1,1'-BINAPHTHYL-BASED INHIBITORS OF NAD+-DEPENDENT DEACETYLASE ACTIVITY AND SIR2-FAMILY MEMBERS

摘要

Aspects of the present invention provide novel compositions and methods for inhibiting NAD+-dependent deacetylase activity (e.g., SIR2) and for affecting and/or treating SIR2-related biological conditions and disorders including but not limited to cancer, HIV/AIDS, silenced genes, metabolism, apoptosis, aging, and conditions such as Malaria and infectious disease (e.g., Trypanosoma brucei (African sleeping sickness); Leishmaniasis (e.g., Leishmania infantum, etc.); Mycobacterium tuberculosis; and Anthrax). The novel compositions and methods comprising use of novel small molecule inhibitors of NAD+-dependent deacetylase activity (e.g., SIR2 inhibitors) that comprise a characteristic a 1,1 -binaphthyl core structure. The novel compounds and compositions provide surprisingly effective inhibitors of NAD+-dependent deacetylase activity, and have substantial therapeutic utility. Further aspects provide methods of treatment, comprising administration of a therapeutically effective amount of one or more of the disclosed compounds, and further comprising administration of an inhibitor of topoisomerase 2 (e.g., etoposide), an inhibitor of type I and/or II histone deacetylase (HDAC) (e.g., suberoylanilide hydroxamic acid (SAHA)), or both.