N1-Benzyl substituted cambinol analogues as isozyme selective inhibitors of the sirtuin family of protein deacetylases

The human deacetylase SIRT2 is believed to promote neurodegeneration with recent studies demonstrating that a reduction in the activity of SIRT2 can rescue alpha synuclein toxicity in Parkinson's disease models. In contrast, a second member of the sirtuin family, SIRT1, is believed to play a neuroprotective role. This dichotomy places an additional challenge in the path of sirtuin inhibitor development as a need for isozyme selectivity arises. By combining computational methods with assessment of the biological activity of novel N1-substituted cambinol analogues, further insights that are relevant to this challenge are obtained.