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P3.4 Conformational analysis of three oligosaccharides related to the branch region of multivalent sLex glycans
Posters
P3.4 CONFORMATIONAL ANALYSIS OF THREE OLIGOSACCHARIDES RELATED TO THE BRANCH REGION OF MULTIVALENT sLex GLYCANS H Maaheimol, 0 Aitio*2, J Taskinenz & 0 Renkonent 1Inst. of Biotechnology and Div. of Biochemistry; 2Div. of Pharmaceutical Chemistry; POB 56, FIN-00014 Univ. of Helsinki Multivalent and thus branched oligosaccharides have proved to be excellent inhibitors of E- and L-selectin mediated lymphosyte extravasation. The best characterized binding epitopc to selectins is the sialyl Lewis x (sLex) tetrasaccharide sequence The NeuSAccr2-3Gal~1-4(Fucal-2)GlcNac. conformation of di- or multivalent sLex saccharides has not been reported and hence the factors behind their superiority as selectin ligands remain uncertain. As first step of conformational analysis of divalent sLex glycans analysis of solution conformations of three oligosaccharides by NMR and molecular dynamic simulations is presented. The saccharides have common branched structure GlcNA$l3(GlcNAcPl-6) GalBl-R, where R is either 4GlcNAcPl -OMe, 4GlcP 1-OMe or OMe.
P3.6 INFLUENCE OF PHYSICOCHEMISTRY ON THE BRAIN PENETRATION OF THE ‘TRIPTANS IN THERAT D O’Connor*, C Capel, W Rycroft, D Tattersall, B Sohal, M 1 Graham & D C Evans Merck Sharp & Dohme Res. Lab., Neuroscience Res. Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK Eletriptan, naratriptan, sumatriptan and zohnitriptan are existing or emerging antimigraine therapies which have proven agonist activity at 5HTru receptors and demonstrable efficacy in man. It has been claimed that zolmitriptan may access central 5HTrn receptors thus contributing to its enhanced efficacy whereas sumatriptan is reported to act in the periphery. In assessing the central mechanism, the varying extents to which these molecules penetrate into the brain is of interest. The relationship between the physicochemistry (Log D, pKa, plasma protein binding) of the ‘triptans and the extent and rate to which these compounds penetrate the brain has therefore been investigated.
s41
P3.5 ESTIMATION OF THE AQUEOUS SOLUBILITY OF DRUGS USING ARTIFICIAL NEURAL NETWORKS J Huuskonen*, M Sale & J Taskinen Div. of Pharmaceutical Chemistry, Dept. of Pharmacy, POB 56, FIN-00014 Univ. of Helsinki A QSPR study was conducted for a diverse set of drugs to estimate their aqueous solubilities. Electrotopological state (E-state) indices which encode electronic and topological information for each skeletal atom or atom group in a molecule (1) were used as molecular descriptors in artificial neural network (ANN). Published aqueous solubilities were collected for 209 compounds representing neutral and ionizable, acidic and basic drugs from various structural classes. Solubilities were expressed as log unit (mol/l) and varied from -5.6 to 0.5. The data set was divided in a training set of 153 compounds and in a randomly chosen test set of 56 compounds. The statistics were r2 0.91 and s 0.40 for the fitting of the training set, and r’ 0.88 and s 0.49 for the prediction of the test set using 34-3- 1 ANN architecture.
P3.7 STRUCTURAL CHARACTERIZATION OF EAND Z-ENTACAPONE GLUCURONIDES L Luukkanenl, J Taskinenl, I Kilpelainen2 & P Ottoila3 1Dept. of Pharmacy, Div. of Pharmaceutical Chemistry; 2Inst. of Biotechn., NMR-laboratory; FIN-00014 Univ. of Helsinki; 3Orion Co., Orion Pharma, POB 65, FIN-02101 Espoo Entacapone, a potent inhibitor of catechol-O-metbyltransferase (COMT, EC 2.1.1.6) is in clinical studies for the treatment of Parkinsons disease. In physiological environment entacapone is partly isomer&d to its Z-isomer which is also a potent COMT inhibitor. The main biotransformation reaction for entacapone and its Z-isomer is glucuronidation, over 80% of oral dose is excreted as glucuronides in human urine. Both isomers have two possible glucuronidation sites, 3- and 4-hydroxyl groups. Entacapone and Z-entacapone glucuronides were prepared using rat liver microsomes as catalyst and their structures were confirmed based on high resolution negative ion FAB-MS, ’H and I3C NMR spectral data. ’H and l3 C NMR resonances were fully assigned based on DQF COSY, HMQC and HMBC spectra. The glucuronides were also characterized by UVNIS, IR and fluorescence spectra. The glucuronidation of entacapone and its Z-isomer was highly regioselective producing only 30-glucuronides.
