TY - JOUR
T1 - Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors
AU - Dallavalle, Sabrina
AU - Cincinelli, Raffaella
AU - Nannei, Raffaella
AU - Merlini, Lucio
AU - Morini, Gabriella
AU - Penco, Sergio
AU - Pisano, Claudio
AU - Vesci, Loredana
AU - Barbarino, Marcella
AU - Zuco, Valentina
AU - De Cesare, Michelandrea
AU - Zunino, Franco
PY - 2009/5
Y1 - 2009/5
N2 - A series of hydroxamic acid-based histone deacetylase (HDAC) inhibitors were designed on the basis of a model of the HDAC2 binding site and synthesized. They are characterized by a cinnamic spacer, capped with a substituted phenyl group. Modifications of the spacer are also reported. In an in vitro assay with the isoenzyme HDAC2, a good correlation of the activity with the docking energy was found. In human ovarian carcinoma IGROV-1 cells, selected compounds produced significant acetylation of p53 and α-tubulin. Most compounds showed an antiproliferative activity comparable to that of SAHA. At equitoxic concentrations, the tested compounds were more effective than SAHA in inducing apoptotic cell death. Compounds selected for in vivo evaluation exhibited a significant antitumor activity on three tumor models at well tolerated doses, thus suggesting a good therapeutic index.
AB - A series of hydroxamic acid-based histone deacetylase (HDAC) inhibitors were designed on the basis of a model of the HDAC2 binding site and synthesized. They are characterized by a cinnamic spacer, capped with a substituted phenyl group. Modifications of the spacer are also reported. In an in vitro assay with the isoenzyme HDAC2, a good correlation of the activity with the docking energy was found. In human ovarian carcinoma IGROV-1 cells, selected compounds produced significant acetylation of p53 and α-tubulin. Most compounds showed an antiproliferative activity comparable to that of SAHA. At equitoxic concentrations, the tested compounds were more effective than SAHA in inducing apoptotic cell death. Compounds selected for in vivo evaluation exhibited a significant antitumor activity on three tumor models at well tolerated doses, thus suggesting a good therapeutic index.
KW - Antiproliferative activity
KW - Histone deacetylase
KW - Synthesis
UR - http://www.scopus.com/inward/record.url?scp=62749154929&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=62749154929&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2008.11.005
DO - 10.1016/j.ejmech.2008.11.005
M3 - Article
C2 - 19084294
AN - SCOPUS:62749154929
VL - 44
SP - 1900
EP - 1912
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
IS - 5
ER -