title: Novel amide derivatives as inhibitors of histone deacetylase: design, synthesis and SAR.
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).
authors.affiliation: Latvian Institute of Organic Synthesis, Aizkraules 21, Riga, LV-1006, Latvia.
authors.forename: Victor
authors.initials: V
authors.lastname: Andrianov
authors.forename: Vija
authors.initials: V
authors.lastname: Gailite
authors.forename: Daina
authors.initials: D
authors.lastname: Lola
authors.forename: Einars
authors.initials: E
authors.lastname: Loza
authors.forename: Valentina
authors.initials: V
authors.lastname: Semenikhina
authors.forename: Ivars
authors.initials: I
authors.lastname: Kalvinsh
authors.forename: Paul
authors.initials: P
authors.lastname: Finn
authors.forename: Kamille Dumong
authors.initials: KD
authors.lastname: Petersen
authors.forename: James W A
authors.initials: JW
authors.lastname: Ritchie
authors.forename: Nagma
authors.initials: N
authors.lastname: Khan
authors.forename: Anthony
authors.initials: A
authors.lastname: Tumber
authors.forename: Laura S
authors.initials: LS
authors.lastname: Collins
authors.forename: Sree M
authors.initials: SM
authors.lastname: Vadlamudi
authors.forename: Fredrik
authors.initials: F
authors.lastname: Björkling
authors.forename: Maxwell
authors.initials: M
authors.lastname: Sehested
mesh_terms: D000577:Amides / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors