Epimers Switch Galectin-9 Domain Selectivity: 3 N-Aryl Galactosides Bind the C-Terminal and Gulosides Bind the N-Terminal

Mukul Mahanti; Kumar Bhaskar Pal; Anders P Sundin; Hakon Leffler; Ulf J Nilsson

doi:10.1021/acsmedchemlett.9b00396

Epimers Switch Galectin-9 Domain Selectivity: 3 N-Aryl Galactosides Bind the C-Terminal and Gulosides Bind the N-Terminal

ACS Med Chem Lett. 2019 Dec 4;11(1):34-39. doi: 10.1021/acsmedchemlett.9b00396. eCollection 2020 Jan 9.

Authors

Mukul Mahanti¹, Kumar Bhaskar Pal¹, Anders P Sundin¹, Hakon Leffler², Ulf J Nilsson¹

Affiliations

¹ Centre for Analysis and Synthesis, Department of Chemistry, Lund University, Box 124, SE-221 00 Lund, Sweden.
² Department of Laboratory Medicine, Section MIG, Lund University BMC-C1228b, Klinikgatan 28, 221 84 Lund, Sweden.

Abstract

A series of 3-deoxy-3-N-arylated-β-d-galactoside and -guloside derivatives have been synthesized by cesium fluoride/trimetylsilylaryl triflate-mediated benzyne generation and N-arylation of 3-deoxy-3-amino-β-d-galactosides and -gulosides, respectively. Evaluation as ligands to galectin-1, 2, 3, 4N (N-terminal domain), 4C (C-terminal domain), 7, 8N, 8C, 9C, and 9N revealed that the galactosides selectively bound galectin-9C, whereas the gulosides selectively bound galectin-9N. Hence, the N-aryl group induces galectin-9 selectivity and the ligand 3C-configuration acts as an epimeric selectivity switch between the two domains of galectin-9. Furthermore, MD simulations revealed that galacto derivatives in galectin-9C and gulo derivatives in galectin-9N find stable poses with specific interactions, which proposes a possible explanation to the gal/gulo 9C/9N selectivity.