Electronic structure of some adenosine receptor antagonists. III. Quantitative investigation of the electronic absorption spectra of alkyl xanthines

Quantitative and comparative investigation of the electronic absorption spectra of theophylline, caffeine and their derivatives is reported. The spectra of theophylline, caffeine and theobromine were compared to establish the predominant tautomeric species in solution. This comparison, analysis of solvent effects and assignments of the observed transitions via MO computations indicate the exits of only one tautomeric species in solution that is the N7 form. A low-lying triplet state was identified which corresponds to a HOMO-LUMO transition. This relatively long-lived T1 state is always less polar than the ground state and may very well underlie the photochemical reactivity of alkyl xanthines. Substituents of different electron donating or withdrawing strengths and solvent effects are investigated and analyzed. The present analysis is facilitated via computer deconvolution of the observed spectra and MO computation.     

Electronic structure of some adenosine receptor antagonists: I. Equilibrium geometries,charge density distributions,and substituent effects

Ab initio molecular orbital calculations were implemented to investigate the variation of the electronic structure of a series of different xanthine derivatives. MP2(full)/6‐31G calculations have been carried out and used to investigate the geometric features of the studied compounds. Alkyl xanthines studied in the present work are highly polarized with the σ and π frameworks polarized in opposite directions. This polarization is sensitive to substitution. The trend observed for the variation of dipole moment with substitution is interesting. Thus, electron‐withdrawing substituents lower the magnitude of the dipole moment, which reaches its smallest value in the case of ? CF₃ substituent. The ? NO₂ group not only reduces the dipole moment but it also inverts its direction as well. The effect of the basis set on these geometric features has been investigated through implementation of polarization function in MP2(full)/6‐31G/6‐311G** calculations, where it was found that inclusion of the polarization function led to a noticeable redistribution of the charge density. Thus, charge density that was originally accumulated on the atomic centers is redistributed into the bonding regions and this is the reason for the smaller net charges and the larger bond orders predicted at the 6‐311G** level. © 2002 Wiley Periodicals, Inc. Int J Quantum Chem, 2002     

Electronic structure of some mesoscopic systems: II. Electronic composites

We study the electronic properties of a mesoscopic system composed of an array of straight, infinite rods made of an isotropic medium and embedded in a regular way in an isotropic background. Such a composite system has two-dimensional periodicity in the plane perpendicular to the rods. Using a Fourier series expansion, the corresponding Schrödinger equation is solved within the effective-mass approximation. The electronic band structure is computed for the wave vector in the transverse plane, and is illustrated by dispersion curves along the principal directions of the two-dimensional Brillouin zone as well as by the histograms of the density of states. The main result is the appearance of absolute energy gaps in the two-dimensional band structure.     

Electronic structure of some mesoscopic systems: I. Semiconductor superlattices

As an example of a mesoscopic system, a Kronig-Penney-type model of a semi-infinite GaAs/Ga_1−xAl_xAs superlattice is considered. The effect of the superlattice termination on the formation of a surface state as well as on the density-of-states distributions is discussed. Varying the position of the superlattice surface (i.e., superlattice/substrate interface) within a superlattice period influences strongly the appearance and position of surface states. They occur in particular minigaps for some ranges of the outermost layer thickness only.     

Electronic spectra and structure of some phenoxazone-type dyes

Quantum-mechanical calculations of the electronic structure and spectra of a number of phenoxazone dyes are given. The distribution analysis of pi-electron density in the ground and excited states makes clear the origin of the colour of these compounds and gives the possibility of direct assessment of organic reagents in terms of colour contrast and sensitivity of analytical reactions. This is illustrated for a series of dihydroxy derivatives of phenoxazone dyes.     

Comparative pharmacophore modeling of human adenosine receptor A1 and A3 antagonists

Adenosine receptors are promising therapeutic targets in drug discovery. In this study, three-dimensional pharmacophore models of human adenosine receptor A1 and A3 antagonists were developed based on 26 and 23 diverse compounds, respectively. The best A1 pharmacophore model (A 1 _Hopy1) consists of four features: one hydrogen bond donor, one hydrophobic point and two ring aromatics, while the best A 3 pharmacophore model (A3 _Hopy1) also has four features: one hydrogen bond acceptor, one hydrophobic point and two ring aromatics. The correlation coefficients were 0.840 for A 1 test set with 146 diverse compounds and 0.827 for A3 test set with 238 diverse compounds. In the simulated virtual screening experiments, high enrichment factors of 6.51 and 6.90 were obtained for A 1 _Hopy1 and A3 _Hopy1 models, respectively. Moreover, two models also showed high subtype-selectivity in the simulated virtual screening experiments. These results could be helpful for the discovery of novel potent and selective A 1 and A3 antagonists.     

Structure-activity relationship for some xanthines as adenosine A1 receptor antagonists, bronchodilators and phosphodiesterase inhibitors: an electric field mapping approach

Some alkylxanthines which are known as adenosine receptor antagonists or bronchodilators and phosphodiesterase (PDE) inhibitors have been studied using geometry optimisation by the AM1 molecular orbital method and electric field mapping using Mulliken charges. The possible atomic sites of these molecules which may be involved in interaction with the adenosine receptor and with the receptor related to bronchodilatory activity have been identified, and thus structure-activity relationships have been established for them. PDE inhibitor and bronchodilatory activities seem to have similar molecular structural requirements.     

