Design and synthesis of 4-[(s-triazin-2-ylamino)methyl]-N-(2-aminophenyl)-benzamides and their analogues as a novel class of histone deacetylase inhibitors.
Inhibition of histone deacetylases (HDAC) is emerging as a new strategy in human cancer therapy. The synthesis and biological evaluation of a variety of 4-(heteroarylaminomethyl)-N-(2-aminophenyl)-benzamides is presented herein. From the different series bearing a six-membered heteroaromatic ring studied, the s-triazine series showed the best HDAC1 enzyme and in vitro anti-proliferative activities with IC(50) values below micromolar range. Some of these compounds can also significantly reduce tumor growth in human tumor xenograft models in mice.
Paquin
Isabelle
I
MethylGene Inc., Department of Medicinal Chemistry, 7220 Frederick-Banting, Montréal, QC, Canada.
Raeppel
Stéphane
S
Leit
Silvana
S
Gaudette
Frédéric
F
Zhou
Nancy
N
Moradei
Oscar
O
Saavedra
Oscar
O
Bernstein
Naomy
N
Raeppel
Franck
F
Bouchain
Giliane
G
Fréchette
Sylvie
S
Woo
Soon H
SH
Vaisburg
Arkadii
A
Fournel
Marielle
M
Kalita
Ann
A
Robert
Marie-France
MF
Lu
Aihua
A
Trachy-Bourget
Marie-Claude
MC
Yan
Pu Theresa
PT
Liu
Jianhong
J
Rahil
Jubrail
J
MacLeod
A Robert
AR
Besterman
Jeffrey M
JM
Li
Zuomei
Z
Delorme
Daniel
D
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D011743:Pyrimidines / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011743:Pyrimidines; D014227:Triazines; C523184:mocetinostat