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Design and Optimization of Thioglycosyl-naphthalimides as Efficient Inhibitors Against Human O-GlcNAcase.

ABSTRACT: ?-N-acetylhexosaminidases represent an important class of exoglycosidases and have emerged as the promising targets for drug and pesticide discovery. Among these, human O-GlcNAcase (hOGA) has been reported to be closely linked to several diseases such as Alzheimer's disease, diabetes, and cancer. Potent hOGA inhibitors with high selectivity are therefore of great significance for the regulation of the corresponding physiological processes. In this study, several classes of novel and readily available thioglycosyl-naphthalimides bearing the amide linker were designed and synthesized. To investigate their potency and selectivity, the inhibitory efficiencies toward hOGA and human ?-N-acetylhexosaminidase B (HsHexB) were assayed. Especially, compounds 10a (K i = 0.61 ?M) and 16l (K i = 0.72 ?M) exhibited excellent inhibitory potency against hOGA and high selectivity (HsHexB, K i > 100 ?M). In addition, during the preparation of these thioglycosyl-naphthalimides, a new practical method was developed for the synthesis of ureido glycosides from trichloroethyl carbamates at room temperature and normal pressure without catalyst. Furthermore, the possible binding modes of hOGA with 10a, 10d, and 16j were studied using molecular docking and molecular dynamics simulations to explore the molecular basis for the potency of these thioglycosides. This work present here provides useful clues for the further structural optimization toward hOGA.

SUBMITTER: Shen S

PROVIDER: S-EPMC6669961 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Design and Optimization of Thioglycosyl-naphthalimides as Efficient Inhibitors Against Human O-GlcNAcase.

Shen Shengqiang S Dong Lili L Chen Wei W Wu Renjie R Lu Huizhe H Yang Qing Q Zhang Jianjun J

Frontiers in chemistry 20190725

β-N-acetylhexosaminidases represent an important class of exoglycosidases and have emerged as the promising targets for drug and pesticide discovery. Among these, human O-GlcNAcase (hOGA) has been reported to be closely linked to several diseases such as Alzheimer's disease, diabetes, and cancer. Potent hOGA inhibitors with high selectivity are therefore of great significance for the regulation of the corresponding physiological processes. In this study, several classes of novel and readily avai ...[more]

PMID: 31403045

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Project description:MotivationTarget-specific hybridization depends on oligo-probe characteristics that improve hybridization specificity and minimize genome-wide cross-hybridization. Interplay between specific hybridization and genome-wide cross-hybridization has been insufficiently studied, despite its crucial role in efficient probe design and in data analysis.ResultsIn this study, we defined hybridization specificity as a ratio between oligo target-specific hybridization and oligo genome-wide cross-hybridization. A microarray database, derived from the Genomic Comparison Hybridization (GCH) experiment and performed using the Affymetrix platform, contains two different types of probes. The first type of oligo-probes does not have a specific target on the genome and their hybridization signals are derived from genome-wide cross-hybridization alone. The second type includes oligonucleotides that have a specific target on the genomic DNA and their signals are derived from specific and cross-hybridization components combined together in a total signal. A comparative analysis of hybridization specificity of oligo-probes, as well as their nucleotide sequences and thermodynamic features was performed on the database. The comparison has revealed that hybridization specificity was negatively affected by low stability of the fully-paired oligo-target duplex, stable probe self-folding, G-rich content, including GGG motifs, low sequence complexity and nucleotide composition symmetry.ConclusionFiltering out the probes with defined 'negative' characteristics significantly increases specific hybridization and dramatically decreasing genome-wide cross-hybridization. Selected oligo-probes have two times higher hybridization specificity on average, compared to the probes that were filtered from the analysis by applying suggested cutoff thresholds to the described parameters. A new approach for efficient oligo-probe design is described in our study.Contactshabalin@ncbi.nlm.nih.gov or olga.matveeva@gmail.comSupplementary informationSupplementary data are available at Bioinformatics online.

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Design and Optimization of Thioglycosyl-naphthalimides as Efficient Inhibitors Against Human O-GlcNAcase.

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Design and Optimization of Thioglycosyl-naphthalimides as Efficient Inhibitors Against Human O-GlcNAcase.

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