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Conformational Analysis of Geometric Isomers of Pitavastatin Together with Their Lactonized Analogues
Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, Ljubljana SI-1000, Slovenia
EN-FIST Centre of Excellence, Dunajska cesta 156, Ljubljana SI-1000, Slovenia
Cadonic Consultancy Services, LL.C., Cesta na postajo 74, Brezovica pri Ljubljani SI-1351, Slovenia
Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Lek Pharmaceuticals, d.d., Kolodvorska 27, Mengeš SI-1234, Slovenia
Sandoz GmbH, Global Portfolio Management API, Biochemiestrasse 10, Kundl A-6250, Austria
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana SI-1000, Slovenia
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva cesta 5, Ljubljana SI-1000, Slovenia
* Author to whom correspondence should be addressed.
Received: 24 September 2013; in revised form: 17 October 2013 / Accepted: 19 October 2013 / Published: 28 October 2013
Abstract: Super-statins are synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which is the rate-limiting enzyme responsible for the biosynthesis of cholesterol. All of the super-statins with a C=C double bond spacer between the heterocyclic and the dihydroxycarboxylic moiety that are currently on the market exist as E-isomers. To extend the understanding of conformational and thermodynamic preferences of Z-isomeric super-statin analogues, this study focused on analyzing pitavastatin and its lactonized derivatives via NMR spectroscopy and ab initio calculations. Z-isomeric pitavastatin analogues exist in solution as a pair of interconverting rotamers, where the Gibbs free energies between the major and minor rotamers are within 0.12 and 0.25 kcal mol−1 and the rotational energy barriers are between 15.0 and 15.9 kcal mol−1. The analysis of long-range coupling constants and ab initio calculations revealed that rotation across the C5'–C7 single bond is essential for generating a pair of atropisomers. The overall comparison of the results between Z-isomeric pitavastatin and rosuvastatin analogues demonstrated that the former are to some extent more flexible to attain numerous conformations. Demonstrating how structural differences between super-statin analogues induce distinctive conformational preferences provides important insight into the super-statins’ conformational variability and may well improve future drug design.
Keywords: conformational analysis; intramolecular dynamics; NMR studies; barriers to rotation; super-statins
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Makuc, D.; Fabris, J.; Časar, Z.; Plavec, J. Conformational Analysis of Geometric Isomers of Pitavastatin Together with Their Lactonized Analogues. Molecules 2013, 18, 13283-13296.
Makuc D, Fabris J, Časar Z, Plavec J. Conformational Analysis of Geometric Isomers of Pitavastatin Together with Their Lactonized Analogues. Molecules. 2013; 18(11):13283-13296.
Makuc, Damjan; Fabris, Jan; Časar, Zdenko; Plavec, Janez. 2013. "Conformational Analysis of Geometric Isomers of Pitavastatin Together with Their Lactonized Analogues." Molecules 18, no. 11: 13283-13296.