Design and Synthesis of Activity Probes for Aryl Sulfatase
Date Issued
2008
Date
2008
Author(s)
Tai, Chih-Hsuan
Abstract
Sulfatases play a key role in regulating the sulfation status of many physiologically important biomolecules, and have become a target for drug development. In this thesis we report the design and synthesis of activity-based probes for this important enzyme family. An activity-based probe consists of four structural components; a recognition head, a trapping device, a linker, and a reporter group. Since most arylsulfatases could hydrolyze simple aryl sulfates therefore we attempted to develop two series of probes utilizing tyrosine derivatives as the core structure for the recognition heads and the trapping devices. These two series of probes differ in their mechanism of action. The first series exploits the concept of suicide substrate. When the probe is hydrolyzed by the target sulfatase, it will release an intermediate that undergoes elimination to form a reactive quinone methide which in turn reacts with nearby nucleophiles. The second series belongs to an electrophilic reagent which utilizes a cyclic sulfamate moiety serving both as the recognition unit and the trapping device. It is expected to form a covalent linkage with the target enzyme at the active site. A biotin and an azido group were respectively used as the reporter group for the one-stage and two-stage labeling protocols. Their labeling performance is currently under investigation.
Subjects
sulfatases
activity-based probes
suicide substrate
electrophilic reagent
two-stage labeling
SDGs
Type
thesis
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