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See detailA PREFERENTIAL FOLDED CONFORMATION OF SOME BIS-(8-ISOPROPYL-ISOQUINOLINIUM) DERIVATIVES EXPLAINS STEREOSELECTIVE REDUCTION BY SODIUM BOROHYDRIDE
Dilly, Sébastien ULg; Badarau, Eduard; Dufour, Fabien et al

Poster (2014, June 05)

Small conductance Ca2+-activated K+ (SK) channels play a role in modulating the firing rate and the firing pattern of neurons [Waroux, Eur J Neurosci, 2005, 22, 3111]. A blockade of these targets could be ... [more ▼]

Small conductance Ca2+-activated K+ (SK) channels play a role in modulating the firing rate and the firing pattern of neurons [Waroux, Eur J Neurosci, 2005, 22, 3111]. A blockade of these targets could be useful for the treatment of cognitive dysfunction, neuronal hyperexcitability or dopamine related disorders [Liégeois, Curr Med Chem, 2003, 10, 625]. At the peripheral level, the inhibition of these channels was demonstrated to prevent and terminate atrial fibrillation [Diness, Circ Arrhythm Electrophysiol, 2010, 3, 380]. Moreover, SK channels might represent potential targets for a new class of anticancer agents due to their involvement in breast cancer cell migration [Potier, Mol Cancer Ther, 2006, 5, 2946]. So far, available blockers are not suitable CNS pharmacological tools being either peptides or small molecules with permanent positive charges [Liégeois, Curr Med Chem, 2003, 10, 625; Graulich, J Med Chem, 2007, 50, 5070; Badarau, Bioorg Med Chem Lett, 2011, 21, 6756]. Therefore, symmetrical bis-isoquinolinium compounds have subsequently been transformed to 1,2,3,4-tetrahydroisoquinoline analogues by using sodium borohydride leading to a diastereoisomeric mixture (figure 1) in order to obtain potential CNS-penetrating agents [Graulich, Bioorg Med Chem Lett, 2008, 18, 3440; Neny, Proceedings of the 12th International Conference on In Vivo Methods, Vancouver, Canada, 2008, 267; Koulchitsky, Acta Physiologica, 2009, 195, 670]. Resolution of these mixtures and characterization of the corresponding stereoisomers [Wouters, Eur J Med Chem, 2010, 45, 3240] are necessary before further biological evaluation. In a series of 8- isopropyl analogues, chiral resolution failed for the analogues with propyl and m-xylyl linkers since two and one peaks, respectively, were detected [Nistor, J Pharm Biomed Anal, 2013, 74, 273]. Could these results be explained by an ineffective resolution or would another phenomenon be involved? Further analysis using chiral chromatography, mass spectroscopy and circular dichroism of a sample of the propyl analogue revealed that it is a racemic mixture. X-ray cristallography and conformational analysis indicated a folded conformation of the propyl and m-xylyl analogues (figure 2) responsible for a stereoselective attack of the borohydride reagent during the reduction step. Additional 1H-NMR investigations support structural features detected by theoretical analysis. [less ▲]

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See detailStructural analysis of some bis-(8-isopropyl-isoquinolinium) derivatives reveals a preferential folded conformation leading to a stereoselective attack by sodium borohydride
Dilly, Sébastien ULg; Badarau, Eduard; Dufour, Fabien et al

in Journal of Molecular Structure (2014)

Reduction of symmetrical bis-isoquinolinium derivatives with sodium borohydride generates normally a mixture of three 1,2,3,4-tetrahydroisoquinoline stereoisomers. In a series of 8- isopropyl analogues ... [more ▼]

Reduction of symmetrical bis-isoquinolinium derivatives with sodium borohydride generates normally a mixture of three 1,2,3,4-tetrahydroisoquinoline stereoisomers. In a series of 8- isopropyl analogues, chiral resolution failed for the analogues with propyl and m-xylyl linkers since two and one peaks respectively were detected by HPLC. Further analysis by MS and CD of both peaks of the propyl analogue revealed that each peak corresponds to an enantiomer. Conformational analysis and X-ray cristallography showed a folded conformation of the propyl and m-xylyl analogues responsible for the observed stereoselectivity following the reduction step. Additional 1H NMR investigations confirm structural features detected by theoretical analysis. [less ▲]

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See detailImplementation of a Design Space Approach for Enantiomeric Separations in Polar Organic Solvent Chromatography
Nistor, Iolanda; Lebrun, Pierre ULg; Ceccato, Attilio ULg et al

in Journal of Pharmaceutical & Biomedical Analysis (2013), 74

This paper focuses on implementing a Design Space approach and on the critical process parameters (CPPs) to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9 and Q10 ... [more ▼]

This paper focuses on implementing a Design Space approach and on the critical process parameters (CPPs) to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9 and Q10 to analytical method development and optimization for three chiral compounds developed as modulators of small conductance calcium-activated potassium (SK) channels. In this sense, an HPLC method using a polysaccharide-based stationary phase containing a cellulose tris (4-chloro-3-methylphenylcarbamate) chiral selector in polar organic solvent chromatography mode was considered. The effects of trifluoroacetic acid (TFA) and n-hexane concentration in an acetonitrile (MeCN) mobile phase were investigated under a wide range of column temperatures. Good correlations were found between the observed data obtained after using a central composite design and the expected chromatographic behaviours predicted by applying the design of experiments-design space (DoE-DS) methodology. The critical quality attribute represented here by the separation criterion (Scrit) allowed assessing the quality of the enantioseparation. Baseline separation for the compounds of interest in an analysis time of less than 20 minutes was possible due to the original and powerful tools applied which facilitated an enhanced method comprehension. Finally, the advantage of the DoE-DS approach resides in granting the possibility to concurrently assess robustness and identify the optimal conditions which are compound dependent. [less ▲]

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