Elucidation of a common structure of selective fibrinogen receptor antagonists

In this paper, we investigate the common structural and electrostatic parameters of a series of specific inhibitors of the IIb3 integrin. Molecular dynamics simulations with an explicit aqueous environment led to an original theoretical pattern. Our results may suggest that the studied non-peptide IIb3 antagonists developed upon the Arg-Gly-Asp ubiquitous recognition sequence, in fact, should mimic the C-terminus part of the fibrinogen chain. This assumption could, therefore, explain their specificity with respect to other Arg-Gly-Asp-dependent integrins.     

Investigation of some chalcogenides with spinel structure

The unusual combination of magnetic, semiconducting, and optical properties of the chalcochromites and other chalcogenide phases with spinel structure AB₂X₄ has attracted considerable attention for researchers (1–3). Although the physics of magnetic semiconductors is based on highly developed theoretical models and numerous experiments, the physical chemistry of these materials has many gaps. Knowledge of the thermal stability of the chalcogenide spinels, of the equilibrium conditions of their formation, and of their thermodynamics is lacking, although extremely important for the synthesis and thermal processing of single crystals and polycrystalline materials of the AB₂X₄ type. This paper presents the results of a study of the thermal stability and thermochemical, thermodynamic, and crystallochemical properties of the chalcochromites MeCr₂X₄ (Me = Cd, Co, Zn, Fe, Cu; X = S, Se, Te), thiocobaltites MeCo₂S₄ (Me = Cu, Co), thiorhodites Me_xRh_3−xS₄ (Me = Cu, Co, Fe), thioaluminates MeAl₂S₄ (Me = Zn, Cr), and solid solutions based on these. An attempt is made to show how much the investigated properties influence the magnetic and electrical properties of the chalcogenide spinels. This work is a continuation of the systematic investigation of chalcospinels, including, in particular, nonstoichometry and defect formation in the chalcochromites (4–7) homo- and heterovalent replacement in the chalcochromites (6, 8), and compound chalcochromites with replacement in the cation sublattice (9–11).     

Electronic structure of some mercury chalcogenides using Compton spectroscopy

We report the first ever isotropic Compton profiles of mercury chalcogenides using our 740 GBq ¹³⁷Cs Compton spectrometer. To analyze our measurements, theoretical Compton profiles, energy bands, density of states and Mulliken's populations are computed using pseudopotentials within the Hartree–Fock and density functional theories. A comparison of Compton data on equal-valence-electron-density scale shows the decrease of ionicity from HgS to HgTe. It is seen that these semiconductors have narrow band gap and exhibit inverted-type band structure.     

Androgen receptor antagonists and anti-prostate cancer activities of some synthesized steroidal candidates

In continuation of our previous work, a novel series of steroid derivatives were synthesized and their androgen receptor (AR) antagonist activities and in vivo antiandrogenic properties were evaluated. Twenty-one heterocyclic derivatives containing a cyanopyrane ring fused to a steroidal moiety were conveniently synthesized and screened for their antagonistic, antiandrogen and prostate anticancer activities comparable to that of bicalutamide as the reference control. Some of the compounds exhibited better antagonistic, antiandrogen and prostate anticancer activities than the reference controls. Initially the acute toxicity of the compounds was assayed via the determination of their LD(50). Synthetic steroidal structures fused to a substituted cyanopyrane ring seem to be a promising approach in the search for novel leads for potent antagonistic, antiandrogen and prostate anticancer agents.     

Electronic spectra and π-electronic structure of some hydroxyazo dyes

The electronic spectra of some hydroxyazo dyes, derivatives of azobenzene and benzeneazonaphthalene, are investigated and electronic transitions in the UV and visible regions assigned.The difference in spectral assignment of o- and p-hydroxyazobenzenes is explained using MO theory.Observations are made about possible azo—quinonehydrazone tautomerism in o-,m- and p-hydroxy derivatives of 4-phenylazo-1-naphthol and 1-phenylazo-2-naphthol and the quantitative value for the contribution of each tautomeric form is calculated.Calculations using the SCl—Cl method, within the PPP approximation, are performed for some hydroxyazo derivatives. The results of the calculations agreed significantly with the experimental spectral curves. Spectral differences between o- and p-hydroxyazobenzenes are established. It is shown that there is charge transfer from the aromatic rings to the azo group in the first excited singlet state.     

