Identification of a series of substituted 2-piperazinyl-5-pyrimidylhydroxamic acids as potent histone deacetylase inhibitors.
Pursuing our efforts in designing 5-pyrimidylhydroxamic acid anti-cancer agents, we have identified a new series of potent histone deacetylase (HDAC) inhibitors. These compounds exhibit enzymatic HDAC inhibiting properties with IC(50) values in the nanomolar range and inhibit tumor cell proliferation at similar levels. Good solubility, moderate bioavailability, and promising in vivo activity in xenograft model made this series of compounds interesting starting points to design new potent HDAC inhibitors.
Angibaud
Patrick
P
Ortho-Biotech Oncology Research & Development, Department of Medicinal Chemistry, campus de Maigremont BP615, 27106, Val de Reuil, France. pangibau@prdfr.jnj.com
Van Emelen
Kristof
K
Decrane
Laurence
L
van Brandt
Sven
S
Ten Holte
Peter
P
Pilatte
Isabelle
I
Roux
Bruno
B
Poncelet
Virginie
V
Speybrouck
David
D
Queguiner
Laurence
L
Gaurrand
Sandrine
S
Mariën
Ann
A
Floren
Wim
W
Janssen
Lut
L
Verdonck
Marc
M
van Dun
Jacky
J
van Gompel
Jacky
J
Gilissen
Ron
R
Mackie
Claire
C
Du Jardin
Marc
M
Peeters
Jozef
J
Noppe
Marc
M
Van Hijfte
Luc
L
Freyne
Eddy
E
Page
Martin
M
Janicot
Michel
M
Arts
Janine
J
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D006655:Histone Deacetylases