Pawel Serda

Effects of a Carane Derivative Local Anesthetic on a Phospholipid Bilayer Studied by Molecular Dynamics Simulation

Molecular dynamics (MD) simulations of two hydrated palmitoyloleoylphosphatidylcholine (POPC) bilayers each containing eight carane derivative (KP-23) local anesthetic (LA) molecules in neutral (POPC-LA) or protonated (POPC-LAH) forms were carried out to investigate the effect of KP-23 and its protonation on the bilayer. 3-ns trajectories were used for analyses. A pure POPC bilayer was employed as a reference system. In both POPC-LA and POPC-LAH systems a few KP-23 molecules intercalated into the bilayer and moved near the bilayer/water interface. They were located on the hydrophobic core side of the interface in the POPC-LA bilayer, but on the water phase side in the POPC-LAH bilayer. The order of the POPC chains was higher in the POPC-LA bilayer than in the pure POPC bilayer and was lower in the POPC-LAH bilayer. Interactions between polar groups of KP-23 and POPC or water were responsible for a lower hydration of POPC headgroups in POPC bilayers containing KP-23 than in the pure POPC bilayer. KP-23 molecules were found to form aggregates both in POPC-LA and POPC-LAH bilayers. Due to higher amphiphilicity of LAH, the LAH aggregate was more micelle-like and larger than the LA one. The results demonstrate the rapid timescales of the initial processes that take place at and near the bilayer interface as well as details of the atomic level interactions between local anesthetic and the lipid matrix of a cell membrane.

Conformation of eight-membered benzoannulated lactams by combined NMR and DFT studies.

The title compounds were synthesized, and their structure and conformational behavior in solution (NMR and DFT), in the gas phase (DFT), and, for some of them, in the solid state (X-ray) were investigated. The variable-temperature NMR spectra were employed to determine the conformational equilibria and the activation energy of the conformational changes of the eight-membered ring. The coalescence effects are assigned to racemization of the chiral ground-state conformation with a ring inversion barrier in the range of 38-100 kJ mol(-1) depending on the relative setting of the two strong conformational constraints: benzoannulation and the amide function. The second conformational process, interconversion between two different conformers, in the molecules of benzo[c]azocin-3-one, benzo[d]azocin-2-one, and benzo[d]azocin-4-one was observed. The natures of the conformers observed in solution were elucidated by analysis of experimental and calculated NMR data. The present results are discussed in conjunction with previous experimental and theoretical data on (Z,Z)-cyclooctadienes and their benzo analogues.

Stereochemistry of terpene derivatives. Part 3: Hydrolytic kinetic resolution as a convenient approach to chiral aminohydroxyiminocaranes with local anaesthetic activity

Abstract We have developed a stereoselective hydrolytic kinetic resolution process for diastereoisomeric mixtures of epoxyiminocarene intermediates in the presence of ( R , R )-(−)-(salen)Co(III)OAc catalyst, this was applied as the first step in the synthesis of novel chiral aminohydroxyiminocarane derivatives with local anaesthetic activity. The absolute configuration of the product was confirmed by X-ray crystallography.

Conformation in the solid state and in solution of (9R, 10R, 21R,-22R)-9, 10, 21, 22-Tetramethyl-9, 10, 21, 22-tetrahydro-7H, 12H,-19H, 24H-dinaphtho-[1, 8-f, g: 1′, 8′o, p][1.4.10.13]- tetraoxacyclooctadecin

Abstract The helical conformation of a new, optically active heterocyclic system 1 in solution has been determined from CD spectra by application of the exciton coupling theory. The molecule in the crystal adopts a conformation possessing an approximate 2-fold axis, with naphthyl groups nearly coplanar. Absolute configuration at four chiral centres as determined unequivocally by X-ray anomalous scattering method agrees with the known configuration of the starting (R,R)-2,3-butanediol. The conformations in the solid state and in solution are compared with those resulting from AM1 calculations.

