Organoruthenium Glycomimetics Exhibit High Selectivity and Nanomolar Affinity for Human Galectin-1

Human galectin-1 (<i>h</i>Gal-1) is an abundant β-galactoside-binding animal lectin that plays an essential role in promoting the immunosuppressive tumor microenvironment. Although <i>h</i>Gal-1 has been identified as a promising target for pharmacological inhibition, developing potent and selective <i>h</i>Gal-1 inhibitors has been complicated by the high degree of sequence similarity of the glycan-binding site across the galectin family. Herein, we present potent nanomolar <i>h</i>Gal-1 inhibitors with unprecedented selectivity of 2 to 3 orders of magnitude over human galectin-3 (<i>h</i>Gal-3). Their primary structural feature is the modification of a thiodigalactoside scaffold at the 3- and 3'-positions with a half-sandwich ruthenium(II) arene complex containing a bidentate 4-(2-pyridyl)-1<i>H</i>-1,2,3-triazol-1-yl ligand. The most potent inhibitor in the series efficiently blocked the binding of <i>h</i>Gal-1 to the surface of MDA-MB-231 tumor cells, reduced their viability, and completely suppressed <i>h</i>Gal-1-induced phosphatidylserine exposure in Jurkat cells, a process previously described as preaparesis rather than classical apoptosis.