding of only one 9-EtGua, coordinated via the N7 atom. The product has been isolated as alpha-[Ru(azpy)(bpy)(9-EtGua)(H(2)O)](PF(6))(2), 2, and characterized by 2D NOESY NMR spectroscopy. The NOE data show that the 9-EtGua coordinates (under these conditions) at the position trans to the azo nitrogen atom. Surprisingly, time-dependent (1)H NMR data of the 9-EtGua adduct 2 in acetone-d(6) show an unprecedented positional shift of the 9-EtGua from the position trans to the azo nitrogen to the position trans to the bpy nitrogen atom, resulting in the adduct alpha'-[Ru(azpy)(bpy)(9-EtGua)(H(2)O)](PF(6))(2) (alpha' indicating 9-EtGua is trans to the bpy nitrogen). This positional isomerization of 9-EtGua is correlated to the cytotoxicity of 1 in comparison to both the cytotoxicity and 9-EtGua coordination of cis-[Ru(bpy)(2)Cl(2)], alpha-[Ru(azpy)(2)Cl(2)], and beta-[Ru(azpy)(2)Cl(2)]. This positional isomerization process is unprecedented in model base metal chemistry and could be of considerable biological significance.     

Asymmetric synthesis and applications of beta-amino Weinreb amides: asymmetric synthesis of (S)-coniine

Conjugate addition of lithium (S)-N-benzyl-N-alpha-methylbenzylamide to a range of alpha, beta-unsaturated Weinreb amides proceeds with high levels of diastereoselectivity (>95% de). The beta-amino Weinreb amide products may be transformed into beta-amino ketones via reactions with Grignard reagents, while treatment with DIBAL-H furnishes beta-amino aldehydes. Trapping of the aldehyde via Wadsworth-Emmons reaction and subsequent manipulation offers an efficient route to homochiral delta-amino acid derivatives and 2-substituted piperidines. The application of this methodology for the synthesis of (S)-coniine is demonstrated.     

Production and characterisation of polyclonal antibodies to a derivative of 3-amino-2-oxazolidinone, a metabolite of the nitrofuran furazolidone

Polyclonal antibodies were produced to detect 3-amino-2-oxazolidinone (AOZ), a stable metabolite of the nitrofuran antibiotic furazolidone, following derivatisation with o-nitrobenzaldehyde. A carboxyphenyl derivative of AOZ was prepared, purified and conjugated to immunogenic carrier protein. Six antisera were produced from the immunisation of seven rabbits using various immunogen doses and time-scales. IC₅₀ values, as determined by competitive enzyme-linked immunosorbent assay (ELISA) suggested that reducing immunogen dose from 0.3 to 0.05 mg, while lengthening rest periods between booster immunisations from 2 to 8 weeks, increased the sensitivity of the antibodies to 3-{[(2-nitrophenyl)methylene]amino}-2-oxazolidinone (NPAOZ) from 3.8 to 0.3 μg l⁻¹. An IC₅₀ of 0.065 μg l⁻¹ (AOZ in the form of NPAOZ) was achieved with antiserum R670 by altering ELISA conditions. This antibody was highly specific for NPAOZ and did not cross-react with various nitrofuran metabolites, their nitrophenyl derivatives or a range of veterinary drugs. Antibody R670 is suitable for incorporation into an immunoassay for AOZ with sufficient sensitivity to satisfy current criteria for monitoring of veterinary drug residues. This is the first publication of an antibody for detection of a nitrofuran metabolite.