Thioureido N-acetyllactosamine derivatives as potent galectin-7 and 9N inhibitors.
Derivatives of N-acetyllactosamine carrying structurally diverse thioureido groups at galactose C3 were prepared from a C3'-azido N-acetyllactosamine derivative in a three-step reaction sequence involving azide reduction and isothiocyanate formation by thiophosgene treatment of the C3-amine, followed by reaction of the isothiocyanate with a panel of amines. Evaluation of the N-acetyllactosamine thioureas as inhibitors against galectins-1, 3, 7, 8N (N-terminal domain), and 9N (N-terminal domain) revealed thiourea-mediated affinity enhancements for galectins-1, 3, 7, and 9N. In particular, good inhibitors were discovered against galectin-7 and 9N (K(d) 23 and 47 microM, respectively, for a 3-pyridylmethylthiourea derivative), which represents more than an order of magnitude affinity enhancement over the parent natural N-acetyllactosamine.
Salameh
B A
BA
Organic Chemistry, Lund University, Sweden.
Sundin
A
A
Leffler
H
H
Nilsson
U J
UJ
D000606:Amino Sugars / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D037161:Galectins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
D000606:Amino Sugars; D037161:Galectins; C508670:thioureido N-acetyllactosamine; D013890:Thiourea