title: Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors.
abstract: The histone deacetylases (HDACs) are able to regulate gene expression, and histone deacetylase inhibitors (HDACi) emerged as a new class of agents in the treatment of cancer as well as other human disorders such as neurodegenerative diseases. In the present investigation, we report on the synthesis and biological evaluation of compounds derived from the expansion of a HDAC inhibitor scaffold having N-hydroxy-3-phenyl-2-propenamide and N-hydroxy-3-(pyridin-2-yl)-2-propenamide as core structures and containing a phenyloxopropenyl moiety, either unsubstituted or substituted by a 4-methylpiperazin-1-yl or 4-methylpiperazin-1-ylmethyl group. The compounds were evaluated for their ability to inhibit nuclear HDACs, as well as for their in vitro antiproliferative activity. Moreover, their metabolic stability in microsomes and aqueous solubility were studied and selected compounds were further characterized by in vivo pharmacokinetic experiments. These compounds showed a remarkable stability in vivo, compared to hydroxamic acid HDAC inhibitors that have already entered clinical trials. The representative compound 30b showed in vivo antitumor activity in a human colon carcinoma xenograft model.
authors.affiliation: Genextra Group, Congenia s.r.l., Via Adamello 16, 20139 Milan, Italy. florian.thaler@ifom-ieo-campus.it
authors.forename: Florian
authors.initials: F
authors.lastname: Thaler
authors.forename: Andrea
authors.initials: A
authors.lastname: Colombo
authors.forename: Antonello
authors.initials: A
authors.lastname: Mai
authors.forename: Raffaella
authors.initials: R
authors.lastname: Amici
authors.forename: Chiara
authors.initials: C
authors.lastname: Bigogno
authors.forename: Roberto
authors.initials: R
authors.lastname: Boggio
authors.forename: Anna
authors.initials: A
authors.lastname: Cappa
authors.forename: Simone
authors.initials: S
authors.lastname: Carrara
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cataudella
authors.forename: Fulvia
authors.initials: F
authors.lastname: Fusar
authors.forename: Eleonora
authors.initials: E
authors.lastname: Gianti
authors.forename: Samuele Joppolo
authors.initials: SJ
authors.lastname: di Ventimiglia
authors.forename: Maurizio
authors.initials: M
authors.lastname: Moroni
authors.forename: Davide
authors.initials: D
authors.lastname: Munari
authors.forename: Gilles
authors.initials: G
authors.lastname: Pain
authors.forename: Nickolas
authors.initials: N
authors.lastname: Regalia
authors.forename: Luca
authors.initials: L
authors.lastname: Sartori
authors.forename: Stefania
authors.initials: S
authors.lastname: Vultaggio
authors.forename: Giulio
authors.initials: G
authors.lastname: Dondio
authors.forename: Stefania
authors.initials: S
authors.lastname: Gagliardi
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
authors.forename: Mario
authors.initials: M
authors.lastname: Varasi
mesh_terms: D000178:Acrylamides / Q000138:chemical synthesis* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D001555:Benzene Derivatives; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D011725:Pyridines; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011725:Pyridines