Molecules 2013, 18(11), 13283-13296; doi:10.3390/molecules181113283
Article

Conformational Analysis of Geometric Isomers of Pitavastatin Together with Their Lactonized Analogues

1,2email, 3,4email, 4,5,6email and 1,2,7,* email
Received: 24 September 2013; in revised form: 17 October 2013 / Accepted: 19 October 2013 / Published: 28 October 2013
(This article belongs to the Special Issue Dynamic Stereochemistry)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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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MDPI and ACS Style

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.

AMA Style

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.

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