Unexpected Heterocyclization of Electrophilic Alkenes by Tetranitromethane in the Presence of Triethylamine. Synthesis of 5-Nitroisoxazoles.

A novel reaction of tetranitromethane with electrophilic alkenes in the presence of triethylamine affording substituted 5-nitroisoxazoles is described. Triethylamine reacts with tetranitromethane to generate N-nitrotriethylammonium and trinitromethanide. This process provides the heterocyclization of electrophilic alkenes. A variety of α,ß-unsaturated aldehydes, ketones, esters, amides, phosphonates, nitro, and sulfur compounds was involved in the heterocyclization reaction, and a wide range of functionalized 5-nitroisoxazoles was obtained in good to high yields. The scope and limitations of the reaction and the mechanistic proposal are discussed.

Quinone reductase 2 and antidepressant effect of melatonin derivatives.

Melatonin and its immediate precursor, N-acetylserotonin (NAS), exert antidepressant effects in experimental models and clinical studies. We reported that melatonin and NAS decreased immobility time (an indicator of antidepressant activity) in the mouse tail suspension test. Melatonin type 3 receptor (MT3) was identified as the same protein as quinone reductase 2 (QR2) detoxifying and antioxidant enzyme. To further elucidate the role of QR2/MT3 in antidepressant action of NAS and melatonin, we studied the effect of QR2/MT3 agonist and antagonist in a tail suspension test. QR2/MT3 agonist 5-MCA-NAT decreased, while the QR2/MT3 antagonist prazosin increased the duration of immobility in the tail suspension test in a dose-dependent manner. Prazosin, in a dose that did not affect the duration of immobility, attenuated the antidepressant-like effect of NAS, melatonin, and typical tricyclic antidepressant, amitriptyline, in the tail suspension test. Our results suggest that the modulation of QR2/MT3 might contribute to mechanism(s) of antidepressant effect. New antidepressants might be searched among the agonists of QR2/MT3.

Unexpected heterocyclization of electrophilic alkenes by tetranitromethane in the presence of triethylamine. Synthesis of 3-nitroisoxazoles.

Novel reaction of tetranitromethane (TNM) with electrophilic alkenes in the presence of triethylamine yielding substituted 3-nitroisoxazoles was found and studied. Triethylamine increases the reactivity of TNM toward electrophilic alkenes promoting their heterocyclization, and the reactions proceed in an unusual way. A variety of alpha,beta-unsaturated aldehydes, ketones, esters, amides, phosphonates, and nitro and sulfur compounds was involved in the heterocyclization reaction, and a wide range of functionalized 3-nitroisoxazoles was obtained in good to high yields. The scope and limitations of the reaction and the mechanistic aspects are discussed.

Neural networks in building QSAR models.

This chapter critically reviews some of the important methods being used for building quantitative structure-activity relationship (QSAR) models using the artificial neural networks (ANNs). It attends predominantly to the use of multilayer ANNs in the regression analysis of structure-activity data. The highlighted topics cover the approximating ability of ANNs, the interpretability of the resulting models, the issues of generalization and memorization, the problems of overfitting and overtraining, the learning dynamics, regularization, and the use of neural network ensembles. The next part of the chapter focuses attention on the use of descriptors. It reviews different descriptor selection and preprocessing techniques; considers the use of the substituent, substructural, and superstructural descriptors in building common QSAR models; the use of molecular field descriptors in three-dimensional QSAR studies; along with the prospects of "direct" graph-based QSAR analysis. The chapter starts with a short historical survey of the main milestones in this area.

Kirchhoff atomic charges fitted to multipole moments: implementation for a virtual screening system.

The Kirchhoff charge model is a viable method of generating inexpensive and electrostatically reasonable atomic charges for molecular mechanical force fields. The charging method uses a computationally fast algorithm based on the principle of electronegativity relaxation. Parameters of the method, orbital electronegativities and hardnesses, are fitted to reproduce reference, ab initio calculated dipole and quadrupole moments of a representative training set of neutral and charged organic molecules covering most medicinal chemistry relevant bonding situations. Transferability and accuracy of the derived parameters are confirmed on an external test set. Comparisons to other charge models are made. Implementation of the new Kirchhoff charges into a virtual screening engine is elucidated.

Generation of molecular graphs for QSAR studies: an approach based on supergraphs.

A new algorithm for generation of substituted derivatives of a given structure and its software implementation are described. The program has deterministic and stochastic generation modes and efficiently supports various types of structural constraints. The problem of exhaustive and irredundant generation is discussed, and a new algorithm of the complete rejection of isomorphic molecular graphs is proposed. The main application of the generator is QSAR studies; however, applications in combinatorial chemistry are also possible.

Computer aided comparative analysis of the binding modes of the adenosine receptor agonists for all known subtypes of adenosine receptors.

Molecular models of all known subtypes (A1, A2A, A2B, and A3) of the human adenosine receptors were built in homology with bovine rhodopsin. These models include the transmembrane domain as well as all extracellular and intracellular hydrophilic loops and terminal domains. The molecular docking of adenosine and 46 selected derivatives was performed for each receptor subtype. A binding mode common for all studied agonists was proposed, and possible explanations for differences in the ligand activities were suggested.

Molecular modeling and molecular dynamics simulation of the human A2B adenosine receptor. The study of the possible binding modes of the A2B receptor antagonists.

A molecular model of the human A(2B) adenosine receptor containing seven transmembrane alpha helices connected by three intracellular and three extracellular hydrophilic loops had been constructed. A molecular docking of seven structurally diverse xanthine antagonists of the A(2B) receptor was performed, and the differences in their binding modes were investigated. The 1 ns molecular dynamics (MD) simulations of several obtained ligand-receptor complexes inserted into the phospholipid bilayer were carried out. The conformational changes of the A(2B) receptor occurring during MD simulations were explored, and the stable binding modes of the studied antagonists were determined. According to the models presented in this work, the involvement of the His251, Asn282, Ser92, Thr89, and some aromatic residues in ligand recognition was determined. The obtained binding modes of the A(2B) antagonists demonstrate good agreement with the site-directed mutagenesis data.

