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Chloromethyl Glycosides as Versatile Synthons to Prepare Glycosyloxymethyl-Prodrugs.

ABSTRACT: This work investigates the addition of monosaccharides to marketed drugs to improve their pharmacokinetic properties for oral absorption. To this end, a set of chloromethyl glycoside synthons were developed to prepare a variety of glycosyloxymethyl-prodrugs derived from 5-fluorouracil, thioguanine, propofol and losartan. Drug release was studied in vitro using β-glucosidase confirming rapid conversion of the monosaccharide prodrugs to release the parent drug, formaldehyde and the monosaccharide. To showcase this prodrug approach, a glucosyloxymethyl conjugate of the tetrazole-containing drug losartan was used for in vivo experiments and showed complete release of the drug in a dog-model.

SUBMITTER: Elferink H

PROVIDER: S-EPMC9304170 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Chloromethyl Glycosides as Versatile Synthons to Prepare Glycosyloxymethyl-Prodrugs.

Elferink Hidde H Titulaer Willem H C WHC Derks Maik G N MGN Veeneman Gerrit H GH Rutjes Floris P J T FPJT Boltje Thomas J TJ

Chemistry (Weinheim an der Bergstrasse, Germany) 20220124 9

This work investigates the addition of monosaccharides to marketed drugs to improve their pharmacokinetic properties for oral absorption. To this end, a set of chloromethyl glycoside synthons were developed to prepare a variety of glycosyloxymethyl-prodrugs derived from 5-fluorouracil, thioguanine, propofol and losartan. Drug release was studied in vitro using β-glucosidase confirming rapid conversion of the monosaccharide prodrugs to release the parent drug, formaldehyde and the monosaccharide. ...[more]

PMID: 35045197

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