P3.4 CONFORMATIONAL ANALYSIS OF THREE OLIGOSACCHARIDES RELATED TO THE BRANCH REGION OF MULTIVALENT sLex GLYCANS H Maaheimol, 0 Aitio*2, J Taskinenz & 0 Renkonent 1Inst. of Biotechnology and Div. of Biochemistry; 2Div. of Pharmaceutical Chemistry; POB 56, FIN-00014 Univ. of Helsinki Multivalent and thus branched oligosaccharides have proved to be excellent inhibitors of E- and L-selectin mediated lymphosyte extravasation. The best characterized binding epitopc to selectins is the sialyl Lewis x (sLex) tetrasaccharide sequence The NeuSAccr2-3Gal~1-4(Fucal-2)GlcNac. conformation of di- or multivalent sLex saccharides has not been reported and hence the factors behind their superiority as selectin ligands remain uncertain. As first step of conformational analysis of divalent sLex glycans analysis of solution conformations of three oligosaccharides by NMR and molecular dynamic simulations is presented. The saccharides have common branched structure GlcNA$l3(GlcNAcPl-6) GalBl-R, where R is either 4GlcNAcPl -OMe, 4GlcP 1-OMe or OMe.
P3.6 INFLUENCE OF PHYSICOCHEMISTRY ON THE BRAIN PENETRATION OF THE ‘TRIPTANS IN THERAT D O’Connor*, C Capel, W Rycroft, D Tattersall, B Sohal, M 1 Graham & D C Evans Merck Sharp & Dohme Res. Lab., Neuroscience Res. Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK Eletriptan, naratriptan, sumatriptan and zohnitriptan are existing or emerging antimigraine therapies which have proven agonist activity at 5HTru receptors and demonstrable efficacy in man. It has been claimed that zolmitriptan may access central 5HTrn receptors thus contributing to its enhanced efficacy whereas sumatriptan is reported to act in the periphery. In assessing the central mechanism, the varying extents to which these molecules penetrate into the brain is of interest. The relationship between the physicochemistry (Log D, pKa, plasma protein binding) of the ‘triptans and the extent and rate to which these compounds penetrate the brain has therefore been investigated.
s41
P3.5 ESTIMATION OF THE AQUEOUS SOLUBILITY OF DRUGS USING ARTIFICIAL NEURAL NETWORKS J Huuskonen*, M Sale & J Taskinen Div. of Pharmaceutical Chemistry, Dept. of Pharmacy, POB 56, FIN-00014 Univ. of Helsinki A QSPR study was conducted for a diverse set of drugs to estimate their aqueous solubilities. Electrotopological state (E-state) indices which encode electronic and topological information for each skeletal atom or atom group in a molecule (1) were used as molecular descriptors in artificial neural network (ANN). Published aqueous solubilities were collected for 209 compounds representing neutral and ionizable, acidic and basic drugs from various structural classes. Solubilities were expressed as log unit (mol/l) and varied from -5.6 to 0.5. The data set was divided in a training set of 153 compounds and in a randomly chosen test set of 56 compounds. The statistics were r2 0.91 and s 0.40 for the fitting of the training set, and r’ 0.88 and s 0.49 for the prediction of the test set using 34-3- 1 ANN architecture.
P3.7 STRUCTURAL CHARACTERIZATION OF EAND Z-ENTACAPONE GLUCURONIDES L Luukkanenl, J Taskinenl, I Kilpelainen2 & P Ottoila3 1Dept. of Pharmacy, Div. of Pharmaceutical Chemistry; 2Inst. of Biotechn., NMR-laboratory; FIN-00014 Univ. of Helsinki; 3Orion Co., Orion Pharma, POB 65, FIN-02101 Espoo Entacapone, a potent inhibitor of catechol-O-metbyltransferase (COMT, EC 2.1.1.6) is in clinical studies for the treatment of Parkinsons disease. In physiological environment entacapone is partly isomer&d to its Z-isomer which is also a potent COMT inhibitor. The main biotransformation reaction for entacapone and its Z-isomer is glucuronidation, over 80% of oral dose is excreted as glucuronides in human urine. Both isomers have two possible glucuronidation sites, 3- and 4-hydroxyl groups. Entacapone and Z-entacapone glucuronides were prepared using rat liver microsomes as catalyst and their structures were confirmed based on high resolution negative ion FAB-MS, ’H and I3C NMR spectral data. ’H and l3 C NMR resonances were fully assigned based on DQF COSY, HMQC and HMBC spectra. The glucuronides were also characterized by UVNIS, IR and fluorescence spectra. The glucuronidation of entacapone and its Z-isomer was highly regioselective producing only 30-glucuronides.