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Chloromethyl Glycosides as Versatile Synthons to Prepare Glycosyloxymethyl‐Prodrugs
Author(s) -
Elferink Hidde,
Titulaer Willem H. C.,
Derks Maik G. N.,
Veeneman Gerrit H.,
Rutjes Floris P. J. T.,
Boltje Thomas J.
Publication year - 2022
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202103910
Subject(s) - synthon , prodrug , glycoside , chemistry , combinatorial chemistry , organic chemistry , biochemistry
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.