Synthesis of the α-L-iduronidase substrate and inhibitors

• Main Authors: Wayne Hsi, 奚偉恩
• Other Authors: 羅禮強
• Format: Others
• Language: en_US
• Published: 2013
• Online Access: http://ndltd.ncl.edu.tw/handle/f6etyc

碩士 === 國立臺灣大學 === 化學研究所 === 102 === 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.