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-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).
Andrianov
Victor
V
Latvian Institute of Organic Synthesis, Aizkraules 21, Riga, LV-1006, Latvia.
Gailite
Vija
V
Lola
Daina
D
Loza
Einars
E
Semenikhina
Valentina
V
Kalvinsh
Ivars
I
Finn
Paul
P
Petersen
Kamille Dumong
KD
Ritchie
James W A
JW
Khan
Nagma
N
Tumber
Anthony
A
Collins
Laura S
LS
Vadlamudi
Sree M
SM
Björkling
Fredrik
F
Sehested
Maxwell
M
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
D000577:Amides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors