A structurally simplified analogue of geldanamycin exhibits neuroprotective activity.

The syntheses of a structurally simplified geldanamycin analogue 2 and two related compounds are described. Compound 2 conferred cytoprotection and quenched ROS and lipid peroxidation in a dose-dependent manner in Friedreich's ataxia (FRDA) lymphocytes at low micromolar concentrations. It also prevented ROS-induced damage of cellular lipid membranes and maintained the mitochondrial membrane potential of FRDA lymphocytes. In addition, 2 did not inhibit Hsp90 when tested at micromolar concentrations, exhibited no cytotoxicity, and afforded neuroprotection to differentiated SH-SY5Y cells under conditions of Aß-induced cell toxicity.