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Conformational Analysis of Geometric Isomers of Pitavastatin Together with Their Lactonized Analogues
AbstractSuper-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.
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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.View more citation formats
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.Chicago/Turabian Style
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.