A common method for the determination of several calcium channel blockers using an HPLC system with ultraviolet detection

We report a common HPLC method for the single or simultaneous determination of four calcium channel blockers (CCB), namely diltiazem (DTZ), verapamil (VER), nifedipine (NIF) and nitrendipine (NIT) and their active metabolites demetildiltiazem and deacetildiltiazem (MA and M1), norverapamil (NOR), and dehydronifedipine (DHN). DHN was first synthesised in our laboratory and different pH values of the mobil phase were subsequently prepared and tested for chromatographic separation. The detection system and the environmental light conditions were optimised. The best separations of all analytes were obtained using a C₁₈ column and a mobile phase of methanol, 0.04 M ammonium acetate, acetonitrile and triethylamine (2:2:1:0.04 v/v). Quantitation was performed using imipramine (IMI) as the internal standard. For DTZ and its metabolites (M1 and MA), the wavelength chosen was 237 nm; for VER and its metabolite NOR, it was 210 nm; and, finally for NIF and its metabolite DHN and NIT it was 216 nm. When a simultaneous analysis was carried out the wavelength was of 230 nm. The optimum pH were 7.90 and 7.10 when the separation of NIT and DTZ or VER and NIF were carried out, respectively, and 7.90 when a simultaneous separation was carried out. The detection limit of the assay was less than 8 ng ml⁻¹ for all compounds, with coefficients of variation less than 7% (for inter- and intra-day) over the concentration range of 1–1000 ng ml⁻¹. The retention times were less than 11 min. When NIF or NIT were studied, it was necessary to use a sodium vapour lamp in order to avoid the photodegradation which takes place under daylight conditions.     

Hydrophobic Molecular Similarity from MST Fractional Contributions to the Octanol/water Partition Coefficient

Summary The use of a recently proposed hydrophobic similarity index for the alignment of molecules and the prediction of their differences in biological activity is described. The hydrophobic similarity index exploits atomic contributions to the octanol/water transfer free energy, which are evaluated by means of the fractional partitioning scheme developed within the framework of the Miertus-Scrocco-Tomasi continuum model. Those contributions are used to define global and local measures of hydrophobic similarity. The suitability of this computational strategy is examined for two series of compounds (ACAT inhibitors and 5-HT₃ receptor agonists), which are aligned to maximize the global hydrophobic similarity using a Monte Carlo-simulated protocol. Indeed, the concept of local hydrophobic similarity is used to explore structure–activity relationships in a series of COX-2 inhibitors. Inspection of the 3D distribution of hydrophobic/hydrophilic contributions in the aligned molecules is valuable to identify regions of very similar hydrophobicity, which can define pharmacophoric recognition patterns. Moreover, low similar regions permit to identify structural elements that modulate the differences in activity between molecules. Finally, the quantitative relationships found between the pharmacological activity and the hydrophobic similarity index points out that not only the global hydrophobicity, but its 3D distribution, is important to gain insight into the activity of molecules. J.M.M. and S.P. have contributed equally to this study.     

Ab initio and DFT modeling of stereoselective deamination of aziridines by nitrosyl chloride

The stereochemical course of the deamination of cis‐2,3‐dimethylaziridine by nitrosyl chloride was investigated at the QCISD/6‐31G(d) level. Calculations reveal that the reaction takes place in two steps. In the first step, the reactants form a pre‐reactive complex, followed by a spiro‐type bicyclic transition state, which on dissociative cycloelimination gives the N‐nitrosoaziridine intermediate. In the second step, this intermediate undergoes cycloreversion through a slightly asynchronous concerted transition state to form an alkene with the same stereochemistry, which is in total agreement with experiment. In the whole reaction, the denitrosation step is found to be rate‐determining. For comparison, geometry optimizations and energies were also obtained at the B3LYP/6‐31G(d) level. It was found that the B3LYP energy results differed significantly from the QCISD ones. To analyze the reason for this difference, B3LYP calculations were repeated by varying the contribution of exact exchange in the Becke functional. With respect to the QCISD results, it has been shown that the functional with 0% exact exchange yields the best activation barriers, whereas the functional with 30% exact exchange is the most suitable one to carry out the complexation and reaction energy calculations. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Characterisation of pitch by HPLC

Summary A new high performance liquid chromatography method for the characterisation of toluene-soluble fractions of pitches has been developed. Although a chromatographic system typical of size exclusion chromatography was used, results indicate that, for these structurally complex samples, separation does not follow the usual discrimination by molecular size. A differentiation between several classes of polyaromatic hydrocarbons is achieved instead. Data are reported on the analysis of individual standard polyaromatic hydrocarbons, showing that four different elution ranges can be observed: three ofcata-condensed compounds (Cata1, Cata2 and Cata3) and one ofperi-condensed compounds (Peri). Results are reported proving the capacity of this high performance liquid chromatography method to distinguish between pitches of different origin and nature. It is also effective for the study of the chemical reactions occurring during heat treatment.     

