Thioureido N-acetyllactosamine derivatives as potent galectin-7 and 9N inhibitors

Bioorg Med Chem. 2006 Feb 15;14(4):1215-20. doi: 10.1016/j.bmc.2005.09.050. Epub 2005 Oct 18.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Sugars / chemical synthesis
  • Amino Sugars / chemistry*
  • Amino Sugars / pharmacology*
  • Galectins / antagonists & inhibitors*
  • Galectins / chemistry
  • Galectins / metabolism
  • Molecular Structure
  • Structure-Activity Relationship
  • Thiourea / analogs & derivatives*
  • Thiourea / chemical synthesis
  • Thiourea / chemistry
  • Thiourea / pharmacology

Substances

  • Amino Sugars
  • Galectins
  • thioureido N-acetyllactosamine
  • Thiourea