PYRAZOLO[3,4-d]PYRIMIDINE DERIVATIVES AS SIRTUIN INHIBITORS: DESIGN, SYNTHESIS AND PRELIMINARY in vitro EVALUATION

SIRTs are a family of enzymes classified as class III histone deacetylases. In mammals, the seven known sirtuins, named SIRT-1 to SIRT-7, play a critical role in cancer, acting either as oncopromoter or oncosuppressor, depending on the sirtuin and on the cancer type. The recent identification of sirtuin small molecule inhibitors (SIRTIs) has garnered attention not only for the treatment of various cancers, but also for the treatment of diabetes, autoimmune disorders, and neurological diseases. The availability of many X-crystallographic data about SIRT-2−ligand complexes made it possible to build up a structure-based investigation in the hunt for SIRT-2 inhibitors. A first series of in-house of pyrazolo[3,4-d]pyrimidine derivatives was evaluated in silico and tested in vitro as a novel class of SIRT-2 inhibitors, leading to the identification of the most effective compounds, 1 and 2, which showed an inhibitory activity at 150 μM of 81.2% and 79.8%, respectively. Further modeling screening studies drove the synthesis of a set of ten analogue compounds (3a-d, 4a-c, 5, 6a,b) that have been tested in vitro in order to individuate other pyrazolo[3,4-d]pyrimidines derivatives potentially active as SIRTIs.