77698-99-8Relevant academic research and scientific papers
A Fluorescence Polarization Activity-Based Protein Profiling Assay in the Discovery of Potent, Selective Inhibitors for Human Nonlysosomal Glucosylceramidase
Lahav, Dani?l,Liu, Bing,Van Den Berg, Richard J.B.H.N.,Van Den Nieuwendijk, Adrianus M. C. H.,Wennekes, Tom,Ghisaidoobe, Amar T.,Breen, Imogen,Ferraz, Maria J.,Kuo, Chi-Lin,Wu, Liang,Geurink, Paul P.,Ovaa, Huib,Van Der Marel, Gijsbert A.,Van Der Stelt, Mario,Boot, Rolf G.,Davies, Gideon J.,Aerts, Johannes M. F. G.,Overkleeft, Herman S.
supporting information, p. 14192 - 14197 (2017/10/17)
Human nonlysosomal glucosylceramidase (GBA2) is one of several enzymes that controls levels of glycolipids and whose activity is linked to several human disease states. There is a major need to design or discover selective GBA2 inhibitors both as chemical tools and as potential therapeutic agents. Here, we describe the development of a fluorescence polarization activity-based protein profiling (FluoPol-ABPP) assay for the rapid identification, from a 350+ library of iminosugars, of GBA2 inhibitors. A focused library is generated based on leads from the FluoPol-ABPP screen and assessed on GBA2 selectivity offset against the other glucosylceramide metabolizing enzymes, glucosylceramide synthase (GCS), lysosomal glucosylceramidase (GBA), and the cytosolic retaining β-glucosidase, GBA3. Our work, yielding potent and selective GBA2 inhibitors, also provides a roadmap for the development of high-throughput assays for identifying retaining glycosidase inhibitors by FluoPol-ABPP on cell extracts containing recombinant, overexpressed glycosidase as the easily accessible enzyme source.
Convenient one-pot synthesis of thiosugars and their efficient conversion to polyoxygenated cycloalkenes
Zhang, Jingjing,Niu, Youhong,Cao, Xiaoping,Ye, Xin-Shan
experimental part, p. 4242 - 4247 (2012/07/14)
A convenient synthesis of polyoxygenated tetrahydrothiopyrans and thiepanes from various alditol derivatives with xylo, ribo, manno, gluco, galacto, and fuco configurations is described. The preparation started from the corresponding partially protected a
Dual-action lipophilic iminosugar improves glycemic control in obese rodents by reduction of visceral glycosphingolipids and buffering of carbohydrate assimilation
Wennekes, Tom,Meijer, Alfred J.,Groen, Albert K.,Boot, Rolf G.,Groener, Johanna E.,Van Eijk, Marco,Ottenhoff, Roelof,Bijl, Nora,Ghauharali, Karen,Song, Hang,O'Shea, Tom J.,Liu, Hanlan,Yew, Nelson,Copeland, Diane,Van Den Berg, Richard J.,Van Der Marel, Gijsbert A.,Overkleeft, Herman S.,Aerts, Johannes M.
supporting information; experimental part, p. 689 - 698 (2010/07/06)
The lipophilic iminosugar N-[5-(adamantan-1-ylmethoxy)pentyl]-1- deoxynojirimycin (2, AMP-DNM) potently controls hyperglycemia in obese rodent models of insulin resistance. The reduction of visceral glycosphingolipids by 2 is thought to underlie its beneficial action. It cannot, however, be excluded that concomitant inhibition of intestinal glycosidases and associated buffering of carbohydrate assimilation add to this. To firmly establish the mode of action of 2, we developed a panel of lipophilic iminosugars varying in configuration at C-4/C-5 and N-substitution of the iminosugar. From these we identified the L-ido derivative of 2, L-ido-AMP-DNM (4), as a selective inhibitor of glycosphingolipid synthesis. Compound 4 lowered visceral glycosphingolipids in ob/ob mice and ZDF rats on a par with 2. In contrast to 2, 4 did not inhibit sucrase activity or sucrose assimilation. Treatment with 4 was significantly less effective in reducing blood glucose and HbA1c. We conclude that the combination of reduction of glycosphingolipids in tissue and buffering of carbohydrate assimilation by 2 produces a superior glucose homeostasis.
Stereocontrolled formation of protected aminodeoxyalditols from simple carbohydrate precursors by debenzylating cycloetherification
Jiang, Yuhua,Fang, Zhijie,Zheng, Qiangang,Jia, Hailang,Cheng, Jie,Zheng, Baohui
experimental part, p. 2756 - 2760 (2010/01/21)
A new and highly efficient methodology for the stereocontrolled synthesis of aminodeoxyalditols is described through a dimesylation/intramolecular SN2 nucleophilic substitution ringforming reaction sequence from glucose, mannose, and galactose derivatives
Regioselective eliminations in reactions of carbohydrate derivatives with superoxide, or with borohydride in 2-propanol
Rao, Vanga S.,Perlin, Arthur S.
, p. 333 - 338 (2007/10/02)
The reaction between 2,3,4,6-tetra-O-benzyl-1,5-di-O-mesyl-D-glucitol (2) and potassium superoxide resulted in the loss of H-4 and the 5-mesyloxy (as well as 1-mesyloxy) substituent, and an almost quantitative conversion into enol ether 4, i.e., 1,3,4,5-tetra-O-benzyl-3-dehydro-2-deoxy-L-threo-hex-2-enitol.When the reaction was performed with 8, in which the 1-O-mesyl group (of 2) is replaced by O-(methoxy)trityl, the outcome was wholly different: an olefin was formed through the removal of a primary (H-6) rather than a secondary (H-4) proton, and nucleophilic displacement also took place.Results similar to those for 8 were obtained with the 2-epimer of 2, i.e., 2,3,4,6-tetra-O-benzyl-1,5-di-O-mesyl-D-mannitol (12).It is suggested that selective displacement of the 1-O-mesyl group of 2 by superoxide generates a 1-peroxy anion (6) that abstracts H-4 intramolecularly, promoting concomitant loss of the 5-mesyloxy group.The transition state for proton abstraction within anion 6 appears to be more stable than that of the corresponding anion in the manno series, accounting for the different reaction routes for 2 and 12.Elimination occured also in the reduction of 2,3,4,6-tetra-O-benzyl-D-glucopyranose with sodium borohydride in 2-propanol, en route to 2, affording 2,4,6-tri-O-benzyl-2-dehydro-3-deoxy-D-threo-hex-2-enitol (21).The (1)H nmr spectra of alditol derivatives 2, 8, and 12 show that these molecules depart substantially from extended zigzag conformations, in contrast to configurationally related peracetylated acyclic derivatives.
