RÉSUMÉ
Herein we present the methodology for obtaining glycosyltransferase inhibitors, analogues of natural enzyme substrates of donor-type: UDP-glucose and UDP-galactose. The synthesis concerned glycoconjugates, nucleoside analogues containing an acyclic ribose mimetic linked to a uracil moiety in their structure. The biological activity of the synthesised compounds was determined on the basis of their ability to inhibit the model enzyme action of ß-1,4-galactosyltransferase from bovine milk. The obtained results allowed to expand and supplement the existing library of synthetic compounds that are able to regulate the biological activity of enzymes from the GT class.
Sujet(s)
Glycoconjugués/synthèse chimique , Glycoconjugués/pharmacologie , Uridine/synthèse chimique , Uridine/pharmacologie , Antienzymes/synthèse chimique , Antienzymes/composition chimique , Antienzymes/pharmacologie , Glycoconjugués/composition chimique , Glycosyltransferase/antagonistes et inhibiteurs , Structure moléculaire , Uridine/analogues et dérivés , Uridine/composition chimiqueRÉSUMÉ
A series of UDP-sugar analogues was synthesized and their preliminary biological activity was evaluated. Glycoconjugates of uridine 1 and 2 were synthesized by condensation of uridine-5'-carboxylic acid and 1-amino sugars derivatives of d-glucose and d-galactose, glycoconjugates 3 and 4 were synthesized by azide-alkyne 1,3-dipolar cycloaddition (CuAAC) of 1-azido sugars and propargylamide derivatives of uridine while glycoconjugates 5 and 6 were synthesized by CuAAC of propargyl ß-O-glycosides and 5'-azido uridine. Evaluation of inhibitory activity of compounds 1-6 against commercially available ß-1,4-galactosyltransferase I (ß4GalT) show that compound 5 inhibited the enzyme in µmolar range. Additionally, the antitumor activity of the obtained glycoconjugates 1-6 were tested using MTT assay.
Sujet(s)
Amides/pharmacologie , Galactosyltransferases/antagonistes et inhibiteurs , Glycoconjugués/pharmacologie , Triazoles/pharmacologie , Uridine/pharmacologie , Amides/composition chimique , Animaux , Bovins , Lignée cellulaire , Relation dose-effet des médicaments , Galactosyltransferases/métabolisme , Glycoconjugués/synthèse chimique , Glycoconjugués/composition chimique , Humains , Lait/enzymologie , Structure moléculaire , Relation structure-activité , Triazoles/composition chimique , Uridine/analogues et dérivés , Uridine/composition chimiqueSujet(s)
Antienzymes/synthèse chimique , Fucose/composition chimique , Glycoconjugués/synthèse chimique , Glycosyltransferase/antagonistes et inhibiteurs , Uridine/composition chimique , Chromatographie sur couche mince , Antienzymes/composition chimique , Antienzymes/pharmacologie , Glycoconjugués/composition chimique , Glycoconjugués/pharmacologie , Spectroscopie par résonance magnétique , Structure moléculaireRÉSUMÉ
A hexadentate ligand built on an amine-bis(phenol) skeleton with an aminal, self-immolative moiety is presented. Synthesis of the ligand is convenient and relatively high yielded. Moreover, it enables synthesis of many derivatives, both in the amino-phenol and aminal fragment (various heterocycles). Once the final hexadentate ligand is synthesized via the Katritzky reaction, it becomes prone to hydrolysis. Bioactivation by ß-galactosidase cleaves the glycosylic bond and a spontaneous collapse of the aminal fragment occurs, thus leading to a pentadentate chelate. This bioactivation has been shown for pyrazole, 1,2,4-triazole and benzotriazole derivatives.
Sujet(s)
Amines/composition chimique , Composés hétérocycliques/composition chimique , Composés hétérocycliques/synthèse chimique , Phénols/composition chimique , Techniques de chimie synthétique , Cristallographie aux rayons X , Hétérosides/composition chimique , Ligands , ProtonsRÉSUMÉ
The synthesis of (5-nitro-2-pyridyl) 2-deoxy-1-thioglycosides is presented. Obtained compounds were used in the synthesis of uridine derivatives, potential glycosyltransferases inhibitors. In the first stage of the research 2-deoxyglucose and 2-deoxygalactose were connected to aglycone (nitropyridine derivative) via alpha-1-thioglycosidic bond. Therefore, protected 1.2-unsaturated D-glucose or D-galactose derivatives were treated with 2-thio-5-nitropyridine in the presence of the catalyst. In the next step nitro group in the aglycone was reduced in the reaction with the use of zinc dust in acetic acid. Then, these compounds were connected to selectively protected uridine derivatives by amide bond with or without succinic spacer. The obtained glycoconjugates differ in the protecting group of the carbohydrate part and in the presence of the spacer between the sugar and uridine moiety.
Sujet(s)
Glycoconjugués/synthèse chimique , Thioglycosides/synthèse chimique , Uridine/composition chimiqueRÉSUMÉ
The title compounds, variously protected 2.3-anhydrosugars linked with genistein through an alkyl chain, were synthesized in a sequence of reactions. First step involved Ferrier rearragement of 3,4-di-O-acetyl-L-rhamnal with 3-bromopropanol to obtain 2,3-unsaturated bromoalkylglycosides. The next step was epoxidation with m-CPBA and finally these compounds were connected with genistein in reaction of 7-O-genistein tetra-butylamonium salt with 2,3-anhydro bromoalkylglycosides. Obtained glycoconjugates differ in orientation of an oxirane ring and the protecting group in a sugar moiety. All compounds were tested in vitro for antiproliferative potential in cancer cells.
Sujet(s)
Antinéoplasiques/synthèse chimique , Prolifération cellulaire/effets des médicaments et des substances chimiques , Génistéine/analogues et dérivés , Glycoconjugués/synthèse chimique , Antinéoplasiques/pharmacologie , Génistéine/pharmacologie , Glycoconjugués/pharmacologie , Cellules HCT116 , HumainsRÉSUMÉ
5-Nitro-2-pyridyl-1-thioglucosides were used in synthesis of complex uridine derivatives (13-16) in two different sequences of reactions. In one route, the first step was glycosylation of selectively protected 5-nitro-2-pyridyl-1-thioglucoside 1 with two different glycosyl donors (5 or 6), next, the nitro group in aglycone of obtained disaccharides 7 or 8 was reduced and then obtained products 9 or 10 were condensed with uridine derivatives 3 or 4 using DMT-MM as condensing agent under microwave irradiation. In the second route, condensation and glycosylation reactions were applied in reverse order. As it turned up, a sequence of reactions affected the yield of final glycoconjugates 13-16 and depended on the type of uridine derivatives used.