3 research outputs found
Glikomimetrikumok előállĂtása anhidro-aldiminekbĹ‘l = Synthesis of glycomimetics from anhydro-aldimines
CĂ©lkitűzĂ©sĂĽnk potenciális glikoenzim (glikozil-transzferáz, glikozidáz vagy glikogĂ©n foszforiláz) inhibitorok előállĂtása volt, melyek szerepet játszhatnak a működĂ©smĂłd felderĂtĂ©sben, illetve szerepĂĽk lehet pĂ©ldául a rák, diabetes, egyes lizoszomális tárolási betegsĂ©gek (Gaucher and Tay-Sachs kĂłr), kardiovaszkuláris iszkĂ©mia, valamint az AIDS gyĂłgyĂtásában. Glikozil-transzferázok gátlására N-Glikozil-N”-(5’-uridil) biureteket Ă©s 5’-uridil N-glikozil-allofanátokat állĂtottunk elĹ‘. In silico vizsgálatok alapján várhatĂłan glikogĂ©n foszforiláz gátlĂł N-β-D-glĂĽkopiranozil-N”-β-D-glikopiranozil biureteket Ă©s N-glĂĽkopiranozil-N’-glikopiranozil-karbonil-karbamidokat állĂtottunk elĹ‘. C-glikozil α- Ă©s β-aminosav származĂ©kok előállĂtásához prekurzorokat kĂ©szĂtettĂĽnk, anhidro-aldĂłz-benzoilhidrazonok nukleofil addĂciĂłs reakciĂłival. Anhidro-aldĂłz-benzoilhidrazonok oxidatĂv gyűrűzárásával potenciális glikogĂ©n foszforiláz inhibitorokat, 2-(D-glikopiranozil)-5-szubsztituált-1,3,4-oxadiazolokat állĂtottunk elĹ‘. | The goal of our work was the synthesis of potential glycoenzyme (glycosyl-transferase, glycosidase or glycogen phosphorylase) inhibitors. These molecules can play a role in understanding the mechanism of action of these enzymes, and in treatment of cancer, diabetes, lysosomal storage disease (Gaucher and Tay-Sachs syndromes), cardiovascular ischemia, and AIDS. N-Glycosyl-N”-(5’-uridyl) biurets and 5’-uridyl N-glycosylallophanates were synthesized for glycosyl transferase inhibition. On the basis of in silico studies N-β-D-glucopyranosyl-N”-β-D-glycopyranosyl biurets and N-glucopyranosyl-N’-glycopyranosylcarbonyl ureas were prepared as potential glycogen phosphorylase inhibitors. Precursors towards C-glycosylated α- and β-amino acid derivatives were synthesized by addition of nucleophiles to anhydro-aldose-benzoylhydrazones. Potential glycogen phosphorylase inhibitors, 2-(D-glycopyranosyl)-5-substituted-1,3,4-oxadiazoles were synthesized by the oxidative ring clousure of anhydro-aldose-benzoylhydrazones
Glikozil-azidok szerepe az anomer szĂ©natomhoz nitrogĂ©nen kötĹ‘dĹ‘ funkciĂłs csoportok kialakĂtásában = Role of glycosyl azides in the formation of N-bound functional groups at the anomeric centre
A kutatás cĂ©lkitűzĂ©se az N-glikozil-amidok szintĂ©zismĂłdszereinek fejlesztĂ©se Ă©s szerkezeti mĂłdosĂtásuk volt. A Györgydeák Zoltán által mĂłdosĂtott Staudinger-körĂĽlmĂ©nyeket (PMe3 diklĂłrmetánban vagy toluolban) alkalmaztuk a per-O-acetilezett 2-acetamido- Ă©s a 2-ftálimido-2-dezoxi-D-glĂĽkopiranozil-azidok, az 5-tio-D-glĂĽkopiranozil-azidok Ă©s a b-L-fukopiranozil-azid átalakĂtására a megfelelĹ‘ trimetil-foszfinimiddĂ©, melyeket (amino)karbonsavakkal vagy savkloridokkal vagy savanhidridekkel N-glikozil-amidokká alakĂtottunk. Ezen az Ăşton megoldottuk a "glĂĽkĂłzamin-aszparagin", az N-glikopeptidek kapcsolĂłdási pontját kĂ©pezĹ‘ amid előállĂtását is. Alifás, aromás Ă©s más összetett mono- Ă©s dikarbonsavak vagy származĂ©kaik segĂtsĂ©gĂ©vel előállĂtottunk számos N-b-D-glĂĽkopiranozil-amidot, melyek glikogĂ©n foszforiláz b enzimre mĂ©rt inhibitorállandĂłja több esetben az alacsony mikromĂłlos tartományba esik. Az emlĂtett körĂĽlmĂ©nyek alkalmazásakor per-O-acilezett (b-D-hex-2-ulopiranozil-azid)onsavnitrilek, -amidok Ă©s -Ă©szterek körĂ©ben az intermedier foszfinimidek anomerizáciĂłja Ă©s az acilezĂ©s, illetve más mellĂ©kreakciĂłk sebessĂ©ge összemĂ©rhetĹ‘, ezĂ©rt a mĂłdszer a megfelelĹ‘ N-glikozil-amidok előállĂtására kevĂ©ssĂ© alkalmas. HasználhatĂł az eljárás N-glikopiranozil-szulfonamidok Ă©s -amidoximok kĂ©pzĂ©sĂ©re is. A glikozil-azidok kĂ©miájárĂłl könyvfejezet kĂ©szĂĽlt mintegy 350 publikáciĂł alapján. | Aims of the research were to develop the synthetic methodology of N-glycopyranosyl amides and their structural modification. Staudinger-conditions modified by Zoltán Györgydeák (PMe3 in dichloromethane or toluene) were applied for the transformation of per-O-acetylated 2-acetamido- and 2-phthalimido-2-deoxy-D-glucopyranosyl