Design, synthesis, and evaluation of biphenyl-4-yl-acrylohydroxamic acid derivatives as histone deacetylase (HDAC) inhibitors.
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 alpha-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.
Dallavalle
Sabrina
S
Dipartimento di Scienze Molecolari Agroalimentari, Università di Milano, Via Celoria 2, 20133 Milano, Italy.
Cincinelli
Raffaella
R
Nannei
Raffaella
R
Merlini
Lucio
L
Morini
Gabriella
G
Penco
Sergio
S
Pisano
Claudio
C
Vesci
Loredana
L
Barbarino
Marcella
M
Zuco
Valentina
V
De Cesare
Michelandrea
M
Zunino
Franco
F
D000107:Acetylation; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011485:Protein Binding; D014404:Tubulin / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D014404:Tubulin; D016159:Tumor Suppressor Protein p53