Glycosyltransferases (GTs) are enzymes that catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules. The result of the reaction catalyzed by these type of enzymes is the formation of a new glycosidic linkage [1-2].
This contribution describes preparation of precursors of glycosyltransferase inhibitors as a possible element for treatment of large scale diseases based on errors in glycosylation. Its course as well as changes in glycosylation have become the subject of various studies of scientific and pharmaceutical research.
Based on the calculated structural features of transition state model, a new scaffold has been proposed. Donor part is mimicking by hexofuranose skeleton (D-fructose, D-tagatose, D-psicose) and acceptor part is mimicked by different substituted thioglycosides (methyl, ethyl, phenyl or benzyl). The leaving group (uridine diphosphate) is mimicked as well by corresponding esthers of phosphoric acid at C-1 position. Then is obtained negative charge by hydrolysis. These type enzymes required presence of metal co-factor (Mn2+ or Mg2+) [3].
We describe preparation of selected key intermediates and precursors of GTs inhibitors by sequential synthesis starting from benzyl-2-thio-α-D-fructofuranoside prepared in our laboratory [4]. The structures of all compounds were confirmed by NMR spectral data (1H, 13C, COSY, HSQC, 31P) and elemental analyses.
Acknowledgement. Financial support of this work by the Slovak Grant Agency (VEGA 2/0024/16) is gratefully appreciated.
[1] Beyer T. A.; Sadler J. E.; Rearick J. I.; et al. Adv. Enzymol. 1981, 52, 23-175.
[2] Kleene R.; Berger E. G. Biochim. Biophys. Acta 1993, 1, 1154, 283-325.
[3] Tvaroška, I.; André, I.; Carver, J. P. Glycobiology 2003, 13, 559–566.
[4] Hirsch J.; Koóš M.; Tvaroška I. Chem. Pap. 2009, 63, 329-335.
Sirsie suvislosti?
Dobry den, prepacte moju zvedavost, ale co myslite, v akych biologickych systemoch by bolo mozne otestovat vami pripravene sacharidove prekurzory. A ktore konkretne ochorenia by bolo mozne modifikovat inhibitormi glykozyltranferaz pripravenymi z tychto prekurzorov?
Re: Sirsie suvislosti?
Dobrý večer prajem, ďakujem Vám za Vašu otázku. Cieľom našej práce je príprava takýchto zlúčenín ako potenciálnych inhibítorov ľudských glykozyltransferáz, konkrétne GnT-I, OGT a C2GnT, ktorých donorným substrátom je N-acetylglukózamín. Takéto deriváty by mali slúžiť ako predlohy pre vývoj liekov na kontrolu nežiaducich porúch glykozylácie spôsobujúcich ochorenia napríklad neurodegeneratívne, onkologické, či autoimunitné (nádory, diabetes, Alzheimerova choroba,...). Uvedené prekurzory by sme chceli testovať napríklad na Pichia supernatante, ktorá obsahuje rekombinantné C-elegans - teda in vitro testami homológy králičej GnT-I, ktorej 3D štruktúra je známa. Najskôr však musíme dať urobiť testy cytotoxicity, MTM testy.