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Characterization of the Dynamic Equilibrium between Closed and Open Forms of the Benzoxaborole Pharmacophore.

ABSTRACT: Benzoxaboroles are a class of five-membered hemiboronic acids that recently attracted significant attention as a new pharmacophore on account of their unique structural and physicochemical properties and their ability to interact selectively with biomolecules. Their structural behavior in water and its effect on their physiological properties remain unclear, especially the question of dynamic hydrolytic equilibrium of the oxaborole ring. Herein, we used NMR spectroscopy, in mixed aqueous-organic solvent, to confirm the strong preference for the closed form of benzoxaborole and its six- and seven-membered homologues over the open boronic acid form. Only with the eight-membered homologue does the cyclic form become unfavorable. Using dynamic VT-NMR studies with designed probe compound 20, we demonstrate that the oxaborole ring undergoes rapid hydrolytic ring closing-opening at ambient temperature at a rate of >100 Hz via a mechanism featuring rate-limiting proton-transfer steps. This knowledge can help provide a better understanding of the behavior of benzoxaboroles in biological systems.

SUBMITTER: Vshyvenko S

PROVIDER: S-EPMC5151146 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Characterization of the Dynamic Equilibrium between Closed and Open Forms of the Benzoxaborole Pharmacophore.

Vshyvenko Sergey S Clapson Marissa L ML Suzuki Itaru I Hall Dennis G DG

ACS medicinal chemistry letters 20160921 12

Benzoxaboroles are a class of five-membered hemiboronic acids that recently attracted significant attention as a new pharmacophore on account of their unique structural and physicochemical properties and their ability to interact selectively with biomolecules. Their structural behavior in water and its effect on their physiological properties remain unclear, especially the question of dynamic hydrolytic equilibrium of the oxaborole ring. Herein, we used NMR spectroscopy, in mixed aqueous-organic ...[more]

PMID: 27994745

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Project description:Introduction: Previous studies have shown significant conditional differences between eyes open, fixated at an image (EO) and eyes closed (EC) in the acquired resting-state functional magnetic resonance imaging (rs-fMRI) data. Aim: We recently showed significant functional network connectivity (FNC) differences between EO and EC across a variety of networks. In this study, we aim at further evaluating differences in dynamic FNC (dFNC) between EO and EC. Materials and Methods: Rs-fMRI were collected from adolescents aged 9-15 years old during both EO and EC conditions, and dFNC was calculated by using the independent component analysis framework. Results: We found that out of five states (clusters), state 1 was observed to be more dominant in the EO condition, whereas state 2 was observed to be more dominant in the EC condition. States 1 and 2 showed significant differences in the mean dwell time based on false discovery rate, and states 1, 2, 3, and 4 differed in the frequency of occurrences. These results are consistent with our previous study of static connectivity in suggesting that EO and EC differences not only are relatively strong but also importantly reveal that these differences vary over time, especially in one particularly transient connectivity pattern. Conclusion: Our results manifest as changes in the proportion of time spent in unique functional connectivity patterns, and they show unique transient functional connectivity patterns in a subset of identified states. Overall, our findings indicate that both static and dynamic rs-fMRI connectivity patterns are strongly impacted by basic conditional differences such as EO and EC. Impact statement Our findings not only suggest that eyes open, fixated at an image (EO) and eyes closed (EC) condition-related resting state functional magnetic resonance imaging differences are relatively strong, but they also reveal an important attribute of these conditions that these differences vary over time, especially in one particularly transient connectivity pattern. Our results manifest as changes in the proportion of time spent in unique functional connectivity patterns, and they show unique transient functional connectivity patterns in a subset of identified states. We believe there is benefit in having the EO/EC as a contrast of interest in future studies, if time allows.

Dataset Information

Characterization of the Dynamic Equilibrium between Closed and Open Forms of the Benzoxaborole Pharmacophore.

Publications

Characterization of the Dynamic Equilibrium between Closed and Open Forms of the Benzoxaborole Pharmacophore.

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