Synthesis and Evaluation of Hybrid Structures Composed of Two Glucosylceramide Synthase Inhibitors.
Glucosylceramide metabolism and the enzymes involved have attracted significant interest in medicinal chemistry, because aberrations in the levels of glycolipids that are derived from glucosylceramide are causative in a range of human diseases including lysosomal storage disorders, type 2 diabetes, and neurodegenerative diseases. Selective modulation of one of the glycoprocessing enzymes involved in glucosylceramide metabolism-glucosylceramide synthase (GCS), acid glucosylceramidase (GBA1), or neutral glucosylceramidase (GBA2)-is therefore an attractive research objective. In this study we took two established GCS inhibitors, one based on deoxynojirimycin and the other a ceramide analogue, and merged characteristic features to obtain hybrid compounds. The resulting 39-compound library does not contain new GCS inhibitors; however, a potent (200 nm) GBA1 inhibitor was identified that has little activity toward GBA2 and might therefore serve as a lead for further biomedical development as a selective GBA1 modulator.
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands.
Richard J B H N
RJ
van den Berg
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands.
Erwin R
ER
van Rijssel
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands.
Maria Joao
MJ
Ferraz
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands.
Judith
J
Houben
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Anneke
A
Strijland
Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Wilma E
WE
Donker-Koopman
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands.|Laboratory of Organic Chemistry, Wageningen University, Dreijenplein 8, 6703 HB, Wageningen, The Netherlands.
Tom
T
Wennekes
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands.
Kimberly M
KM
Bonger
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands.
Amar B T
AB
Ghisaidoobe
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands.
Sascha
S
Hoogendoorn
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands.
Gijsbert A
GA
van der Marel
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands.
Jeroen D C
JD
Codée
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands. h.s.overkleeft@chem.leidenuniv.nl.
Herman S
HS
Overkleeft
Leiden Institute of Chemistry, Leiden University, Gorlaeus Laboratories, Einsteinweg 55, 2300 RA, Leiden, The Netherlands. j.m.aerts@amc.uva.nl.|Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. j.m.aerts@amc.uva.nl.
Johannes M F G
JM
Aerts
D017485:1-Deoxynojirimycin / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D002518:Ceramides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D005944:Glucosamine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D011485:Protein Binding; D013329:Structure-Activity Relationship
D002518:Ceramides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C501633:deoxynojirimycine; D017485:1-Deoxynojirimycin; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D005944:Glucosamine
acid glucosylceramidase; ceramide analogues; deoxynojirimycin; glucosylceramide synthase; neutral glucosylceramidase