Hydration of GABA and of the GABA·ZN2+ complex: A Monte Carlo simulation study

With empirical and theoretical atom–atom potentials the GABA·nH₂O, n = 25, 192 and GABA·Zn²⁺ · nH₂O, n = 25, 50, 100 complexes are simulated at 298.15 K by the Monte Carlo technique. The results show that the carboxyl group of GABA coordinates six water molecules. Two geometries of the GABA·Zn²⁺ complex, corresponding to the “direct” and “through-water” interaction of Zn²⁺ with the carboxyl group of GABA were found. For the latter interaction a GABA·Zn²⁺ · 6H₂O complex was found whereas the hydration of the former interaction leads to a GABA·Zn²⁺ · 5H₂O complex. Here the carboxyl group of GABA displaces only one water molecule in the first hydration shell of Zn²⁺. Energetically the “direct” and “through-water” geometries seem to be competitive, the former being slightly favored.     

Quantum Riemann surfaces I. The unit disc

We construct a non-commutative ^*-algebra which is a quantum deformation of the algebra of continuous functions on the closed unit disc . is generated by the Toeplitz operators on a suitable Hilbert space of holomorphic functions onU.Supported in part by the National Science Foundation under grant DMS/PHY 88-16214     

Calculations of the electrostatic free energy contributions to the binding free energy of sulfonamides to carbonic anhydrase

The interactions between biologically important enzymes and drugs are of great interest. In order to address some aspects of these interactions we have initiated a program to investigate enzymedrug interactions. Specifically, the interactions between one of the isozymes of carbonic anhydrase and a family of drugs known as sulfonamides have been studied using computational methods. In particular the electrostatic free energy of binding of carbonic anhydrase II with acetazolamide, methazolamide,p-chlorobenzenesulfonamide,p-aminobenzenesulfonamide and three new compounds (MK1, MK2, and MK3) has been computed using finite-difference Poisson-Boltzmann (FDPB) [1] method and the semimacroscopic version [2, 3] of the protein dipole Langevin dipole (PDLD) method [4]. Both methods, FDPB and PDLD, give similar results for the electrostatic free energy of binding even though different charges and different treatments were used for the protein. The calculated electrostatic binding free energies are in reasonable agreement with the experimental data. The potential and the limitation of electrostatic models for studies of binding energies are discussed.     

Mass spectrometric behaviour of carboxylated polyethylene glycols and carboxylated octylphenol ethoxylates

Mass spectrometric behaviour of mono- and di-carboxylated polyethylene glycols (PEGCs and CPEGCs) and carboxylated octylphenol ethoxylates (OPECs) are discussed. The tendency for ionisation (deprotonation, protonation and cationisation by alkali metal cations) of carboxylated PEGs was compared with that of non-carboxylated correspondents by using both secondary ion mass spectrometry (SIMS) and electrospray ionisation (ESI). The fragmentation of the PEGCs and CPEGCs is discussed and also compared with their neutral correspondents, PEGs. The B/E mass spectra were recorded, using secondary ion mass spectrometry as a method for generation, for deprotonated and protonated molecules and molecules cationised by alkali metal cations. The fragmentation behaviour of PEGs is found to be different from that of CPEGCs, The presence of carboxylic groups may be confirmed not only by the determination of molecular weights of the ethoxylates studied, but also on the basis of the fragment ions formed. The metastable decomposition of the [OPEC-H](-) ions proceed through the cleavage of the bond between the octylphenol moiety and the ethoxylene chain leading to the octylphenoxy anions. It permits determination of the mass of the hydrophobic moiety of the studied carboxylated alkylphenol ethoxylate. ESI mass spectra recorded in the negative ion mode were found to be more suitable for the determination of the average molecular weight of carboxylated ethoxylates than SI mass spectra.     

Orthorhombic polymorphs of two trans‐4‐aminoazoxybenzenes

The two isomeric compounds 4‐amino‐ONN‐azoxy­benzene [or 1‐(4‐amino­phenyl)‐2‐phenyl­diazene 2‐oxide], i.e. the α isomer, and 4‐amino‐NNO‐azoxy­benzene [or 2‐(4‐amino­phenyl)‐1‐phenyl­diazene 2‐oxide], i.e. the β isomer, both C₁₂H₁₁N₃O, crystallized from a polar solvent in orthorhombic space groups, and their crystal and molecular structures have been determined using X‐ray diffraction. There are no significant differences in the bond lengths and valence angles in the two isomers, in comparison with their monoclinic polymorphs. However, the conformations of the mol­ecules are different due to rotation along the Ar—N bonds. In the α isomer, the benzene rings are twisted by 31.5 (2) and 14.4 (2)° towards the plane of the azoxy group; the torsion angles along the Ar—N bond in the β isomer are 24.3 (3) and 23.5 (3)°. Quantum‐mechanical calculations indicate that planar conformations are energetically favourable for both isomers. The N—H?O hydrogen bonds observed in both networks may be responsible for the deformation of these flexible mol­ecules.     

