Synthesis and high-throughput screening of N-acetyl-beta-hexosaminidase inhibitor libraries targeting osteoarthritis.
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.
Liu
Junjie
J
Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Numa
Mehdi M D
MM
Liu
Haitian
H
Huang
Shi-Jung
SJ
Sears
Pamela
P
Shikhman
Alexander R
AR
Wong
Chi-Huey
CH
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*
D004791:Enzyme Inhibitors; D001619:beta-N-Acetylhexosaminidases