Chloromethyl Glycosides as Versatile Synthons to Prepare Glycosyloxymethyl-Prodrugs.

Hidde Elferink, Willem H C Titulaer, Maik G N Derks, Gerrit H Veeneman, Floris P J T Rutjes, Thomas J Boltje

Chemistry (Weinheim an der Bergstrasse, Germany) 2022 Feb 16

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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. © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.

Citation

Hidde Elferink, Willem H C Titulaer, Maik G N Derks, Gerrit H Veeneman, Floris P J T Rutjes, Thomas J Boltje. Chloromethyl Glycosides as Versatile Synthons to Prepare Glycosyloxymethyl-Prodrugs. Chemistry (Weinheim an der Bergstrasse, Germany). 2022 Feb 16;28(9):e202103910