title: Conformational analysis of geometric isomers of pitavastatin together with their lactonized analogues.
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.
authors.affiliation: Slovenian NMR Centre, National Institute of Chemistry, Hajdrihova 19, Ljubljana SI-1000, Slovenia. janez.plavec@ki.si.
authors.forename: Damjan
authors.initials: D
authors.lastname: Makuc
authors.forename: Jan
authors.initials: J
authors.lastname: Fabris
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Časar
authors.forename: Janez
authors.initials: J
authors.lastname: Plavec
mesh_terms: D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D011804:Quinolines / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D011804:Quinolines; C108475:pitavastatin