title: Synthesis and high-throughput screening of N-acetyl-beta-hexosaminidase inhibitor libraries targeting osteoarthritis.
abstract: C1 Nitrogen iminocyclitols are potent inhibitors of N-acetyl-beta-hexosaminidases. Given hexosaminidases' important roles in osteoarthritis, we developed two straightforward and efficient syntheses of C1 nitrogen iminocyclitols from two readily available starting materials, D-mannosamine hydrochloride and the microbial oxidation product of fructose. A diversity-oriented synthetic strategy was then performed by coupling these core structures with various aldehydes, carboxylic acids, and alkynes to generate three separate libraries. High-throughput screening of the generated libraries with human N-acetyl-beta-hexosaminidases produced only moderate inhibitory activities. However, the synthetic approach and screening strategy for these compounds will be applied to develop new potent inhibitors of human N-acetyl-beta-hexosaminidases, particularly when combined with the structural information of these enzymes.
authors.affiliation: Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Junjie
authors.initials: J
authors.lastname: Liu
authors.forename: Mehdi M D
authors.initials: MM
authors.lastname: Numa
authors.forename: Haitian
authors.initials: H
authors.lastname: Liu
authors.forename: Shi-Jung
authors.initials: SJ
authors.lastname: Huang
authors.forename: Pamela
authors.initials: P
authors.lastname: Sears
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Shikhman
authors.forename: Chi-Huey
authors.initials: CH
authors.lastname: Wong
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000627:therapeutic use*; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010003:Osteoarthritis / Q000188:drug therapy*; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D001619:beta-N-Acetylhexosaminidases