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

Molecules

Damjan Makuc³  Jan Fabris²  Zdenko ჊sar¹ 

[1] Sandoz Development Center Slovenia, API Development, Organic Synthesis Department, Lek Pharmaceuticals, d.d., Kolodvorska 27, Mengeš SI-1234, Slovenia; E-Mail:;Cadonic Consultancy Services, LL.C., Cesta na postajo 74, Brezovica pri Ljubljani SI-1351, Slovenia; E-Mail:;Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, Ljubljana SI-1000, Slovenia; E-Mail:

关键词: conformational analysis;    intramolecular dynamics;    NMR studies;    barriers to rotation;    super-statins;   

DOI  :  10.3390/molecules181113283

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.