azides, 5-thio-D-glucopyranosyl azides, and b-L-fucopyranosyl azide to the corresponding trimethyl-phosphinimides which were acylated by (amino)carboxylic acids or acid chlorides or anhydrides to N-glycosyl amides. ?Glucoseamine asparagin? the coupling element of N-glycopeptides was also prepared in this way. By using aliphatic, aromatic, and other complex carboxylic acids or their derivatives several N-b-D-glucopyranosyl amides were obtained some of which had an inhibition constant against glycogen phosphorylase b in the low micromolar range. In reactions of per-O-acetylated (b-D-hex-2-ulopyranosyl azide)ononitriles, -onamides, and -onate esters under the above conditions rates of anomerization of the phosphinimide and that of the acylation as well as other side-reactions proved comparable, therefore, the method seemed less suitable for the preparation of the correponding N-glycosyl amides. The procedure can be used for getting N-glycopyranosyl sulfonamides and -amidoximes, as well. Chemistry of glycosyl azides was surveyed in a book chapter based on approximately 350 publications
Glikoenzim-inhibĂtorok előállĂtása = Synthesis of glycoenzyme inhibitors
A szĂ©nhidrát alapĂş gyĂłgyszerek kifejlesztĂ©sĂ©nek egyik iránya a glikoenzimek gátlĂłszereinek Ă©s szerkezet?hatás összefĂĽggĂ©seiknek (SAR) felderĂtĂ©se. A kutatás során glikozidázokat, amilázokat Ă©s glikogĂ©n foszforilázokat (GP) gátlĂł cukorszármazĂ©kokat kĂ©szĂtettĂĽnk, melyek - fĹ‘kĂ©pp antidiabetikus - terápiás cĂ©lokra lehetnek alkalmasak. A GP elsĹ‘ nanomĂłlos glĂĽkĂłzanalĂłg inhibitorait kĂ©szĂtettĂĽk el N-beta-D-glĂĽkopiranozil-N'-szubsztituált karbamidok, analĂłgjaik Ă©s származĂ©kaik szintĂ©zise során. RĂ©szletes SAR-t állĂtottunk fel Ăşj gátlĂłszerek kifejlesztĂ©sĂ©hez. MegfigyeltĂĽk e származĂ©kok kötĹ‘dĂ©sĂ©t a katalitikus helyen kĂvĂĽl az Ăşj allosztĂ©rikus helyhez is, Ă©s cĂ©lzottan ide irányĂthatĂł cukorvegyĂĽleteket kĂ©szĂtettĂĽnk. A GP Ăşjabb nanomĂłlos gátlĂłszereit fedeztĂĽk fel glikopiranozilidĂ©n-spiro-oxadiazolok, -szulfahidantoinok, -tiazolonok, -imidazolonok Ă©s -oxatiazolok szintĂ©zisĂ©nek vizsgálatakor. Egyes oxatiazolok az E. coli galaktozidáz millimĂłlos inhibitorai. Az enzimatikusan szintetizált akarviozinil-izomaltozil-spiro-tiohidantoin a nyál amiláz akarbĂłznál nĂ©gyszer jobb inhibitora. SztereoszelektĂv mĂłdszerekkel anomer alfa-aminosavat tartalmazĂł di- Ă©s tripeptideket kĂ©szĂtettĂĽnk. A 2,2,2-triklĂłretil-alapĂş vĂ©dĹ‘csoportok kemoszelektĂv lehasĂtását Ărtuk le redukciĂłra Ă©s savakra Ă©rzĂ©keny csoportok mellett. FelkĂ©rĂ©sre több összefoglalĂłt Ărtunk a GP gátlĂłk tervezĂ©sĂ©rĹ‘l Ă©s antidiabetikus alkalmazási lehetĹ‘sĂ©geikrĹ‘l. | Discovery of inhibitors of glycoenzymes and revealing their structure?activity relationship (SAR) is a principal trend in the development of carbohydrate based drugs. In our research sugar derivatives of therapeutic (mainly antidiabetic) potential inhibiting glycosidases, amylases, and glycogen phosphorylases (GP) were prepared. The first nanomolar glucose analog inhibitors of GP were obtained by syntheses of N-beta-D-glucopyranosyl-N'-substituted ureas, their analogs and derivatives. A detailed SAR was deduced for developing new inhibitors. Binding of these derivatives to the new allosteric site vs. the catalytic site of GP was observed, and sugar compounds to be diverted to this site were synthesized. Further novel nanomolar inhibitors of GP were found during investigation of syntheses for glycopyranosylidene-spiro-oxadiazoles, -sulfahydantoins, -thiazolones, -imidazolones, and -oxathiazoles. Some oxathiazoles are millimolar inhibitors of E. coli galactosidase. Acarviosinyl-isomaltosyl-spiro-thiohydantoin obtained by enzymatic synthesis proved a 4-fold better inhibitor of salivary amylase than acarbose. Di- and tripeptides containing anomeric alpha-amino acids were made by stereoselective methods. A chemoselective method was described for deprotection of 2,2,2-trichloroethyl based blocking groups next to reducible and acid sensitive functionalities. On invitation several reviews were written about design and possible antidiabetic utilization of GP inhibitors