Understanding the structure and dynamics of anti-inflammatory corticosteroid dexamethasone by solid state NMR spectroscopy

Dey, Krishna Kishor; Ghosh, Manasi

doi:10.1039/d0ra05474g

Cited by 12 publications

(11 citation statements)

References 49 publications

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“…In the principal axis system (PAS), only the diagonal components of the CS tensor survive and these are called the principal components of the CS tensor. The information about the structure and dynamics of a molecule resides on these parameters. − These parameters can be calculated by Density Functional Theory (DFT) and these can also be extracted by applying sophisticated NMR methodologies like ROCSA (recoupling of chemical shift anisotropy), 2DMAF (two-dimensional magic angle flipping), − SUPER (separation of undistorted powder patterns by effortless recoupling), 2DMAT (two-dimensional magic angle turning), 2D MAS/CSA NMR experiment, RNCSA (γ-encoded RN n ν -symmetry-based chemical shift anisotropy), and 2D phase-adjusted spinning side-band (2DPASS) magic angle spinning (MAS). , Previously, we had determined the principal components of the CS-tensor of carbon nuclei of biopolymers, − biomedicine, − and charge transfer co-crystal by applying 13 C 2DPASS CP-MAS ssNMR experiments. The principal components of the CS tensor of prednisone, prednisolone, prednisolone acetate, methylprednisolone, and methylprednisolone acetate are determined by the 2D phase-adjusted spinning sideband (2DPASS) cross-polarization (CP) magic angle spinning (MAS) solid-state NMR experiment.…”

Section: Introductionmentioning

confidence: 99%

Investigation of the Influence of Various Functional Groups on the Dynamics of Glucocorticoids

et al. 2022

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The basic configuration of glucocorticoid consists of four-fused rings associated with one cyclohexadienone ring, two cyclohexane rings, and one cyclopentane ring. The ways the structure and dynamics of five glucocorticoids (prednisone, prednisolone, prednisolone acetate, methylprednisolone, and methylprednisolone acetate) are altered because of the substitution of various functional groups with these four-fused rings are studied thoroughly by applying sophisticated solid-state nuclear magnetic resonance (NMR) methodologies. The biological activities of these glucocorticoids are also changed because of the attachment of various functional groups with these four-fused rings. The substitution of the hydroxyl group (with the C11 atom of the cyclohexane ring) in place of the keto group enhances the potential of the glucocorticoid to cross the cellular membrane. As a result, the bioavailability of prednisolone (the hydroxyl group is attached with the C11 atom of the cyclohexane ring) is increased compared to prednisone (the keto group is attached with the C11 atom of cyclohexane rings). Another notable point is that the spin–lattice relaxation rate at crystallographically distinct carbon nuclei sites of prednisolone is increased compared to that of the prednisone, which implies that the motional degrees of freedom of glucocorticoid is increased because of the substitution of the hydroxyl group in place of the keto group of the cyclohexane ring. The attachment of the methyl group with the C6 atom of cyclohexane rings further reduces the spin–lattice relaxation time at crystallographically distinct carbon nuclei sites of glucocorticoid and its bioactivity is also increased. By comparing the spin–lattice relaxation time and the local correlation time at crystallographically different carbon nuclei sites of three steroids prednisone, prednisolone, and methylprednisolone, it is observed that both the spin–lattice relaxation time and the local correlation time gradually decrease at each crystallographically distinct carbon nuclei sites when we move from prednisone to prednisolone to methyl-prednisolone. On the other hand, if we compare the same for prednisolone, prednisolone acetate, and methylprednisolone acetate, then we also observe that both the spin–lattice relaxation time and the local-correlation time gradually decrease from prednisolone to prednisolone acetate to methylprednisolone acetate for all chemically different carbon nuclei. It is also noticeable that both the spin–lattice relaxation time and the local-correlation time gradually decrease from prednisone to prednisolone to prednisolone acetate to methylprednisolone to methylprednisolone acetate for most of the carbon nuclei sites. From in silico analysis, it is also revealed that the bioavailability and efficacy of the glucocorticoid increase from prednisone to prednisolone to prednisolone acetate to methylprednisolone to methylprednisolone acetate. Hence, it can be concluded that the biological activity and the motional degrees of freedom of the glu...

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Section: Introductionmentioning

confidence: 99%

Investigation of the Influence of Various Functional Groups on the Dynamics of Glucocorticoids

et al. 2022

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“…The 2DPASS CP-MAS NMR experiment can be applied to extract the values of principal components of CS tensor of 13 C nuclei when the homonuclear and heteronuclear dipole–dipole interactions are weak. Previously, we had applied that technique to determine the 13 C CS tensor of biopolymers, − biomedicine, − and charge transfer cocrystal …”

