Alexey V. Eliseev

Target-induced formation of neuraminidase inhibitors from in vitro virtual combinatorial libraries

Neuraminidase, a key enzyme responsible for influenza virus propagation, has been used as a template for selective synthesis of small subsets of its own inhibitors from theoretically highly diverse dynamic combinatorial libraries. We show that the library building blocks, aldehydes and amines, form significant amounts of the library components resulting from their coupling by reductive amination only in the presence of the enzyme. The target amplifies the best hits at least 120-fold. The dynamic libraries synthesized and screened in such an in vitro virtual mode form the components that possess high inhibitory activity, as confirmed by enzyme assays with independently synthesized individual compounds.

Contributions of electrostatic and hydrophobic interactions to the host–guest complexation of pyrocatecholate anions with cationic cyclodextrins

Binding constants of a series of 4-substituted pyrocatechols (1,2-dihydroxybenzenes) to four 6-deoxy, 6-amino derivatives of β-cyclodextrin have been determined from the kinetics of their auto-oxidation at pH 10.0. In several cases, the binding constants at pH 6.0 have been determined by spectrophotometry. Cationic forms of amino derivatives of β-cyclodextrin bind pyrocatecholate anions with equilibrium constants up to 105 dm3 mol–1. The electrostatic and hydrophobic interactions were shown to contribute additively to the free energy of the host–guest complexation.

Cyclopalladated o-carboranes. Palladium transfer from cyclopalladated N,N-dimethylbenzylamines, 1C-diphenylphosphino-o-carborane and η3-allyls in carboxylic acid solvents☆

1-Diphenylphosphinomethyl-o-carborane, o-HCB10H1OCCH2PPh2 (DPMC), reacts with Na2PdCl4 (methanol) or PdCl2(PhCN)2 (benzene) to give the “bis-adduct” trans- [PdCl2(DPMC)2], which on thermolysis in n-propanol transforms into the five-membered PdPCCB palladacycle, di-μ-chlorobis[(1-diphenylphosphinomethyl-o-carboranyl-B,P)palladium(II)] (IIa), as a mixture of B(3) and B(4) metallated isomers according to 1H and 31P NMR. If the internal palladation is performed in the presence of LiBr or NaI, the corresponding bromo- or iodo-bridged dimers are obtained. Complex IIa can also be prepared via ligand exchange in carboxylic acid solvents. In particular, palladium(II) migrates from cyclopalladated chloro-bridged N,N-dimethylbenzylamine or 1C-diphenylphosphino-o-carborane, i.e. from complexes with C,N-five- and B,P-four-membered palladacycles, respectively, to 1-diphenylphosphinomethyl-o -carborane yielding IIa. Migration of palladium(II) is also observed from the compounds with great stability towards acetic acid, namely the [PdCl(η3-allyl)]2 dimers. No such processes except with this particular ligand were found in the case of palladium(II) allyls and other entering ligands (azobenzene, 2-phenylpyridine, α-methylstyrene). The exchange processes described clearly show that complex IIa is characterized by a remarkable thermodynamic stability in acetic acid which accounts for the course of many exchange reactions.

Electrostatic molecular recognition in rigid frameworks

Complexation of six organic dianionic hosts (1cc–2tt) with methylguanidinium, tetramethylammonium and ammonium salts in various protic solvents has been studied by NMR spectroscopy. Stability of the 1∶1 electrostatic complexes is shown to decrease with increasing distances between the carboxylate groups in the host compounds. Spectroscopic data and the results of molecular modelling support non-symmetrical structures of some of the complexes which contain one tight and one loose ion pair. The difference between the contributions of the tight and loose ion pair formation into the binding free energy can be predicted by the Fuoss theory of ion pairing on the basis of interionic distances calculated by molecular modelling.