Antioxidant and antihypoxic properties of neuroprotective drugs

The screening of the library containing 320 drugs and biologically active compounds was carried out. The library was created for testing potent agents on Rett syndrome models (SMART library) using new-generation luciferase reporters to identify stabilizers of transcription factors triggering genetic programs for defense against hypoxia and oxidative stress (HIF1 and Nrf2, respectively). Nine compounds proved to be activators of HIF1, and 18 compounds were shown to activate Nrf2. A histone deacetylase inhibitor (oxamflatin) and a carbonic anhydrase inhibitor (ethamide) were found to be the most powerful Nrf2 activators, which are equipotent or superior to sulforaphane and quercetin. Oxamflatin was also shown to activate HIF with potency comparable or superior to the commercial HIF activators developed by Fibrogen (USA) and GlaxoSmithKline (UK), but it was a significantly weaker activator than branched tail oxyquinolines, developed in our previous studies. The structural motif identified in oxamflatin can be used in the future design of branched oxyquinolines having higher activity and/or more specific against individual isoforms of HIF prolyl hydroxylase.