Synthesis and in Vitro Evaluation of N-[[4-[2-(Carboxyl)-1-Cycloalken-1-yl]Phenyl]Methyl]Imidazoles as Nonpeptide Angiotensin II Receptor Antagonists

A series of nonpeptide angiotensin II receptor antagonists was synthesized via palladium-assisted cross coupling of aryl stannane and cycloalkenyl triflates and subsequent alkylation of silyl-protected imidazole. Our compounds, which have a terminal five- to seven-membered cycloalkenyl ring, are compared to DuPont EXP7711, an N-[(2′-carboxybiphenylyl)methyl]imidazole, which has a terminal phenyl moiety. Physicochemical properties of the compounds, such as lipophilicity, steric bulk, conformation, and the relative spatial proximity of the 2-carboxyl and the middle phenyl, are quantitated by computational chemistry. Potency in terms of binding affinity to AT₁ receptors in rat adrenal glomerulosa and rabbit aorta is maximized when the terminal ring is aromatic.     

Investigation of carbon-13 nuclear magnetic resonance spectra-structure correlation based on novel atomic distance-edge (ADE) vector

A set of novel graph-theoretical parameters,called the atomic distance-edge (ADE) vector,was developed.Based on the connecting C-C bond number between central carbon atom and the other ones,various carbon atoms of alkanes were classified as four types,i.e.,type 1,2,3 and 4 for primary,secondary,ternary and quaternary carbon,respectively; and then four regression equations were obtained to link carbon-13 chemical shift (CS) of each type of atoms.Furthermore,these regression models were used to predict the carbon-13 nuclear magnetic resonance spectra of alkanes and it was found that the estimated CS were in agreement with the experimental results.     

Determining molecular structures and conformations directly from electron diffraction using a genetic algorithm.

A global optimization strategy, based upon application of a genetic algorithm (GA), is demonstrated as an approach for determining the structures of molecules possessing significant conformational flexibility directly from gas-phase electron diffraction data. In contrast to the common approach to molecular structure determination, based on trial-and-error assessment of structures available from quantum chemical calculations, the GA approach described here does not require expensive quantum mechanical calculations or manual searching of the potential energy surface of the sample molecule, relying instead upon simple comparison between the experimental and calculated diffraction pattern derived from a proposed trial molecular structure. Structures as complex as all-trans retinal and p-coumaric acid, both important chromophores in photosensing processes, may be determined by this approach. In the examples presented here, we find that the GA approach can determine the correct conformation of a flexible molecule described by 11 independent torsion angles. We also demonstrate applications to samples comprising a mixture of two distinct molecular conformations. With these results we conclude that applications of this approach are very promising in elucidating the structures of large molecules directly from electron diffraction data.     

Retention modeling and simultaneous optimization of pH value and gradient steepness in RP‐HPLC using feed‐forward neural networks

A novel approach is proposed for the simultaneous optimization of mobile phase pH and gradient steepness in RP‐HPLC using artificial neural networks. By presetting the initial and final concentration of the organic solvent, a limited number of experiments with different gradient time and pH value of mobile phase are arranged in the two‐dimensional space of mobile phase parameters. The retention behavior of each solute is modeled using an individual artificial neural network. An “early stopping” strategy is adopted to ensure the predicting capability of neural networks. The trained neural networks can be used to predict the retention time of solutes under arbitrary mobile phase conditions in the optimization region. Finally, the optimal separation conditions can be found according to a global resolution function. The effectiveness of this method is validated by optimization of separation conditions for amino acids derivatised by a new fluorescent reagent.     