Section: Introductionmentioning

confidence: 99%

NMR Crystallographic Approach to Study the Variation of the Dynamics of Quinine and Its Quasienantiomer Quinidine

et al. 2022

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The structure and dynamics of quinine and its quasienantiomer quinidine were studied at the atomic resolution by measuring the chemical shift anisotropy (CSA) tensor and site-specific spin–lattice relaxation time. For quinine, there are three crystallographically independent molecules “a”, “b”, and “c” in an asymmetric unit since its 13C CP-MAS SSNMR spectrum features three distinct resonance peaks for certain carbon nuclei. The 13C assignments are fulfilled by DFT calculations. The experimental 13C isotropic chemical shifts well match the calculated values. These variations of isotropic chemical shift for three independent molecules are also observed by two-dimensional 13C–1H heteronuclear correlation spectroscopy (HETCOR) of quinine. The spin–lattice relaxation time, and the principal components of CSA parameters are also varied substantially for certain carbon nuclei of “a”, “b”, and “c” molecules. For quinidine, its 13C CP-MAS SSNMR spectrum is remarkably different from that of quinine despite, their almost identical solution NMR spectra. Furthermore, the remarkable change in the structure and dynamics of quasienantiomers are also observed including the steric effect of the substituent vinyl group, the variation of helical motifs, and the variation of the strength of the intermolecular hydrogen bonds. The variation of the structure and dynamics of quasienantiomers are thoroughly studied by solid-state NMR measurements. These types of studies will enrich the field of NMR crystallography.

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“…37 2DPASS CP-MAS ( two-dimensional phase adjusted spinning sideband cross-polarization magic angle spinning) SSNMR experiment 38,39 was developed to separate anisotropic and isotropic chemical shift interactions under low magic angle spinning (MAS) frequency using sequences of five pulses. The correlation between the structure and dynamics of biopolymer and drugs molecules [40][41][42][43][44][45][46][47][48][49][50][51] were studied by measuring principal components of CSA parameters and site specific spin-lattice relaxation time by applying 2DPASS CP-MAS SSNMR experiments 38,39 and Torchia CP experiment 52 respectively. The main focus of the present work is to study the structure and dynamics of antifungal agent ketoconazole by the 2DPASS CP-MAS SSNMR experiments 38,39 and the Torchia CP experiments.…”

Section: Because Of This Property Ketoconazole Is Used For the Treatmentioning

confidence: 99%

Study the Structure and Dynamics of Antifungal Agent Ketoconazole by CSA and Site-Specific Spin-Lattice Relaxation Time Measurements

Dey¹,

Ghosh²

2021

Preprint

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An azole antifungal agent, ketoconazole, is widely used in the treatment of mucosal fungal infections related to AIDS immunosuppression, organ transplantation, and cancer chemotherapy. The structure and dynamics of ketoconazole are thoroughly studied by chemical shift anisotropy tensor and site-specific spin-lattice relaxation time measurements. The molecular correlation time at crystallographically different carbon sites is calculated by considering that the spin-lattice relaxation mechanism for the 13C nucleus is mainly governed by chemical shift anisotropy interaction and hetero-nuclear dipole-dipole coupling. The CSA parameters at the crystallographically distinct sites of ketoconazole are determined by two-dimensional phase adjusted spinning sideband (2D PASS) cross-polarization magic angle spinning (CP-MAS) solid-state NMR experiment. The site-specific spin-lattice relaxation time is measured by the Torchia CP experiment. The spin-lattice relaxation rate is slow for all the carbon nuclei sites except C2, C3, C4, C5, and C26 carbon nuclei reside on the piperazine ring and the methyl group. It suggests the close-pack arrangement of the molecule due to π-π stacking interaction. The molecular correlation time of all the carbon atoms reside on the benzene ring, 1,3-dioxolane ring, imidazole ring, and the 2,4-dichlorobenzene ring is of the order of 10-4 s, while it is of the order of 10-7 s for carbon atoms reside on the piperazine ring. The CSA parameters of the carbon nuclei on the piperazine ring (C2, C3, C4, C5), and the methyl group (C26) are very low compared to other carbon nuclei. The CSA parameters are very high for carbon nuclei reside on the benzene ring, imidazole ring, and the 2,4-dichlorobenzene ring due to the presence of π-electrons. A huge variation of the spin-lattice relaxation time and the molecular correlation time are observed for numerous carbon nuclei situated on the side-chain of ketoconazole. The spin-lattice relaxation time varies from 500 s to 8 s, and the molecular correlation time varies in the range of 10-4s to 10-7s. These types of investigations portrayed the correlation between the structure and dynamics of the antifungal drug ketoconazole, which will help to develop the advanced antifungal drugs. Additionally, the CSA information of the drug molecules will be immensely useful for NMR crystallography.

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Understanding the structure and dynamics of anti-inflammatory corticosteroid dexamethasone by solid state NMR spectroscopy

Abstract: The structure and dynamics of dexamethasone is determined by measuring CSA tensor, site-specific spin–lattice relaxation time.

Cited by 12 publications

References 49 publications

Investigation of the Influence of Various Functional Groups on the Dynamics of Glucocorticoids

Investigation of the Influence of Various Functional Groups on the Dynamics of Glucocorticoids

NMR Crystallographic Approach to Study the Variation of the Dynamics of Quinine and Its Quasienantiomer Quinidine

Study the Structure and Dynamics of Antifungal Agent Ketoconazole by CSA and Site-Specific Spin-Lattice Relaxation Time Measurements

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