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

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Epimers Switch Galectin-9 Domain Selectivity : 3 N-Aryl Galactosides Bind the C-Terminal and Gulosides Bind the N-Terminal. / Mahanti, Mukul; Pal, Kumar Bhaskar; Sundin, Anders P.; Leffler, Hakon; Nilsson, Ulf J.

In: ACS Medicinal Chemistry Letters, Vol. 11, No. 1, 2020, p. 34-39.

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TY - JOUR

T1 - Epimers Switch Galectin-9 Domain Selectivity

T2 - 3 N-Aryl Galactosides Bind the C-Terminal and Gulosides Bind the N-Terminal

AU - Mahanti, Mukul

AU - Pal, Kumar Bhaskar

AU - Sundin, Anders P.

AU - Leffler, Hakon

AU - Nilsson, Ulf J.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - epimers

KW - Galactose

KW - galectin-9

KW - gulose

KW - N-phenyl

KW - selectivity

U2 - 10.1021/acsmedchemlett.9b00396

DO - 10.1021/acsmedchemlett.9b00396

M3 - Article

C2 - 31938460

AN - SCOPUS:85076853871

VL - 11

SP - 34

EP - 39

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 1

ER -