3D-pharmacophore models for selective A2A and A2B adenosine receptor antagonists

Three-dimensional pharmacophore models were generated for A2A and A2B adenosine receptors (ARs) based on highly selective A2A and A2B antagonists using the Catalyst program. The best pharmacophore model for selective A2A antagonists (Hypo-A2A) was obtained through a careful validation process. Four features contained in Hypo-A2A (one ring aromatic feature (R), one positively ionizable feature (P), one hydrogen bond acceptor lipid feature (L), and one hydrophobic feature (H)) seem to be essential for antagonists in terms of binding activity and A2A AR selectivity. The best pharmacophore model for selective A2B antagonists (Hypo-A2B) was elaborated by modifying the Catalyst common features (HipHop) hypotheses generated from the selective A2B antagonists training set. Hypo-A2B also consists of four features: one ring aromatic feature (R), one hydrophobic aliphatic feature (Z), and two hydrogen bond acceptor lipid features (L). All features play an important role in A2B AR binding affinity and are essential for A2B selectivity. Both A2A and A2B pharmacophore models have been validated toward a wide set of test molecules containing structurally diverse selective antagonists of all AR subtypes. They are capable of identifying correspondingly high potent antagonists and differentiating antagonists between subtypes. The results of our study will act as a valuable tool for retrieving structurally diverse compounds with desired biological activities and designing novel selective adenosine receptor ligands.     

Multigram-scale syntheses, stability, and photoreactions of A2A adenosine receptor antagonists with 8-styrylxanthine structure: potential drugs for Parkinson's disease

The improved multigram-scale syntheses of the important 8-styrylxanthine A(2A) adenosine receptor antagonist MSX-2 (8), its water-soluble prodrug MXS-3 (9), and KW-6002 (16) are described. N-Alkylation reactions at different positions of uracil derivatives were optimized. Two different methods for xanthine formation from 6-amino-5-cinnamoylaminouracil precursors were investigated, (a) the elimination of water by alkaline catalysis and (b) hexamethyldisilazane as a condensing agent; the latter was found to be superior. The photosensitivity of 8-styrylxanthines was studied. The (E)-configurated stryrylxanthine MSX-2 (8) isomerized in diluted solution, and the resulting (Z)-isomer (10a) was isolated and characterized. Furthermore, we describe for the first time that solid 8-styrylxanthines can dimerize upon exposition to daylight or irradiation with UV light. The resulting cyclobutane derivatives with head-to-tail (syn) configuration exhibited a considerably lower A(2A) adenosine receptor affinity than their parent compounds. The dimerization product of MSX-2 was a moderately potent nonselective A(1) and A(2A) antagonist (K(i)(A(1)) = 273 nM, K(i) (A(2A)) = 175 nM) while the dimer of the related compound KW-6002 was inactive at A(1) and only weakly active at A(2A) adenosine receptors (K(i) = 1.57 microM). The light sensitivity of 8-styrylxanthine derivatives, not only in solution, but also in the solid state, has to be considered when using those compounds as pharmacological tools or drugs.     

Electronic structure and hyperpolarizability of some conjugated molecules in excited states

For the examples of aromatic and antiaromatic five-membered heterocycles, the static electronic polarizabilities and hyperpolarizabilities are determined in the ground and first singlet- and triplet-excited electronic states. The theoretical calculations are carried out in the SOS formalism and the correlation effects are taken into account using all mono- and biexcited configuration in the PPP approximation. It is shown that the singlet excitation of the molecules for the antiaromatic case is connected to an significant decrease of both polarizabilities and hyperpolarizabilities. Their values are discussed in terms of the index of average bond-order alternation for the ground and excited states and the localization of the electronic transitions in the molecules. © 1993 John Wiley & Sons, Inc.     

Application of capillary zone electrophoresis to the screening of some angiotensin II receptor antagonists

A capillary zone electrophoretic (CZE) method was optimized for the separation of five angiotensin II receptor antagonists (Losartan, Irbesartan, Valsartan, Telmisartan and Eprosartan) and two of their metabolites (EXP 3174 and Candesartan M1) by means of experimental design methodologies. The aim of this study was to define rapidly experimental conditions under which the analytes can be resolved for quantitation. The effects of the buffer (pH, concentration and composition), the organic modifier and voltage were studied. Critical factors were identified in a screening design (fractional factorial design) and sequentially an optimization design (central composite design) was used to choose optimal conditions for separation. The most favorable electrophoretic conditions were found by setting the resolution at a threshold value (Rs < or = 1.5) and minimizing, if possible, analysis time. Successful results were obtained with a 50 mM potassium dihydrogen phosphate:boric acid (25:75 v/v) buffer at pH 5.5 in the presence of 5% methanol and application of a 25 kV voltage. Analysis time was 8 min in a conventional fused-silica capillary (50 cm effective length) in a normal cationic mode (anode at the inlet and cathode at the outlet) after hydrostatical sample injection for 30 s.     

Electronic and molecular structure of some substituted azomethines: A gas-phase u.v. photoelectron spectroscopic investigation

Four azomethinic molecules, three of which present a seven-member ring with two carbon atoms shared with an aromatic system, have been studied by gas-phase u.v. photoelectron spectroscopy with the aim of correlating their electronic and molecular structure. The analysis of the experimental findings, supported by quantum-mechanical calculation (EHT and HAM/3) on model molecules, showed that no appreciable interactions occur between the systems of the aromatic and of the seven-member ring, and that the electronic structure of these molecules depends critically on the geometry. The comparison with smaller parent molecules pointed out that the formation of the seven-member ring induces drastic changes in the electronic structure of the valence levels.