FROM GARCINOL TO BARBITURIC ACID DERIVATIVES: DEVELOPMENT OF NEW AND SELECTIVE P300 INHIBITORS.

Lysine acetylation is among the prominent posttranslational modifications in eukaryotic cells. Protein acetylation level is a consequence of the balance between the opposite activities of protein acetyltransferases (KATs) and deacetylases (KDACs), and its deregulation has been linked to several diseases, including cancer, inflammation and, probably, neurodegenerative diseases. At present, only a small number of KATs modulators have been reported and just a few of them show selectivity between KATs isoforms. Among these, a polyisoprenylated benzophenone, garcinol, isolated from Garcinia indica, is a potent inhibitor of histone acetyltransferases p300 and PCAF. Prompted by our interest in the discovery of small molecule modulators of KATs, we focused our attention on this compound. Here we report the design, synthesis, biological evaluation, stability and permeability profile of new barbiturates derivatives obtained by molecular pruning of garcinol.