The epigenetic covalent modifications of DNA and chromatin proteins strongly affect gene expression and cellular activity. In case, epigenetic regulation occurs in several diseases, especially cancer. First generation drugs targeting the relatively promiscuous DNA methylation and histone acetylation modifiers have had successes in the treatment of hematological cancers. Among epigenetic targets, the silent information regulator 2 (Sir-2) protein and Sir2-like proteins (SIRT1-7 sirtuins) are evolutionary conserved NAD+ dependent class III histone deacetylases and have shown as a target in drug design. A series of 75 compounds 2-anilinobenzamide derivatives were synthesized and tested as sirtuin-2 inhibitors as hematological cancers candidates. To evaluation the structure activity relationship (SAR) and understanding mechanism of action of the compounds QSAR studies were employed using HQSAR, CoMFA and CoMSIA methods. These strategies were applied to obtain a consensus between QSAR methods and suggest structural modifications in design new compounds more potent and selectivity. The compounds from 2-anilinobenzamide derivatives series were tested under the same experimental condition and employed in QSAR studies. Hierarchical cluster analysis was applied in division of the training (80 %) and test set (20%) of the compounds. This method was employed in order to maintain a homogeneous division of training/test set compounds and also to keep its structural/activity diversity in both subsets. HQAR model have presented best results using Atoms (A) and Connections (C) as descriptor, hologram length 401 and fragment size 6-9 (r2=0.963 and q2=0.902). The CoMFA and CoMSIA models suggest very good statistical values (r2=0.981 and q2=0.898; r2=0.962 and q2=0.875 respectively), and the maps suggest modifications and the same regions to obtain more potent and selectivity compounds. In summary of the QSAR models shows the main predicted contributions for Sir-2 inhibition and selectivity by HQSAR maps and CoMFA and CoMSIA contours that will be used in design of new Sir-2 inhibitors.

Quantitative structure-activity relationship applied of a series of 2-anilinobenzamide derivatives as Sirtuin-2 selective compounds hematological cancers candidates

255th National Meeting (2018)

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