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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.

SUBMITTER: Makuc D

PROVIDER: S-EPMC6270003 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Conformational analysis of geometric isomers of pitavastatin together with their lactonized analogues.

Makuc Damjan D Fabris Jan J Časar Zdenko Z Plavec Janez J

Molecules (Basel, Switzerland) 20131028 11

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 ...[more]

PMID: 24169468

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Project description:The structures of a number of stereoisomers of carotenoids have been revealed in three-dimensional X-ray crystallographic investigations of pigment-protein complexes from photosynthetic organisms. Despite these structural elucidations, the reason for the presence of stereoisomers in these systems is not well understood. An important unresolved issue is whether the natural selection of geometric isomers of carotenoids in photosynthetic pigment-protein complexes is determined by the structure of the protein binding site or by the need for the organism to accomplish a specific physiological task. The association of cis isomers of a carotenoid with reaction centers and trans isomers of the same carotenoid with light-harvesting pigment-protein complexes has led to the hypothesis that the stereoisomers play distinctly different physiological roles. A systematic investigation of the photophysics and photochemistry of purified, stable geometric isomers of carotenoids is needed to understand if a relationship between stereochemistry and biological function exists. In this work we present a comparative study of the spectroscopy and excited state dynamics of cis and trans isomers of three different open-chain carotenoids in solution. The molecules are neurosporene (n=9), spheroidene (n=10), and spirilloxanthin (n=13), where n is the number of conjugated pi-electron double bonds. The spectroscopic experiments were carried out on geometric isomers of the carotenoids purified by high performance liquid chromatography (HPLC) and then frozen to 77 K to inhibit isomerization. The spectral data taken at 77 K provide a high resolution view of the spectroscopic differences between geometric isomers. The kinetic data reveal that the lifetime of the lowest excited singlet state of a cis-isomer is consistently shorter than that of its corresponding all-trans counterpart despite the fact that the excited state energy of the cis molecule is typically higher than that of the trans molecule. Quantum theoretical calculations on an n=9 linear polyene were carried out to examine this process. The calculations indicate that the electronic coupling terms are significantly higher for the cis isomer, and when combined with the Franck-Condon factors, predict internal conversion rates roughly double those of the all-trans species. The electronic effects more than offset the decrease in coupling efficiencies associated with the higher system origin energies and explain the observed shorter cis isomer lifetimes.

Project description:The structures of a number of stereoisomers of carotenoids have been revealed in three-dimensional X-ray crystallographic investigations of pigment-protein complexes from photosynthetic organisms. Despite these structural elucidations, the reason for the presence of stereoisomers in these systems is not well understood. An important unresolved issue is whether the natural selection of geometric isomers of carotenoids in photosynthetic pigment-protein complexes is determined by the structure of the protein binding site or by the need for the organism to accomplish a specific physiological task. The association of cis isomers of a carotenoid with reaction centers and trans isomers of the same carotenoid with light-harvesting pigment-protein complexes has led to the hypothesis that the stereoisomers play distinctly different physiological roles. A systematic investigation of the photophysics and photochemistry of purified, stable geometric isomers of carotenoids is needed to understand if a relationship between stereochemistry and biological function exists. In this work we present a comparative study of the spectroscopy and excited state dynamics of cis and trans isomers of three different open-chain carotenoids in solution. The molecules are neurosporene (n = 9), spheroidene (n = 10), and spirilloxanthin (n = 13), where n is the number of conjugated pi-electron double bonds. The spectroscopic experiments were carried out on geometric isomers of the carotenoids purified by high performance liquid chromatography (HPLC) and then frozen to 77 K to inhibit isomerization. The spectral data taken at 77 K provide a high resolution view of the spectroscopic differences between geometric isomers. The kinetic data reveal that the lifetime of the lowest excited singlet state of a cis-isomer is consistently shorter than that of its corresponding all-trans counterpart despite the fact that the excited state energy of the cis molecule is typically higher than that of the trans molecule. Quantum theoretical calculations on an n = 9 linear polyene were carried out to examine this process. The calculations indicate that the electronic coupling terms are significantly higher for the cis isomer, and when combined with the Franck-Condon factors, predict internal conversion rates roughly double those of the all-trans species. The electronic effects more than offset the decrease in coupling efficiencies associated with the higher system origin energies and explain the observed shorter cis isomer lifetimes.

Dataset Information

Conformational analysis of geometric isomers of pitavastatin together with their lactonized analogues.

Publications

Conformational analysis of geometric isomers of pitavastatin together with their lactonized analogues.

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