N-Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi alpha-MannosidaseII

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F18%3A73590536" target="_blank" >RIV/61989592:15110/18:73590536 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1002/cmdc.201700607" target="_blank" >http://dx.doi.org/10.1002/cmdc.201700607</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/cmdc.201700607" target="_blank" >10.1002/cmdc.201700607</a>

Jazyk výsledku

angličtina

Název v původním jazyce

N-Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi alpha-MannosidaseII

Popis výsledku v původním jazyce

Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi -mannosidaseII (GMII) has become a therapeutic target for drugs with anticancer activities. One critical task for successful application of GMII drugs in medical treatments is to decrease their unwanted co-inhibition of lysosomal -mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N-substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 -mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (K-i=50-76m, as determined by enzyme assays) with a significant selectivity index of IC50(LManII)/IC50(GMIIb) &gt;100. These compounds also showed inhibitory activities in invitro assays with cancer cell lines (leukemia, IC50=92-200m) and low cytotoxic activities in normal fibroblast cell lines (IC50&gt;200m). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoi1,2-mannosidase. An appropriate stereo configuration of hydroxymethyl and benzyl functional groups on the pyrrolidine ring of the inhibitor may lead to an inhibitor with the required selectivity for the active site of a target -mannosidase.

Název v anglickém jazyce

N-Benzyl Substitution of Polyhydroxypyrrolidines: The Way to Selective Inhibitors of Golgi alpha-MannosidaseII

Popis výsledku anglicky

Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi -mannosidaseII (GMII) has become a therapeutic target for drugs with anticancer activities. One critical task for successful application of GMII drugs in medical treatments is to decrease their unwanted co-inhibition of lysosomal -mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N-substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 -mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (K-i=50-76m, as determined by enzyme assays) with a significant selectivity index of IC50(LManII)/IC50(GMIIb) &gt;100. These compounds also showed inhibitory activities in invitro assays with cancer cell lines (leukemia, IC50=92-200m) and low cytotoxic activities in normal fibroblast cell lines (IC50&gt;200m). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoi1,2-mannosidase. An appropriate stereo configuration of hydroxymethyl and benzyl functional groups on the pyrrolidine ring of the inhibitor may lead to an inhibitor with the required selectivity for the active site of a target -mannosidase.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ChemMedChem

ISSN

1860-7179

e-ISSN

—

Svazek periodika

13

Číslo periodika v rámci svazku

4

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

11

Strana od-do

373-383

Kód UT WoS článku

000425510600008

EID výsledku v databázi Scopus

2-s2.0-85042229018