Theoretical scales of hydrogen bond acidity and basicity for application in QSAR/QSPR studies and drug design. Partitioning of aliphatic compounds.

Phenomenological analysis of existing hydrogen bond (HB) donor and acceptor scales and apparent physical considerations have enabled the establishment of new quantitative scales of hydrogen bond basicity and acidity. Chemical structures represented by molecular graphs and the orbital electronegativities of Hinze and Jaffe are utilized as an input data. The scales obtained correlate well with several experimental solvent polarity scales such as and, pK(HB), and E(T)(30). To demonstrate the applicability of the new quantities, we have applied them to seven equilibrium partitioning data sets: octanol-water, hexadecane-water, chloroform-water, gas-water, gas-octanol, gas-hexadecane, and gas-chloroform partition coefficients. The hydrogen bond descriptors when supplemented by a cavity-forming term and a dipolarity term show high performance in correlations of the partition coefficients of aliphatic compounds. These new HB descriptors can be used in studying hydrogen bonding and fluid phase equilibria as well as scoring functions in ligand docking and descriptors in ADME evaluations.

Selectivity fields: comparative molecular field analysis (CoMFA) of the glycine/NMDA and AMPA receptors.

An approach for evaluation of binding selectivity was suggested and exemplified using glycine/NMDA and AMPA receptors. For analyzing the pairwise selectivity, we propose to use the difference between biological activities (expressed as -log Ki) of ligands with respect to different receptor subtypes as a dependent variable for building comparative molecular field analysis (CoMFA) models. The resulting fields (which will be referred to as the "selectivity fields") indicate the ways of increasing selectivity of binding, inhibition, etc. As an example, CoMFA of a set of pyrazolo[1,5-c]quinazolines and triazolo[1,5-c]quinazolines was used for considering the binding selectivity with respect to glycine/NMDA and AMPA receptors. In addition, the mapping of these fields onto the molecular models of the corresponding receptors makes it possible to reveal the reasons for experimentally observed selectivity as well as to suggest additional ways of increasing selectivity.

CoMFA and homology-based models of the glycine binding site of N-methyl-d-aspartate receptor.

Homology modeling was used to build 3D models of the N-methyl-d-aspartate (NMDA) receptor glycine binding site on the basis of an X-ray structure of the water-soluble AMPA-sensitive receptor. The docking of agonists and antagonists to these models was used to reveal binding modes of ligands and to explain known structure-activity relationships. Two types of quantitative models, 3D-QSAR/CoMFA and a regression model based on docking energies, were built for antagonists (derivatives of 4-hydroxy-2-quinolone, quinoxaline-2,3-dione, and related compounds). The CoMFA steric and electrostatic maps were superimposed on the homology-based model, and a close correspondence was marked. The derived computational models have permitted the evaluation of the structural features crucial for high glycine binding site affinity and are important for the design of new ligands.

Preparation and chemistry of phosphoranyl-derived iodanes.

The preparation and chemistry of novel phosphoranyl-derived lambda(3)-iodanes is reported. The phosphoranyl-derived phenyliodonium sulfonates were prepared in good yields by the reaction of stabilized phosphonium ylides [1-triphenylphosphoranylidene-2-propanone, methyl(triphenylphosphoranylidene)acetate, (triphenylphosphoranylidene)acetaldehyde, and (triphenylphosphoranylidene)acetonitrile] with the pyridinium complex of iodobenzene ditriflate or with [hydroxy(tosyloxy)iodo]benzene under mild conditions. These compounds represent a potentially useful class of reagents that combine in one molecule synthetic advantages of a phosphonium ylide and an iodonium salt. Specifically, phosphorane-derived phenyliodonium tosylates can react with soft nucleophiles, such as iodide, bromide, benzenesulfinate, and thiophenolate anions, with a selective formation of the respective alpha-functionalized phosphonium ylides, which can be further converted to alkenes by the Wittig reaction with benzaldehyde. The phosphoranyl-derived benziodoxoles can be prepared by the reaction of 1-acetoxybenziodoxole with stabilized phosphonium ylides. An unusual ligand exchange on the iodine(III) center resulting in the substitution of a carbon ligand with an oxygen ligand was observed in the reaction of these compounds with strong acids.

Fragmental approach in QSPR.

Methodological problems of using fragmental descriptors for construction of QSAR/QSPR equations are considered, and the main achievements in this field are summarized and discussed. If a structure-property data set is sufficiently large to allow building statistically significant models, then any topological index can be replaced with a set of fragmental descriptors. Several examples of using the fragmental approach for predicting retention indices and the normal boiling points of organic compounds are considered. Advantages of using fragmental descriptors, namely a "transparency" and interpretability of QSAR/QSPR models, are exemplified.

Structural basis for understanding structure-activity relationships for the glutamate binding site of the NMDA receptor.

We present new homology-based models of the glutamate binding site (in closed and open forms) of the NMDA receptor NR2B subunit derived from X-ray structures of the water soluble AMPA sensitive glutamate receptor. The models were used for revealing binding modes of agonists and competitive antagonists, as well as for rationalizing known experimental facts concerning structure-activity relationships: (i) the switching between the agonist and the antagonist modes of action upon lengthening the chain between the distal acidic group and the amino acid moiety, (ii) the preference for the methyl group attached to the alpha-amino group of ligands, (iii) the preference for the D-configuration of agonists and antagonists, and (iv) the existence of "superacidic" agonists.