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Fluorescence enhancement and pK(a) shift of a rho kinase inhibitor by a synthetic receptor
Yin, Hang1; Chen, Linmin1; Yang, Binrui1; Bardelang, David2; Wang, Chunming1; Lee, Simon M. Y.1; Wang, Ruibing1
2017-05-28
Source PublicationORGANIC & BIOMOLECULAR CHEMISTRY
ISSN1477-0520
Volume15Issue:20Pages:4336-4343
Abstract

Fasudil (FSD), a selective rho kinase (ROCK) inhibitor, was found to form 1 : 1 host-guest inclusion complexes with a synthetic macrocyclic receptor, cucurbit[7] uril(CB[7]), in aqueous solutions, as evidenced by H-1 NMR, photoluminescence and UV-visible spectroscopic titrations, isothermal titration calorimetry (ITC) titration, and electrospray ionization (ESI) mass spectrometry, as well as density functional theory (DFT) molecular modeling. Upon encapsulation, whereas the UV-vis absorbance of FSD experienced a moderate decrease and bathochromic shift, the fluorescence intensity of FSD at 354 nm was dramatically enhanced for up to 69-fold at neutral pH, which could potentially be applied in fluorescent tracking of the drug delivery and release. More interestingly, the binding affinity (K-a = (4.28 +/- 0.21) x 10(6) M-1), of FSD-CB[7] complexes under acidic conditions (pH = 2.0), is approximately three orders of magnitude higher than that (2.2 similar to 6.6 x 10(3) M-1) under neutral pH conditions (pH = 7.0). Accordingly, UV-visible spectroscopic titration of the free and complexed FSD under various pH conditions has demonstrated that the encapsulation of FSD by CB[7] shifted the pK(a) of the isoquinoline-N upward from 3.05 to 5.96 (Delta pK(a) of 2.91). The significantly higher binding affinity of the complexes under acidic conditions may be applied in developing the "enteric" formulation of FSD. Furthermore, our in vitro study of the bioactivity of FSD in the absence and presence of CB[7] on a neural cell line, SH-SY5Y, showed that the complexation preserved the drug's pro-neurite efficacy. Thus this discovery may lead to a fluorescence-trackable, orally administered enteric formulation of rho kinase inhibitors that are stable under gastric conditions, without compromising bioactivity of the drugs.

DOI10.1039/c7ob00547d
URLView the original
Indexed BySCI
Language英语
WOS Research AreaChemistry
WOS SubjectChemistry, Organic
WOS IDWOS:000401944600012
PublisherROYAL SOC CHEMISTRY
The Source to ArticleWOS
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Cited Times [WOS]:5   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionInstitute of Chinese Medical Sciences
Corresponding AuthorWang, Ruibing
Affiliation1.State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, China
2.Aix Marseille Univ, CNRS, ICR, Marseille, France
First Author AffilicationInstitute of Chinese Medical Sciences
Corresponding Author AffilicationInstitute of Chinese Medical Sciences
Recommended Citation
GB/T 7714
Yin, Hang,Chen, Linmin,Yang, Binrui,et al. Fluorescence enhancement and pK(a) shift of a rho kinase inhibitor by a synthetic receptor[J]. ORGANIC & BIOMOLECULAR CHEMISTRY,2017,15(20):4336-4343.
APA Yin, Hang.,Chen, Linmin.,Yang, Binrui.,Bardelang, David.,Wang, Chunming.,...&Wang, Ruibing.(2017).Fluorescence enhancement and pK(a) shift of a rho kinase inhibitor by a synthetic receptor.ORGANIC & BIOMOLECULAR CHEMISTRY,15(20),4336-4343.
MLA Yin, Hang,et al."Fluorescence enhancement and pK(a) shift of a rho kinase inhibitor by a synthetic receptor".ORGANIC & BIOMOLECULAR CHEMISTRY 15.20(2017):4336-4343.
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