Novel amide derivatives as inhibitors of histone deacetylase: Design, synthesis and SAR

Enzymatic inhibition of histone deacetylase (HDAC) activity is emerging as an innovative and effective approach for the treatment of cancer. A series of novel amide derivatives have been synthesized and evaluated for their ability to inhibit human HDACs. Multiple compounds were identified as potent HDAC inhibitors (HDACi), with IC 50 values in the low nanomolar (nM) range against enzyme activity in HeLa cell extracts and sub-μM for their in vitro anti-proliferative effect on cell lines. The introduction of an unsaturated linking group between the terminal aryl ring and the amide moiety was the key to obtain good potency. This approach yielded compounds such as ( E)- N-[6-(hydroxyamino)-6-oxohexyl]-3-(7-quinolinyl)-2-propenamide ( 27) (HDAC IC 50 8 nM) which showed potent in vivo activity in the P388 mouse leukemia syngeneic model (an increased lifespan (ILS) of 111% was obtained). SAR optimization of novel histone deacetylase (HDAC) inhibitors gave compound 27 with potent in vitro (HDAC IC 50 8 nM) and in vivo activity (increased lifespan (ILS) 111%, P388 mouse leukemia model). [Display omitted]