1. Academic Validation
  2. Novel amide derivatives as inhibitors of histone deacetylase: design, synthesis and SAR

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.
Victor Andrianov 1 Vija Gailite Daina Lola Einars Loza Valentina Semenikhina Ivars Kalvinsh Paul Finn Kamille Dumong Petersen James W A Ritchie Nagma Khan Anthony Tumber Laura S Collins Sree M Vadlamudi Fredrik Björkling Maxwell Sehested
Affiliations

Affiliation

  • 1 Latvian Institute of Organic Synthesis, Aizkraules 21, Riga, LV-1006, Latvia.
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).

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