Thermal and photochemical rearrangement of bicyclo[3.1.0]hex-3-en-2-one to the ketonic tautomer of phenol. Computational evidence for the formation of a diradical rather than a zwitterionic intermediate

The ground state (S(0)) and lowest-energy triplet state (T(1)) potential energy surfaces (PESs) concerning the thermal and photochemical rearrangement of bicyclo[3.1.0]hex-3-en-2-one (8) to the ketonic tautomer of phenol (11) have been extensively explored using ab initio CASSCF and CASPT2 calculations with several basis sets. State T(1) is predicted to be a triplet pipi lying 66.5 kcal/mol above the energy of the S(0) state. On the S(0) PES, the rearrangement of 8 to 11 is predicted to occur via a two-step mechanism where the internal cyclopropane C-C bond is broken first through a high energy transition structure (TS1-S(0)()), leading to a singlet intermediate (10-S(0)()) lying 25.0 kcal/mol above the ground state of 8. Subsequently, this intermediate undergoes a 1,2-hydrogen shift to yield 11 by surmounting an energy barrier of only 2.7 kcal/mol at 0 K. The rate-determining step of the global rearrangement is the opening of the three-membered ring in 8, which involves an energy barrier of 41.2 kcal/mol at 0 K. This high energy barrier is consistent with the fact that the thermal rearrangement of umbellulone to thymol is carried out by heating at 280 degrees C. Regarding the photochemical rearangement, our results suggest that the most efficient route from the T(1) state of 8 to ground state 11 is the essentially barrierless cleavage of the internal cyclopropane C-C bond followed by radiationless decay to the S(0) state PES via intersystem crossing (ISC) at a crossing point (S(0)()/T(1)()-1) located at almost the same geometry as TS1-S(0)(), leading to the formation of 10-S(0)() and the subsequent low-barrier 1,2-hydrogen shift. The computed small spin-orbit coupling between the T(1) and S(0) PESs at S(0)()/T(1)()-1 (1.2 cm(-)(1)) suggests that the ISC between these PESs is the rate-determining step of the photochemical rearrangement 8 --> 11. Finally, computational evidence indicates that singlet intermediate 10-S(0)() should not be drawn as a zwitterion, but rather as a diradical having a polarized C=O bond.     

Synthesis and Characterization of [(1,4‐diamine)dichloro]platinum(II) Compounds Preliminary Studies on their Biological Activity

Two 1,4‐diamine ligands were synthesized having 1,2‐bis(aminomethyl)‐cyclohexane and 1,2‐bis(aminomethyl)‐benzene structures. The two ligands have different electron density in the six‐membered ring: a cyclohexane versus a phenyl ring. The organic synthesis of the ligands was carried out by synthetic pathways of seven and four steps, respectively, starting from 1,2,3,6‐tetrahydrophthalic anhydride and diethyl phthalate. The coordination of platinum to these ligands afforded platinum(II) complexes which are analogue to the clinical drug cisplatin but form a seven‐membered chelate ring. The interaction of the platinum compounds with DNA was studied in order to know the relationship between the electron density of ligands and their capability to chelate DNA, by using three techniques: Circular Dichroism, Agarose Gel Electrophoresis and Atomic Force Microscopy. The degree of interaction of both compounds with DNA was slightly different, but both complexes showed a cisplatin‐like behaviour and are promising candidates to follow an extensive study of their cytotoxic activity.     

Emulsion polymerization of styrene and methyl methacrylate using a hydrophobically modified inulin and comparison with other surfactants

The use of a new class of graft polymer surfactants, based on inulin, in emulsion polymerization of poly(methyl methacrylate) (PMMA) and polystyrene (PS) particles is described. PS and PMMA were synthesized by emulsion polymerization, and stable particles with a high monomer content (50 wt %) were obtained with a very small amount of polymeric surfactant ([surfactant]/[monomer] = 0.0033). The latex dispersions were characterized by dynamic light scattering and by transmission electron microscopy to obtain the average particle size and the polydispersity index, and the stability was determined by turbidimetry measurements and expressed in terms of critical coagulation concentration. The last section gives a comparison of PMMA particles prepared by emulsion polymerization using classical surfactants from different types as emulsifiers with that obtained using the copolymer surfactant. It shows the superiority of INUTEC SP1 as it is the only one that allows stable particles at 20 wt % monomer content, with a smaller ratio [surfactant]/[monomer] = 0.002.     

Transition metal-mediated intramolecular [2+2+2] cycloisomerizations of cyclic triynes and enediynes

[reaction: see text] Nitrogen-containing 15-membered triacetylenic macrocycles known as 1,6,11-tris(arylsulfonyl)-1,6,11-triazacyclopentadeca-3,8,13-triynes (1) and enediynic macrocycles called 1,6,11-tris(arylsulfonyl)-1,6,11-triazacyclopentadeca-3-ene-8,13-diynes (4 and 5) were satisfactorily prepared. [2+2+2] cycloisomerization processes catalyzed by transition metals were tested in the above-mentioned macrocycles. Readily available and familiar cyclotrimerization precatalysts were examined for efficiency. Among them, the RhCl(CO)(PPh(3))(2) complex was found to catalyze the cycloisomerization reaction giving the desired cycloadducts in high yields.     

New synthetic “tricks”. Triphenylphosphine-mediated amide formation from carboxylic acids and azides

Equimolar amounts of carboxylic acids, aryl or alkyl azides, and Ph₃P in refluxing benzene (hexane, toluene) afford amides in good yields. Insolubility of zwitterions Ph₃P⁺-NH(CH₂)_nCOO-, arising from μ-azido acids and Ph₃P, limits the utilization of the method for lactame formation.     

A Convenient Stereoselective Synthesis of (1R,2S,3R,4S)-3-(Neopentyloxy)isoborneol

A convenient preparation of (1R,2S,3R,4S)-3-(neopentyloxy)isoborneol (= (1R,2S,3R,4S)-3-(2,2-dimethyl-propoxy)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-ol; 1a ), a valuable chiral auxiliary, is described. The synthesis involves six steps starting from the readily available camphorquinone ( 5 ) and gives 1a in 48% overall yield. The key step is the chemoselective hydrolysis of the less hindered 1,3-dioxolane moiety in the camphorquinone di-acetal 4 .