NMR Study of Conformational Structure of Fluvastatin and Its Complex with Dodecylphosphocholine Micelles

Galiullina, L. F.; Aganova, Oksana V.; Latfullin, I. A.; Musabirova, Guzel; Аганов, А. В.; Клочков, В. В.

doi:10.1007/s12668-016-0232-y

Cited by 14 publications

(5 citation statements)

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“…Solution-state 1 H-1 H NOESY NMR spectra of fluvastatin in dodecylphosphocholine micelles revealed cross peaks between the aromatic protons of the drug and headgroup and hydrocarbon chain protons of the lipid, suggesting that the aromatic ring serves as a hydrophobic anchor and the dihydroxyheptenoic acid is associated with the lipid headgroups. 18,19 Here, a NOESY NMR spectrum of fluvastatin in POPC multilamellar vesicles (MLVs), obtained with magic-angle spinning, revealed cross peaks between protons in the fluoroaromatic ring and hydrocarbon chain protons (Fig. S7, ESI †), confirming that the ring serves as a hydrophobic anchor.…”

mentioning

confidence: 85%

Drug orientations within statin-loaded lipoprotein nanoparticles by ¹⁹F solid-state NMR

et al. 2019

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mentioning

confidence: 85%

Drug orientations within statin-loaded lipoprotein nanoparticles by ¹⁹F solid-state NMR

et al. 2019

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“…Мицеллы додецилфосфохолина представляют собой сфериче-ские агрегаты, распределенные по всему раствору, имеют полярную поверхность, аналогичную поверхности клеточных мембран и являются наиболее подходящей модельной системой с точки зрения метода ЯМР из-за их небольших размеров. Ранее нами было показано, что правастатин, симвастатин, церивастатин и флувастатин образуют комплексы с мицеллами ДФХ [12,13]. Целью данной работы стало изучение пространственного рас-положения вышеуказанных статинов относительно по-верхности модельных клеточных мембран, а также оцен-ка средних межатомных расстояний между молекула-ми статинов и мицелл ДФХ.…”

Section: Statins and Cell Membranes: Nmr Spectroscopy Data статины и unclassified

Statins and Their Interaction With Model Cell Membranes According to the Data of Nuclear Magnetic Resonance Spectroscopy

Latfullin

Galiullina

Musabirova

et al. 2017

Racionalʹnaâ farmakoterapiâ v kardiologii

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Цель. Изучить расположение правастатина, симвастатина, флувастатина и церивастатина в молекулярных комплексах с модельными клеточными мембранами на основе додецилфосфохолина, а также рассчитать средние межатомные расстояния между атомами статинов и мицелл. Материал и методы. В качестве метода исследования была выбрана спектроскопия ядерного магнитного резонанса (ЯМР). ЯМР спектро-скопия ядерного эффекта Оверхаузера (NOESY) является одним из самых эффективных методов в изучении межмолекулярных взаимодей-ствий, в частности, при исследованиях лекарственных препаратов. С помощью NOESY спектроскопии можно получить информацию о про-странственной структуре молекулярного комплекса, а также о фрагментах молекул, ответственных за эффективное взаимодействие, приво-дящее к образованию комплекса. Все ЯМР эксперименты были выполнены на спектрометре Bruker Avance II 500, оборудованном 5 мм z-гра-диентным инверсным датчиком с программным обеспечением TOPSPIN. Расчет межатомных расстояний проводился с точностью до 0,1 Å. Результаты. На основании ЯМР NOESY экспериментов было определено расположение правастатина, симвастатина, флувастатина и церива-статина в молекулярных комплексах с модельными клеточными мембранами на основе додецилфосфохолина, а также рассчитаны средние меж-атомные расстояния между атомами статинов и мицелл. Правастатин слабо связывается с полярной поверхностью модельной мембраны, в то время как симвастатин проникает в пространство между углеводородными цепями мицеллы. Флувастатин взаимодействует, главным образом, с модельными мембранами путем проникновения его ароматических фрагментов в поверхность мицеллы. Церивастатин имеет уникальное рас-положение в модельной мембране. Он расположен глубоко в гидрофобном ядре мицеллы близко к концевой метиленовой группе. Заключение. Показано, что даже незначительные различия в химической структуре статинов приводят к различным характерам их взаимодействия с модельными мембранами. Эти различия могут объяснить особенности фармакологических свойств этих соединений.Ключевые слова: ядерный магнитный резонанс, молекулярный комплекс, додецилфосфохолин, мицеллы, статины. Aim. To study the location of pravastatin, simvastatin, fluvastatin and cerivastatin in molecular complexes with model cell membranes based on dodecylphosphocholine, and also to calculate the average interatomic distances between the atoms of statins and micelles. Material and methods. Nuclear magnetic resonance (NMR) spectroscopy was chosen as a method of study. NMR spectroscopy of the Overhauser nuclear effect (NOESY) is one of the most effective methods in the study of intermolecular interactions, in particular, in studies of drugs. Information on the spatial structure of the molecular complex, as well as on the fragments of molecules responsible for the effective interaction leading to complex formation, was obtained by NOESY spectroscopy. All NMR experiments were performed on a Bruker Avance II 500 spectrometer with a 5 mm zgradient inverse sensor with the TOPSPIN software. The calculation of the interatomic di...

