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Study of the Structural Chemistry of the Inclusion Complexation of 4-Phenylbutyrate and Related Compounds with Cyclodextrins in Solution: Differences in Inclusion Mode with Cavity Size Dependency.

ABSTRACT: 4-phenylbutyrate (PB) and structurally related compounds hold promise for treating many diseases, including cancers. However, pharmaceutical limitations, such as an unpleasant taste or poor aqueous solubility, impede their evaluation and clinical use. This study explores cyclodextrin (CD) complexation as a strategy to address these limitations. The structural chemistry of the CD complexes of these compounds was analyzed using phase solubility, nuclear magnetic resonance (NMR) spectroscopic techniques, and molecular modeling to inform the choice of CD for such application. The study revealed that PB and its shorter-chain derivative form 1:1 αCD complexes, while the longer-chain derivatives form 1:2 (guest:host) complexes. αCD includes the alkyl chain of the shorter-chain compounds, depositing the phenyl ring around its secondary rim, whereas two αCD molecules sandwich the phenyl ring in a secondary-to-secondary rim orientation for the longer-chain derivatives. βCD includes each compound to form 1:1 complexes, with their alkyl chains bent to varying degrees within the CD cavity. γCD includes two molecules of each compound to form 2:1 complexes, with both parallel and antiparallel orientations plausible. The study found that αCD is more suitable for overcoming the pharmaceutical drawbacks of PB and its shorter-chain derivative, while βCD is better for the longer-chain derivatives.

SUBMITTER: Commey KL

PROVIDER: S-EPMC10606765 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Study of the Structural Chemistry of the Inclusion Complexation of 4-Phenylbutyrate and Related Compounds with Cyclodextrins in Solution: Differences in Inclusion Mode with Cavity Size Dependency.

Commey Kindness L KL Nakatake Akari A Enaka Airi A Nakamura Ryota R Nishi Koji K Tsukigawa Kenji K Ikeda Hirohito H Yamaguchi Koki K Iohara Daisuke D Hirayama Fumitoshi F Yamasaki Keishi K Otagiri Masaki M

International journal of molecular sciences 20231011 20

4-phenylbutyrate (PB) and structurally related compounds hold promise for treating many diseases, including cancers. However, pharmaceutical limitations, such as an unpleasant taste or poor aqueous solubility, impede their evaluation and clinical use. This study explores cyclodextrin (CD) complexation as a strategy to address these limitations. The structural chemistry of the CD complexes of these compounds was analyzed using phase solubility, nuclear magnetic resonance (NMR) spectroscopic techn ...[more]

PMID: 37894771

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Project description:The molecular dynamics of spin-labeled compounds included into the solid phase of cyclodextrins (CDs) has been studied using conventional (X-band) ESR at 9 GHz and high-field high-frequency (HFHF) ESR at 240 and 170 GHz. The patterns of axial rotation at these higher frequencies are clear just by inspection of the spectrum, unlike the case for 9 GHz spectra. That is HFHF ESR is sensitive to molecular motion about the diffusion axis collinear with the X, Y or Z-direction of the magnetic g- and A-tensors of the nitroxide moiety (referred to, respectively, as X, Y or Z-rotation). For doxyl stearic acids (Z-rotation) and TEMPOyl caprylate (X-rotation) included in beta- and gamma-CDs we were able to determine the rate of molecular motion and the corresponding potential barriers. We emphasize that determining the rate of Z-rotation by ESR is feasible only using HFHF ESR. For the X-rotation case we suggest that the motion of the nitroxide moiety consists of fast small-angle librations about the magnetic X-axis superimposed by rotational diffusion about the same axis. The potential barrier of 1.7 Kcal mol(-1) for this rotational diffusion is unusually low. A fascinating feature of TEMPO derivatives included in beta-CD is the detectable molecular motion at temperatures below 77 K. For the other CD-spin probe systems, we used multifrequency analysis to assign the conformations of spin-labeled molecules. A dramatic spectral change for 16-sasl in beta- and gamma-CDs at approximately 260 K corresponds to a tilting of the position of the nitroxide moiety on the rotating molecule relative to the long diffusion axis, while for TEMPO derivatives in gamma-cyclodextrin below 200 K, we observe a rapid transition from fast to very slow rotational motion. More complex features are best studied by means of multifrequency ESR experiments. The visual clarity and the simplicity of analysis of the ESR spectra shown in this work should provide a benchmark for future studies of molecular motion by HFHF ESR.

Project description:Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene, PTB) is a natural dietary stilbene, occurring primarily in blueberries and Pterocarpus marsupium heartwood. The interest in this compound is related to its different biological and pharmacological properties, such as its antioxidant, anti-inflammatory, and anticarcinogenic activities and its capacity to reduce and regulate cholesterol and blood sugar levels. Nevertheless, its use in therapy is hindered by its low aqueous solubility; to overcome this limitation we studied the feasibility of the use of cyclodextrins (CDs) as solubility-enhancing agents. CDs are natural macrocyclic oligomers composed of α-d-glucose units linked by α-1,4 glycosidic bonds to form torus-shaped molecules, responsible for inclusion complex formation with organic molecules. In particular, the aim of this study was to evaluate the feasibility of complexation between PTB and native CDs using various preparative methods. The isolated solid products were characterized using differential scanning calorimetry (DSC), simultaneous thermogravimetric/DSC analysis (TGA/DSC), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD) on powder and single crystals. The results indicated little or no evidence of the affinity of PTB to complex with α-CD using the kneading method. However, with β-CD and γ-CD thermal analysis revealed an interaction which was also corroborated by FT-IR and 1H-NMR spectroscopy. With β-CD, a hydrated complex of PTB was isolated and its characterization by single-crystal XRD revealed, for the first time, the mode of inclusion of the PTB molecule in the cavity of a CD. To complement the solid-state data, liquid-phase studies were carried out to establish the effect of CDs on the aqueous solubility of PTB and to determine the complex stoichiometries and the association constants for complex formation. Phase-solubility studies showed AL-type profiles for α- and β-CD and a BS profile for γ-CD, with K1:1 values of 1144, 4950, and 133 M-1 for α-CD·PTB, β-CD·PTB, and γ-CD·PTB, respectively. The stoichiometry of CD·PTB complexes, determined by Job's method, revealed for each system a 1:1 molar ratio. The dissolution rate of PTB was approximately doubled just by employing simple physical mixtures, but the best performance was achieved by products obtained via kneading and co-precipitation, which effected the complete dissolution of PTB in 40 and 20 min for β-CD and γ-CD, respectively.

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Dataset Information

Study of the Structural Chemistry of the Inclusion Complexation of 4-Phenylbutyrate and Related Compounds with Cyclodextrins in Solution: Differences in Inclusion Mode with Cavity Size Dependency.

Publications

Study of the Structural Chemistry of the Inclusion Complexation of 4-Phenylbutyrate and Related Compounds with Cyclodextrins in Solution: Differences in Inclusion Mode with Cavity Size Dependency.

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