Next Article in Journal
Effect of Pressure on Thermal Stability of G-Quadruplex DNA and Double-Stranded DNA Structures
Next Article in Special Issue
Deracemization of Axially Chiral Nicotinamides by Dynamic Salt Formation with Enantiopure Dibenzoyltartaric Acid (DBTA)
Previous Article in Journal
Effect of HT042, Herbal Formula, on Longitudinal Bone Growth in Spontaneous Dwarf Rats
Previous Article in Special Issue
Characterization of Amide Bond Conformers for a Novel Heterocyclic Template of N-acylhydrazone Derivatives
Molecules 2013, 18(11), 13283-13296; doi:10.3390/molecules181113283

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

1 Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, Ljubljana SI-1000, Slovenia 2 EN-FIST Centre of Excellence, Dunajska cesta 156, Ljubljana SI-1000, Slovenia 3 Cadonic Consultancy Services, LL.C., Cesta na postajo 74, Brezovica pri Ljubljani SI-1351, Slovenia 4 Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Lek Pharmaceuticals, d.d., Kolodvorska 27, Mengeš SI-1234, Slovenia 5 Sandoz GmbH, Global Portfolio Management API, Biochemiestrasse 10, Kundl A-6250, Austria 6 Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, Ljubljana SI-1000, Slovenia 7 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 / Revised: 17 October 2013 / Accepted: 19 October 2013 / Published: 28 October 2013
(This article belongs to the Special Issue Dynamic Stereochemistry)
View Full-Text   |   Download PDF [899 KB, 18 June 2014; original version 18 June 2014]   |  


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 conformational analysis; intramolecular dynamics; NMR studies; barriers to rotation; super-statins
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

Supplementary material


Share & Cite This Article

Further Mendeley | CiteULike
Export to BibTeX |
EndNote |
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.

View more citation formats

Related Articles

Article Metrics

For more information on the journal, click here


[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert