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

Article Details

Citation

Andrianov V, Gailite V, Lola D, Loza E, Semenikhina V, Kalvinsh I, Finn P, Petersen KD, Ritchie JW, Khan N, Tumber A, Collins LS, Vadlamudi SM, Bjorkling F, Sehested M

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

Eur J Med Chem. 2009 Mar;44(3):1067-85. doi: 10.1016/j.ejmech.2008.06.020. Epub 2008 Jun 27.

PubMed ID
18672316 [ View in PubMed
]
Abstract

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-microM 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).

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
VorinostatHistone deacetylase 1IC 50 (nM)68.1N/AN/ADetails
VorinostatHistone deacetylase 2IC 50 (nM)163.6N/AN/ADetails
VorinostatHistone deacetylase 3IC 50 (nM)67.1N/AN/ADetails
VorinostatHistone deacetylase 6IC 50 (nM)110.6N/AN/ADetails