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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 |

REPOSITORIES: biostudies-literature

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Ring-opening polymerization of prodrugs: a versatile approach to prepare well-defined drug-loaded nanoparticles.

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Versatile Platinum(IV) Prodrugs of Naproxen and Acemetacin as Chemo-Anti-Inflammatory Agents.

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| S-EPMC10059886 | biostudies-literature

Synthesis of C-Oligosaccharides through Versatile C(sp<sup>3</sup> )-H Glycosylation of Glycosides.

Project description:C-oligosaccharides are pharmacologically relevant because they are more hydrolysis-resistant than O-oligosaccharides. Despite indisputable advances, C-oligosaccharides continue to be underdeveloped, likely due to a lack of efficient and selective strategies for the assembly of the interglycosidic C-C linkages. In contrast, we, herein, report a versatile and robust strategy for the synthesis of structurally complex C-oligosaccharides via catalyzed C(sp3 )-H activations. Thus, a wealth of complex interglycosidic (2→1)- and (1→1)-C-oligosaccharides becomes readily available by palladium-catalyzed C(sp3 )-H glycoside glycosylation. The isolation of key palladacycle intermediates and experiments with isotopically-labeled compounds identified a trans-stereoselectivity for the C(sp3 )-H glycosylation. The glycoside C(sp3 )-H activation manifold was likewise exploited for the diversification of furanoses, pyranoses and disaccharides.

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Metabolic engineering of Escherichia coli into a versatile glycosylation platform: production of bio-active quercetin glycosides.

Project description:BackgroundFlavonoids are bio-active specialized plant metabolites which mainly occur as different glycosides. Due to the increasing market demand, various biotechnological approaches have been developed which use Escherichia coli as a microbial catalyst for the stereospecific glycosylation of flavonoids. Despite these efforts, most processes still display low production rates and titers, which render them unsuitable for large-scale applications.ResultsIn this contribution, we expanded a previously developed in vivo glucosylation platform in E. coli W, into an efficient system for selective galactosylation and rhamnosylation. The rational of the novel metabolic engineering strategy constitutes of the introduction of an alternative sucrose metabolism in the form of a sucrose phosphorylase, which cleaves sucrose into fructose and glucose 1-phosphate as precursor for UDP-glucose. To preserve these intermediates for glycosylation purposes, metabolization reactions were knocked-out. Due to the pivotal role of UDP-glucose, overexpression of the interconverting enzymes galE and MUM4 ensured the formation of both UDP-galactose and UDP-rhamnose, respectively. By additionally supplying exogenously fed quercetin and overexpressing a flavonol galactosyltransferase (F3GT) or a rhamnosyltransferase (RhaGT), 0.94 g/L hyperoside (quercetin 3-O-galactoside) and 1.12 g/L quercitrin (quercetin 3-O-rhamnoside) could be produced, respectively. In addition, both strains showed activity towards other promising dietary flavonols like kaempferol, fisetin, morin and myricetin.ConclusionsTwo E. coli W mutants were engineered that could effectively produce the bio-active flavonol glycosides hyperoside and quercitrin starting from the cheap substrates sucrose and quercetin. This novel fermentation-based glycosylation strategy will allow the economically viable production of various glycosides.

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Project description:A key thioether substituent in readily accessible 2-alkyl-5-(methylthio)tetrazoles enables facile photoinduced denitrogenation and intramolecular nitrile imine 1,3-dipolar cycloaddition to afford a wide range of polycyclic pyrazoline products with excellent diastereoselectivity. The methylthio group red-shifts the UV absorbance of the tetrazole, obviating the requirement in all previous substrate systems for at least one aryl substituent, and can subsequently be converted into a variety of other functionalities. This synthetic platform has been applied to the concise total syntheses of the alkaloid natural products (±)-newbouldine and withasomnine.

| S-EPMC4126266 | biostudies-literature

Glycosyl ortho-(1-phenylvinyl)benzoates versatile glycosyl donors for highly efficient synthesis of both O-glycosides and nucleosides.

Project description:Both of O-glycosides and nucleosides are important biomolecules with crucial rules in numerous biological processes. Chemical synthesis is an efficient and scalable method to produce well-defined and pure carbohydrate-containing molecules for deciphering their functions and developing therapeutic agents. However, the development of glycosylation methods for efficient synthesis of both O-glycosides and nucleosides is one of the long-standing challenges in chemistry. Here, we report a highly efficient and versatile glycosylation method for efficient synthesis of both O-glycosides and nucleosides, which uses glycosyl ortho-(1-phenylvinyl)benzoates as donors. This glycosylation protocol enjoys the various features, including readily prepared and stable donors, cheap and readily available promoters, mild reaction conditions, good to excellent yields, and broad substrate scopes. In particular, the applications of the current glycosylation protocol are demonstrated by one-pot synthesis of several bioactive oligosaccharides and highly efficient synthesis of nucleosides drugs capecitabine, galocitabine and doxifluridine.

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