Synthesis of the α-L-iduronidase substrate and inhibitors
Date Issued
2013
Date
2013
Author(s)
Hsi, Wayne
Abstract
α-L-iduronidase (IDUA), an endoglycosidase, cleaves the 1,4-glycosidic bond between L-iduronic acids (L-IdoA) and D-glucosamine (or D-galactosamine) in heparin and heparan sulfate. The inhibition study of IDUA is important but rarely mentioned in the literature because materials such as L-Idopyranose and L-IdoA are not commercially available. And substrates are expensive. Thus, an economical source of IDUA substrate is needed.
Currently, IDUA has been found to involve with a genetically inherited lysosomal storage disease, mucopolysaccharidosis I (MPS1).
A synthetic route started from 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose, through C-5 inversion of configuration gave a key intermediate 3-OBn-L-idopyranose, followed by trichloroacetimidate-mediated glycosylation with 4-methylumbelliferone and selective primary alcohol oxidation by TEMPO catalyst to give the 4-methylumbelliferyl α-L-iduronide (4MU-α-IdoA) as a fluorogenic substrate for IDUA.
To mimic the oxocarbenium ion generated during IDUA hydrolysis, 2-(aminomethyl) pyrrolidine iminosugar scaffolds were prepared using a five-membered chiral cyclic nitrone as a key intermediate, followed by N-protection and selective oxidation by TEMPO/NaOCl/ NaClO2 to give the aza-L-iduronic acid analogs. An acid was coupled with a scaffold to. diversify at primary amine as a model for further inhibition study.
Subjects
亞胺醣
環硝
艾杜糖
己醛醣酸鹽水解酵素
抑制劑
Type
thesis
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