A series of 19 synthetic alkyl and thioalkyl glycosides derived from d-mannose, d-glucose and d-galactose and having C10-C16 aglycone were investigated for cytotoxic activity against 7 human cancer and 2 non-tumor cell lines as well as for antimicrobial potential on 12 bacterial and yeast strains. The most potent compounds were found to be tetradecyl and hexadecyl β-d-galactopyranosides (18, 19), which showed the best cytotoxicity and therapeutic index against CCRF-CEM cancer cell line. Similar cytotoxic activity showed hexadecyl α-d-mannopyranoside (5) but it also inhibited non-tumor cell lines. Because these two galactosides (18, 19) were inactive against all tested bacteria and yeast strains, they could be a target-specific for eukaryotic cells. On the other hand, β-D-glucopyranosides with tetradecyl (11) and hexadecyl (12) aglycone inhibited only Gram-positive bacterial strain Enterococcus faecalis. The studied glycosides induce changes in the lipid bilayer thickness and lateral phase separation at high concentration, as derived from SAXS experiments on POPC model membranes. In general, glucosides and galactosides exhibit more specific properties. Those with longer aglycone show high cytotoxicity and therefore, they are more promising candidates for cancer cell line targeted inhibition.
- MeSH
- antibakteriální látky chemická syntéza chemie farmakologie MeSH
- antitumorózní látky chemická syntéza chemie farmakologie MeSH
- buněčné linie MeSH
- buňky A549 MeSH
- buňky K562 MeSH
- difrakce rentgenového záření MeSH
- Enterococcus faecalis účinky léků MeSH
- galaktosa chemická syntéza chemie farmakologie MeSH
- glykosidy chemická syntéza chemie farmakologie MeSH
- HCT116 buňky MeSH
- lidé MeSH
- lipidové dvojvrstvy chemie MeSH
- maloúhlový rozptyl MeSH
- mikrobiální testy citlivosti MeSH
- molekulární struktura MeSH
- proliferace buněk MeSH
- sacharidové sekvence MeSH
- viabilita buněk účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus influences progress of tumor growth and metastasis. Golgi α-mannosidase II (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 α-mannosidase (LMan), a weakness of all known potent GMII inhibitors. A series of novel N-substituted polyhydroxypyrrolidines was synthesized and tested with modeled GH38 α-mannosidases from Drosophila melanogaster (GMIIb and LManII). The most potent structures inhibited GMIIb (Ki =50-76 μm, as determined by enzyme assays) with a significant selectivity index of IC50 (LManII)/IC50 (GMIIb) >100. These compounds also showed inhibitory activities in in vitro assays with cancer cell lines (leukemia, IC50 =92-200 μm) and low cytotoxic activities in normal fibroblast cell lines (IC50 >200 μm). In addition, they did not show any significant inhibitory activity toward GH47 Aspergillus saitoiα1,2-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 α-mannosidase.
- MeSH
- Aspergillus enzymologie MeSH
- buněčné linie MeSH
- Drosophila melanogaster enzymologie MeSH
- dusík chemie MeSH
- fungální proteiny antagonisté a inhibitory metabolismus MeSH
- Golgiho aparát enzymologie MeSH
- inhibiční koncentrace 50 MeSH
- katalytická doména MeSH
- lidé MeSH
- mannosidasy antagonisté a inhibitory metabolismus MeSH
- pyrrolidiny chemie metabolismus farmakologie MeSH
- simulace molekulového dockingu MeSH
- vazebná místa MeSH
- viabilita buněk účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
