Synthesis of NAG-thiazoline-derived inhibitors for β-N-acetyl-d-hexosaminidases

Kong, Hanchu; Chen, Wei; Lu, Huizhe; Yang, Qing; Dong, Yanhong; Wang, Daoquan; Zhang, Jianjun

doi:10.1016/j.carres.2015.06.004

Cited by 13 publications

(8 citation statements)

References 26 publications

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“…β- N -acetylhexosaminidases (EC 3.2.1.52) are widely distributed exo-glycosidases that catalyze the release of a β-linked N -acetyl- d -hexosamine unit from non-reducing ends of glycoconjugates. These enzymes are classified into three glycosyl hydrolase family (GH3, GH20 and GH84) based on amino acid sequence similarities in the CAZy classification system ( http://www.cazy.org ) 1 , 2 . And they are involved in various physiological functions, such as energy metabolism 3 , cell communication 4 , cell proliferation 5 and inflammation 6 .…”

Section: Introductionmentioning

confidence: 99%

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Shen

Chen

Dong

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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GH20 human β-N-acetylhexosaminidases (hsHex) and GH84 human O-GlcNAcase (hOGA) are involved in numerous pathological processes and emerged as promising targets for drug discovery. Based on the catalytic mechanism and structure of the catalytic domains of these β-N-acetylhexosaminidases, a series of novel naphthalimide moiety-bearing thioglycosides with different flexible linkers were designed, and their inhibitory potency against hsHexB and hOGA was evaluated. The strongest potency was found for compound 15j (Ki = 0.91 µM against hsHexB; Ki > 100 µM against hOGA) and compound 15b (Ki = 3.76 µM against hOGA; Ki = 30.42 µM against hsHexB), which also exhibited significant selectivity between these two enzymes. Besides, inhibitors 15j and 15b exhibited an inverse binding patterns in docking studies. The determined structure–activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific β-N-acetylhexosaminidase inhibitors.

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Section: Introductionmentioning

confidence: 99%

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Shen

Chen

Dong

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…For the synthesis of the cyclopropane-based CYBOX ligand 5 (Scheme 2) we started from readily available 1,3,4,6-tetra- O -acetyl-2-amino-2-deoxy-β- d -glucopyranose hydrochloride 3 [18] which was condensed with cyclopropane-1,1-dicarboxylic acid under mediation of HBTU/HOBt to afford the corresponding bis-amide 4 . Cyclization to 5 was again achieved by sequential substitution of the anomeric acetate in 4 with HBr in AcOH, followed by treatment of the intermediate glycosyl bromide with Bu 4 NBr and NaHCO 3 (Scheme 2).…”

Section: Resultsmentioning

confidence: 99%

“…N,N′-Bis(1,3,4,6-tetra-O-acetyl-2-deoxy-β- d -glucopyranos-2-yl)-cyclopropane-1,1-dicarboxamide ( 4 ): To an ice cold solution of 1,3,4,6-tetra- O -acetyl-2-amino-2-deoxy-β- d -glucopyranose hydrochloride ( 3 ) [18] (1.20 g, 3.12 mmol) and Hünig’s base (1.63 mL, 9.38 mmol) in dry DMF (15 mL) was added in the following order: HOBt (0.72 g, 4.69 mmol), cyclopropane-1,1-dicarboxylic acid (0.20 g, 1.56 mmol) and HBTU (1.78 g, 4.69 mmol). The resulting mixture was stirred for 1 h at 0 °C followed by rt for 14 h. The mixture was evaporated to dryness and the residue re-dissolved in EtOAc (15 mL).…”

Section: Methodsmentioning

confidence: 99%

Sugar-Annulated Oxazoline Ligands: A Novel Pd(II) Complex and Its Application in Allylic Substitution

2016

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Two novel carbohydrate-derived pyridyl (PYOX)-and cyclopropyl (CYBOX)-substituted oxazoline ligands were prepared from D-glucosamine hydrochloride and 1,3,4,6-tetra-O-acetyl-2-amino-2-deoxy-β-D-glucopyranose hydrochloride in two steps, respectively. The sugar-annulated PYOX ligand formed a stable metal complex with Pd(II), which was fully characterized by NMR spectroscopy and X-ray crystallography. NMR and X-ray analysis revealed a change of the conformation in the sugar moiety upon complexation with the palladium(II) species. Both glycosylated ligands resulted in high asymmetric induction (up to 98% ee) upon application as chiral ligands in the Pd-catalyzed allylic alkylation of rac-1,3-diphenylallyl acetate with dimethyl malonate (Tsuji-Trost reaction). Both ligands provided mainly the (R)-enantiomer of the alkylation product.

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“…11 Further, transition-metal and photoredox catalyzed ammoxidations of aldehydes have been reported. 12 A few examples for the synthesis of nitriles from sp 2 C-H bonds via photocatalysis were reported by Nicewicz 13 and others. 14 However, the abovementioned methods often suffer from several drawbacks, such as the use of transition metals leading to metal residue waste, high temperature, low selectivity or the generation of toxic cyanide.…”

Section: Introductionmentioning

confidence: 99%

Visible-Light-Promoted Metal-Free Ammoxidation of C(sp3)-H bonds

Murugesan¹,

Donabauer²,

Koenig

2020

Preprint

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The metal-free activation of C(<i>sp</i><sup>3</sup>)-H bonds to value-added products is of paramount importance in organic synthesis. Herein, we report the use of the commercially available organic dye 2,4,6-triphenylpyrylium tetrafluoroborate (TPP) for the conversion of methylarenes to the corresponding aryl nitriles via a photo process. Applying this methodology, a variety of cyanobenzenes have been synthesized in good to excellent yield under metal- and cyanide-free conditions. We demonstrate the scope of the method with over 50 examples including late-stage functionalization of drug molecules (celecoxib) and complex structures such as L-menthol, amino acids and cholesterol derivatives. Further, the presented synthetic protocol is applicable for gram-scale reactions. In addition to methylarenes, selected examples for the cyanation of aldehydes, alcohols and oximes are demonstrated as well. Detailed mechanistic investigations have been carried out using time-resolved luminescence quenching studies, control experiments and NMR‑ spectroscopic as well as kinetic studies, all supporting the proposed catalytic cycle.

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Synthesis of NAG-thiazoline-derived inhibitors for β-N-acetyl-d-hexosaminidases

Cited by 13 publications

References 26 publications

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors

Sugar-Annulated Oxazoline Ligands: A Novel Pd(II) Complex and Its Application in Allylic Substitution

Visible-Light-Promoted Metal-Free Ammoxidation of C(sp3)-H bonds

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