Oxazepines and thiazepines, XX: CD-spectra of optically active 2-phenyl-2,3-dihydro-1,5-benzothiazepin-4(5H)-ones and related 3-phenylthio-3-phenyl-propionic acid derivatives, and X-ray diffraction of one phenylethylamide

SummaryThe absolute configuration of (−)-(1′R,3S)-4 has been determined by X-ray diffraction. The UV- and CD-spectra of the title compound8 and the intermediates for its synthesis are discussed. The stronger Cotton effects can be explained by application of the exciton theory to the observed CD-couplets. The CD of the lower homologue9 of known absolute configuration is in full agreement with that of homochirally analogue8.ZusammenfassungDie absolute Konfiguration von (−)-(1′R,3S)-4 wurde durch Röntgenbeugung bestimmt. UV- und CD-Spektren der Titelverbindung8 und der Zwischenprodukte für ihre Synthese werden diskutiert. Die stärkeren Cottoneffekte können durch Anwendung der Excitontheorie auf die erhaltenen CD-Couplets erklärt werden. Der CD des niederen Homologen9 bekannter absoluter Konfiguration steht in voller Übereinstimmung mit dem des homochiral analogen8.

Conformational analysis of benzoannulated nine-membered rings: Part 2. X-ray analysis and force-field calculations of 1,4,5,7-tetrahydro-3H-2,6-benzodithionin and its derivatives☆

Abstract The conformations of 1,4,5,7-tetrahydro-3H-2,6-benzodithionin-4-spiro-(1′-cyclobutane), -(3′-oxacylobutane) and -(cyclopentane) have been determined by X-ray analysis and are compared with previous low-temperature NMR results and with MM2 calculations. Significant changes in bond lengths and torsion angles of the nine-membered ring may be due to differences in intramolecular strain and molecular packing. X-ray data revealed conformational similarities in spite of different substituents. MM2 calculations have shown that the solid-state conformation is close to the most stable of the twelve minimum-energy conformations found for the parent compound without substituents.

A new way to quinazolines, perimidines and dibenzo[d,f][1,3]diazepines

A synthesis of quinazolines, perimidines and dibenzo[d,f][1,3]diazepines is described. The method involves rearrangements following cyclisation of 2-anilino-2-methoxy-3-oxo-N-phenylbutanethioamides with aromatic 1,3-and 1,4-diamines.

Assessing gastric toxicity of xanthone derivatives of anti-inflammatory activity using simulation and experimental approaches.

Xanthones are tricyclic compounds of natural or synthetic origin exhibiting a broad spectrum of therapeutic activities. Three synthetic xanthone derivatives (KS1, KS2, and KS3) with properties typical for nonsteroidal anti-inflammatory drugs (NSAID) were objects of the presented model study. NSAIDs are in common use however; several of them exhibit gastric toxicity predominantly resulting from their direct interactions with the outermost lipid layer of the gastric mucosa that impair its hydrophobic barrier property. Among the studied xanthones, gastric toxicity of only KS2 has been determined in previous pharmacological studies, and it is low. In this study, carried out using X-ray diffraction and computer simulation, a palmitoyloleoylphosphatidylcholine-cholesterol bilayer (POPC-Chol) was used as a model of a hydrophobic layer of lipids protecting gastric mucosa as POPC and Chol are the main lipids in human mucus. X-ray diffraction data were used to validate the computer model. The aim of the study was to assess potential gastric toxicity of the xanthones by analysing their atomic level interactions with lipids, ions, and water in the lipid bilayer and their effect on the bilayer physicochemical properties. The results show that xanthones have small effect on the bilayer properties except for its rigidity whereas their interactions with water, ions, and lipids depend on their protonation state and for a given state, are similar for all the xanthones. As gastric toxicity of KS2 is low, based on MD simulations one can predict that toxicity of KS1 and KS3 is also low.

The structure of marmesinin by powder and single-crystal diffraction methods

The crystal and molecular structure of marmesinin C 20 H 24 O 9 , a furocoumarine β-D-glucoside, an important biocontrolling compound isolated from the fruits of Ammi majus L. was determined from high-resolution powder diffraction using simulated annealing and, independently, from microcrystal diffraction. Both structural models were in good agreement. High-resolution powder diffraction patterns recorded with synchrotron radiation proved to be an efficient method for crystal structure determination of poorly-crystallizing natural products.

The synthesis of a new fused heterocyclic system : hexahydro[1,5 ]oxathiocino [2,3 -b ]pyrazine

A brief synthesis of the new heterocyclic system of 1,2,3,7,8,10a-hexahydro-6H,10H-[1,5]oxathiocino[2,3-b]pyrazin-10-imine was achieved, starting from piperazin-2-one derivatives and 1,3-dibromopropane.