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. 2022 Feb 16;28(9):e202103910.
doi: 10.1002/chem.202103910. Epub 2022 Jan 24.

Chloromethyl Glycosides as Versatile Synthons to Prepare Glycosyloxymethyl-Prodrugs

Hidde Elferink  1 , Willem H C Titulaer  1 , Maik G N Derks  1 , Gerrit H Veeneman  2 , Floris P J T Rutjes  1 , Thomas J Boltje  1
Affiliations

Chloromethyl Glycosides as Versatile Synthons to Prepare Glycosyloxymethyl-Prodrugs

Hidde Elferink et al. Chemistry. .

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.

Keywords: bioavailability; carbohydrates; glucose; glycosidase e; prodrugs.

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Figures

Figure 1
Figure 1
Uptake and hydrolysis of glucosyloxymethyl drug conjugates in enterocytes. SGLT1=sodium dependent glucose transporter 1; LPH=Lactase Phlorizin Hydrolase; CBG=cytosolic beta glucosidase; dotted line=passive diffusion. X=hetero‐atom inherent to the drug molecule.
Figure 2
Figure 2
Enzyme substrate interactions. a) 3D image of the interactions of β‐d‐glucose in the glycone pocket of hCBG (2E9L). The hydrogen bond network is shown in green. b) 2D overview of important residues in the glycone and aglycone pocket of hCBG and Abg (italic). Residues that are situated below the substrate are partially transparent.
Figure 3
Figure 3
Enzymatic hydrolysis studied by quantitative 1H NMR. The hydrolysis of glycosyl conjugates is was studied by tracking key‐signals of the conjugate (in black) and the product (in blue) in the NMR spectrum. Key signals were represented by the aromatic protons (square) and the spacer methylene protons (circle). Reagents and conditions: 5 a (13 mM) was measured in D2O with maleate buffer pD 6.5. Agrobactrium Sp. was added from stock to a final concertation of 1.6 U/mL.
Figure 4
Figure 4
PK‐study of losartan conjugate 19. The parent compound (panel a, losartan) and the prodrug conjugate (panel b, 19) were administered (15 μmol/kg, 1 mL/kg) to female Beagle dogs and circulating concentration of the drug and conjugate were determined at fixed time points. Since no conjugate was detected in the blood circulation, only the concentration of losartan is reported.
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