Thermolytic carbonates for potential 5'-hydroxyl protection of deoxyribonucleosides

Thermolytic groups structurally related to well-studied heat-sensitive phosphate/thiophosphate protecting groups have been evaluated for 5'-hydroxyl protection of deoxyribonucleosides as carbonates and for potential use in solid-phase oligonucleotide synthesis. The spatial arrangement of selected functional groups forming an asymmetric nucleosidic 5'-O-carbonic acid ester has been designed to enable heat-induced cyclodecarbonation reactions, which would result in the release of carbon dioxide and the generation of a nucleosidic 5'-hydroxyl group. The nucleosidic 5'-O-carbonates 3-8, 10-15, and 19-21 were prepared and were isolated in yields ranging from 45 to 83%. Thermolytic deprotection of these carbonates is preferably performed in aqueous organic solvent at 90 degrees C under near neutral conditions. The rates of carbonate deprotection are dependent on the nucleophilicity of the functional group involved in the postulated cyclodecarbonation reaction and on solvent polarity. Deprotection kinetics increase according to the following order: 4 < 5 < 10 < 6 < 12 < 7 < 13 < 8 < 14 congruent with 19-21 and CCl4 < dioxane < MeCN < t-BuOH < MeCN:phosphate buffer (3:1 v/v, pH 7.0) < EtOH:phosphate buffer (1:1 v/v, pH 7.0). Complete thermolytic deprotection of carbonates 7, 8, 13, and 14 is achieved within 20 min to 2 h under optimal conditions in phosphate buffer-MeCN. The 2-(2-pyridyl)amino-1-phenylethyl and 2-[N-methyl-N-(2-pyridyl)]aminoethyl groups are particularly promising for 5'-hydroxyl protection of deoxyribonucleosides as thermolytic carbonates.     

Origins of the activity of PAL and LAP enzyme inhibitors: toward ab initio binding affinity prediction

Interaction energies of phenylalanine ammonia-lyase (PAL) active site residues with a series of PAL inhibitors have been partitioned into electrostatic, exchange, delocalization, and correlation components and compared with analogous results obtained previously for leucine aminopeptidase (LAP). In the latter metalloenzyme, either of the two charged residues controls entirely relative inhibitor binding energies, while at least four residues are required to determine ligand relative stabilization in neutral PAL. Significant correlation with experimental inhibitory activity was found between the stabilization energy at gradually decreasing levels of theory (MP2, SCF) down to the first-order Heitler-London term. Contrary to the LAP case, where the electrostatic term was sufficient to reproduce experimentally observed trends, in the case of PAL, exchange repulsion effects also have to be considered. Computational protocol presented herein constitutes a promising way to incorporate the first principle calculation's accuracy into the process of rational binding affinity prediction, revealing the physical nature of the interactions, where successive approximations can be introduced in a systematic and justifiable manner.     

Computer-assisted studies of molecular structure-biological activity relationships

Computer-assisted methods can be used to investigate the relationships between the molecular structures of compounds and their biological activity. A number of approaches have been reported in the literature, including correlations of activity with substituent constants, conformational analysis and display, quantum mechanical methods, and methods relying on discriminant development and pattern-recognition techniques. Application areas for this technology include drug design, agricultural chemical design, and studies of chemical toxicity and genetic toxicity (mutagenic or carcinogenic potential). These structure-activity methods are introduced, and citations are given. Several current structure-activity relationship (SAR) studies using pattern recognition are presented as examples of typical projects that are feasible with this approach. These include the investigation of a set of 122 antiinflammatory steroids, a study of 153 retinoids for cancer prevention, and a study of chemicals that have been tested in a sister chromatid exchange mutagen screen.     

Can triorganoboroxins exist in a “monomeric” R---B=O form? MNDO calculations and ebulliometric molecular weight determination

MNDO calculations were made for triethylboroxin (EtBO)₃ and triphenylboroxin (PhBO)₃ using both X-ray determined and optimized geometry of these molecules. The results were compared with hypothetical “monomeric” molecules R---B=O. Calculated energies of trimerization are about −200 kJ mol⁻¹ for both compounds and confirm the much higher stability of the “trimer”. Ebulliometric determination of molecular weight of triphenylboroxin in 2-pentanone confirms its trimeric character.     

Dispersive solid-phase extraction for the determination of sulfonamides in chicken muscle by liquid chromatography

A new, fast and low-cost sample preparation for the determination of sulfonamide (SA) residues in chicken muscle by LC technique has been developed. The procedure involves single extraction of sample with acetonitrile, followed by a rapid clean-up and was called "dispersive solid-phase extraction" (dispersive SPE). Using dispersive SPE 25 mg of octadecyl sorbent was added to 1 ml of acetonitrile extract, mixed and centrifuged. The acetonitrile layer was evaporated and residue was dissolved in acetate buffer (pH 3.5). Analysed compounds were detected by fluorescence detector after pre-column derivatization with fluorescamine. The separation of analytes was performed with gradient elution with mobile phase methanol: 2% acetic acid and RP-LC analytical column. The whole procedure was evaluated for six sulfonamides (sulfadiazine, sulfamerazine, sulfamethazine, sulfametoxypirydazine, sulfametoxazole and sulfadimetoxine) according to the European Commission Decision 2002/657/EC. Specificity, decision limit (CCalpha), detection capacity (CCbeta), trueness and precision were determined during validation process. The dispersive SPE with octadecyl sorbent was found suitable for sample preparation before sulfonamide determination in chicken muscle. As it was found the most of endogenous matrix components were removed and the analytes were isolated from spiked samples with recoveries above 90%. The used analytical conditions allow to successively separate all the tested sulfonamides with the limit of detection at the level of 1-5 microg/kg. The method is simple, rapid and more effective than conventional methods.