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“…Additionally, it was shown that FLU crosses membranes by passive diffusion, thanks to the low molecular weight and the amphiphilic characteristics . Hydrophobic interactions between the acyl chains and the aromatic groups of FLU have been also demonstrated . CER has similar hydrophobic/hydrophilic properties to FLU as indicated by the value of log P = 3.40–4.15; this drug is also used in the form of the sodium salt.…”

Section: Introductionmentioning

confidence: 99%

“… 32 Hydrophobic interactions between the acyl chains and the aromatic groups of FLU have been also demonstrated. 33 CER has similar hydrophobic/hydrophilic properties to FLU as indicated by the value of log P = 3.40–4.15; 34 this drug is also used in the form of the sodium salt. However, it is characterized by two p K a values: the lower one corresponding to the carboxylic acid form (p K a = 4.38) and the higher value to the pyridine residue (p K a = 5.29).…”

Section: Introductionmentioning

confidence: 99%

Statin Action Targets Lipid Rafts of Cell Membranes: GIXD/PM-IRRAS Investigation of Langmuir Monolayers

et al. 2023

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Lipid rafts are condensed regions of cell membranes rich in cholesterol and sphingomyelin, which constitute the target for anticholesterolemic drugs - statins. In this work, we use for the first time a combined grazing-incidence X-ray diffraction (GIXD)/polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS)/Brewster angle microscopy (BAM) approach to show the statin effect on model lipid rafts and its components assembled in Langmuir monolayers at the air–water interface. Two representatives of these drugs, fluvastatin (FLU) and cerivastatin (CER), of different hydrophobicity were chosen, while cholesterol (Chol) and sphingomyelin (SM), and their 1:1 mixture were selected to form condensed monolayers of lipid rafts. The effect of statins on the single components of lipid rafts indicated that both the hydrophobicity of the drugs and the organization of the layer determined the drug–lipid interaction. For cholesterol monolayers, only the most hydrophobic CER was effectively changing the film structure, while for the less organized sphingomyelin, the biggest effect was observed for FLU. This drug affected both the polar headgroup region as shown by PM-IRRAS results and the 2D crystalline structure of the SM monolayer as evidenced by GIXD. Measurements performed for Chol/SM 1:1 models proved also that the statin effect depends on the presence of Chol–SM complexes. In this case, the less hydrophobic FLU was not able to penetrate the binary layer at all, while exposure to the hydrophobic CER resulted in the phase separation and formation of ordered assemblies. The changes in the membrane properties were visualized by BAM images and GIXD patterns and confirmed by thermodynamic parameters of hysteresis in the Langmuir monolayer compression–decompression experiments.

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NMR Study of Conformational Structure of Fluvastatin and Its Complex with Dodecylphosphocholine Micelles

Cited by 14 publications

References 10 publications

Drug orientations within statin-loaded lipoprotein nanoparticles by ¹⁹F solid-state NMR

Drug orientations within statin-loaded lipoprotein nanoparticles by ¹⁹F solid-state NMR

Statins and Their Interaction With Model Cell Membranes According to the Data of Nuclear Magnetic Resonance Spectroscopy

Statin Action Targets Lipid Rafts of Cell Membranes: GIXD/PM-IRRAS Investigation of Langmuir Monolayers

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NMR Study of Conformational Structure of Fluvastatin and Its Complex with Dodecylphosphocholine Micelles

Cited by 14 publications

References 10 publications

Drug orientations within statin-loaded lipoprotein nanoparticles by 19F solid-state NMR

Drug orientations within statin-loaded lipoprotein nanoparticles by 19F solid-state NMR

Statins and Their Interaction With Model Cell Membranes According to the Data of Nuclear Magnetic Resonance Spectroscopy

Statin Action Targets Lipid Rafts of Cell Membranes: GIXD/PM-IRRAS Investigation of Langmuir Monolayers

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Drug orientations within statin-loaded lipoprotein nanoparticles by ¹⁹F solid-state NMR

Drug orientations within statin-loaded lipoprotein nanoparticles by ¹⁹F solid-state NMR