期刊
BIOORGANIC & MEDICINAL CHEMISTRY
卷 19, 期 6, 页码 1966-1971出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2011.01.060
关键词
Benzyl and biphenylmethyl sialosides; CD22; Hydrophobic interaction; Selectivity; MAG; ELISA
资金
- Egyptian Government
- Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan [1710100, 22380007]
- CREST of JST (Japan Science and Technology Corporation)
- NIH [GM60938, AI50143]
- Grants-in-Aid for Scientific Research [22380067, 23790531, 21603007, 22380007, 22658038] Funding Source: KAKEN
In earlier studies, we identified the C-9 amido derivative 1 (9-(4'-hydroxy-4-biphenyl)acetamido-9-deoxy-Neu5Gc alpha 2-6GalOMP) and the C-9 amino derivative 2 (9-(4'-hydroxy-4-biphenyl)methylamino-9-deoxy-Neu5Gc alpha 2-6GalOMP) have the most promising affinity for mouse CD22 and human CD22, respectively. Replacing the subterminal galactose residue (2-6Gal-OMP) of 1 with benzyl (5) or biphenylmethyl (6) as aglycone led to even higher potency for mCD22. In this study, both compounds showed improved potency and selectivity for CD22 (IC(50) 70 nM) and 712-fold more selective for CD22 than for MAG. The corresponding derivatives of 2, compounds 8 and 9, showed comparable activity to 2 but lower potency and selectivity than 5 and 6. Although compounds 5-9 are simple and small molecular weight antagonists, they showed much high potency and selectivity than the corresponding compounds having a 2-6Gal linkage. Both biological and computational docking simulation studies suggest that the 2-6GalOMP residues of 1 and 2 are not critical for binding process and could be replaced with hydrophobic non-carbohydrate moieties. The data presented herein has significant implications for the design and discovery of next-generation CD22-antagonists. (C) 2011 Elsevier Ltd. All rights reserved.
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