Some theoretical aspects on morphology development in seeded composite latexes. I. Batch conditions below monomer saturation

In seeded emulsion polymerization, during the second stage, new interfaces appear and the surface area changes. A thermodynamic equilibrium approach is presented which predicts particle morphology of a whole range of non-spherical particles upon polymer conversion. Simulation takes into account swelling ratio, molar volumes and interfacial tension. As the particle geometry is complex, a new mathematical procedure is detailed.The computed data are useful to discuss either the stability or the instability of the particles morphology. These results must be compared with actual experimental structures.Abreviations and symbols G Gibbs' free energy - reduced Gibbs' free energy - _i interfacial tension - ₁₂ interfacial tension between polymer 1 and polymer 2 - _1w interfacial tension between polymer 1 and water - _2w interfacial tension between polymer 2 and water - r ₁ polymer 1 swollen by monomer 2 sphere radius - r ₂ polymer 2 swollen by monomer 2 sphere radius - r _i interfacial radius - h ₁ sphere 1 distance to minimal section - h ₂ sphere 2 distance to minimal section - h _i interfacial sphere distance to minimal section - sign ofh _i, positive when the interface sphere is on the side of the sphere 2, negative when the interface sphere is on the side of the sphere 1 - A ₁₂ surface between polymer 1 and polymer 2 - A _1w surface between polymer 1 and water - A _1w ⁰ surface between polymer 1 and water before polymerization - A _2w surface between polymer 2 and water - v ₁ volume of the polymer 1 swollen by monomer 2 - v _i volume of the polymer 1 swollen by monomer 2 before polymerization - v ₂ volume of the polymer 2 swollen by monomer 2 - V _p1 polymer 1 molar volume - V _p2 polymer 2 molar volume - V _m2 monomer 2 molar volume - n _p2 polymer 2 number of mole - n _p1 polymer 1 number of moles - n _m21 monomer 2 number of mole in the swollen polymer 1 - n _m22 monomer 2 number of mole in the swollen polymer 2 - n _m2 monomer 2 total number of mole - n _m2 monomer 2 number of mole before polymerization - TGn ₁ polymer 1 swelling rate - TGn ₂ polymer 2 swelling rate - TGn _i maximum number of mole of monomer 2 in polymeri by mole of polymeri - x polymer 2 conversion rate - K, p, q mathematical variables - D, r, a mathematical variables     

Structural determinants of steroids for cytochrome P450 3A4-mediated metabolism

Cytochrome P450 3A4 (CYP3A4), a major member of cytochrome P450 isoenzymes, metabolizes the majority of steroids in 6β-position. For the purpose of determining requisite structural features of a series of structurally related steroids for CYP3A4-mediated metabolism, three-dimensional pharmacophore modeling as well as electrotopological state map were conducted for 15 steroids. Though prior studies speculated that the chemical reactivity of the allylic 6β-position might have a greater influence on CYP3A4 selective 6-hydroxylation than steric constraints in the enzyme, our results reveal that for CYP3A4 steroidal substrates, it is not the chemical reactivity of atoms at 6β-site, but the pharmacophoric features, i.e. the two hydrophobic rings together with two H-bond donors, that act as the key factors responsible for determining the CYP3A4 selective 6-hydroxylation of steroids.     

Nanocomposite materials from latex and cellulose whiskers

Composite materials were processed by casting a mixture of aqueous suspensions of latex and microfibrils. These microfibrils, or whiskers, are extracted from a sea animal and are monocrystals of cellulose, with an aspect ratio around 100 and an average diameter of 20 nm. It has been found that the mechanical properties (shear modulus) are increased by more than two orders of magnitude in the rubbery state of the polymeric matrix, when the whisker content was 6% (w/w). This very large effect is discussed on the basis of different types of mechanical models and it is concluded that these whiskers form a rigid network, probably linked by hydrogen bonds. The formation of this network is assumed to be governed by a percolation mechanism.     

An investigation into the construction of molecular models by the template joining method

Summary The results of a wide-ranging investigation into some of the different methods available for performing the joining of templates to build molecular models show that the choice of algorithm can significantly affect the quality of the results obtained, and different algorithms are most suited to particular categories of join.     

Cavity search: An algorithm for the isolation and display of cavity-like binding regions

Summary A set of algorithms designed to enhance the display of protein binding cavities is presented. These algorithms, collectively entitled CAVITY SEARCH, allow the user to isolate and fully define the extent of a particular cavity. Solid modeling techniques are employed to produce a detailed cast of the active site region, which can then be color-coded to show electrostatic and steric interactions between the protein cavity and a bound ligand.