Journal
HETEROCYCLIC COMMUNICATIONS
Volume 23, Issue 3, Pages 187-195Publisher
WALTER DE GRUYTER GMBH
DOI: 10.1515/hc-2017-0092
Keywords
glucuronide; glycosylation; metabolite; silodosin
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Funding
- NIH [R01 GM085267, R01 AI083754]
- National Natural Science Foundation of China [21372130]
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We report here the first chemical synthesis of silodosin glucuronide, a metabolite of the alpha(1A)-adrenoceptor antagonist silodosin, and its deuterium-labeled counterpart. As a key synthetic step, the incorporation of a glucuronosyl unit onto silodosin invariably led to either an undesired orthoester or a complex mixture under an array of standard glycosylation conditions. This problematic O-glycosylation may be attributed to the presence of multiple basic groups that could neutralize the acidic activators, decrease the nucleophilicity of a hydroxy group via hydrogen bond or even facilitate acyl migration side reactions. After elaborate tuning of reaction conditions, success was eventually achieved by using perbenzoylated D-glucuronosyl N-phenyltrifluroacetimidate (PTFA) as donor in combination with a procedure of sequential addition of TMSOTf. This protocol is potentially general for the glycosylation of other nitrogen-containing small molecule drugs.
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