Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors

Florian Thaler, Andrea Colombo, Antonello Mai, Raffaella Amici, Chiara Bigogno, Roberto Boggio, Anna Cappa, Simone Carrara, Tiziana Cataudella, Fulvia Fusar, Eleonora Gianti, Samuele Joppolo Di Ventimiglia, Maurizio Moroni, Davide Munari, Gilles Pain, Nickolas Regalia, Luca Sartori, Stefania Vultaggio, Giulio Dondio, Stefania GagliardiSaverio Minucci, Ciro Mercurio, Mario Varasi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)822-839
Number of pages18
JournalJournal of Medicinal Chemistry
Volume53
Issue number2
DOIs
Publication statusPublished - 2010

Fingerprint

Histone Deacetylase Inhibitors
Histone Deacetylases
Hydroxamic Acids
Microsomes
Heterografts
Neurodegenerative Diseases
Solubility
Colon
Pharmacokinetics
Clinical Trials
Carcinoma
Gene Expression
Neoplasms

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors. / Thaler, Florian; Colombo, Andrea; Mai, Antonello; Amici, Raffaella; Bigogno, Chiara; Boggio, Roberto; Cappa, Anna; Carrara, Simone; Cataudella, Tiziana; Fusar, Fulvia; Gianti, Eleonora; Di Ventimiglia, Samuele Joppolo; Moroni, Maurizio; Munari, Davide; Pain, Gilles; Regalia, Nickolas; Sartori, Luca; Vultaggio, Stefania; Dondio, Giulio; Gagliardi, Stefania; Minucci, Saverio; Mercurio, Ciro; Varasi, Mario.

In: Journal of Medicinal Chemistry, Vol. 53, No. 2, 2010, p. 822-839.

Research output: Contribution to journalArticle

Thaler, F, Colombo, A, Mai, A, Amici, R, Bigogno, C, Boggio, R, Cappa, A, Carrara, S, Cataudella, T, Fusar, F, Gianti, E, Di Ventimiglia, SJ, Moroni, M, Munari, D, Pain, G, Regalia, N, Sartori, L, Vultaggio, S, Dondio, G, Gagliardi, S, Minucci, S, Mercurio, C & Varasi, M 2010, 'Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors', Journal of Medicinal Chemistry, vol. 53, no. 2, pp. 822-839. https://doi.org/10.1021/jm901502p
Thaler, Florian ; Colombo, Andrea ; Mai, Antonello ; Amici, Raffaella ; Bigogno, Chiara ; Boggio, Roberto ; Cappa, Anna ; Carrara, Simone ; Cataudella, Tiziana ; Fusar, Fulvia ; Gianti, Eleonora ; Di Ventimiglia, Samuele Joppolo ; Moroni, Maurizio ; Munari, Davide ; Pain, Gilles ; Regalia, Nickolas ; Sartori, Luca ; Vultaggio, Stefania ; Dondio, Giulio ; Gagliardi, Stefania ; Minucci, Saverio ; Mercurio, Ciro ; Varasi, Mario. / Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 2. pp. 822-839.
@article{d336fbc775f046dd886b26a77ac522b8,
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.",
author = "Florian Thaler and Andrea Colombo and Antonello Mai and Raffaella Amici and Chiara Bigogno and Roberto Boggio and Anna Cappa and Simone Carrara and Tiziana Cataudella and Fulvia Fusar and Eleonora Gianti and {Di Ventimiglia}, {Samuele Joppolo} and Maurizio Moroni and Davide Munari and Gilles Pain and Nickolas Regalia and Luca Sartori and Stefania Vultaggio and Giulio Dondio and Stefania Gagliardi and Saverio Minucci and Ciro Mercurio and Mario Varasi",
year = "2010",
doi = "10.1021/jm901502p",
language = "English",
volume = "53",
pages = "822--839",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "2",

}

TY - JOUR

T1 - Synthesis and biological evaluation of N-hydroxyphenylacrylamides and N-hydroxypyridin-2-ylacrylamides as novel histone deacetylase inhibitors

AU - Thaler, Florian

AU - Colombo, Andrea

AU - Mai, Antonello

AU - Amici, Raffaella

AU - Bigogno, Chiara

AU - Boggio, Roberto

AU - Cappa, Anna

AU - Carrara, Simone

AU - Cataudella, Tiziana

AU - Fusar, Fulvia

AU - Gianti, Eleonora

AU - Di Ventimiglia, Samuele Joppolo

AU - Moroni, Maurizio

AU - Munari, Davide

AU - Pain, Gilles

AU - Regalia, Nickolas

AU - Sartori, Luca

AU - Vultaggio, Stefania

AU - Dondio, Giulio

AU - Gagliardi, Stefania

AU - Minucci, Saverio

AU - Mercurio, Ciro

AU - Varasi, Mario

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=77249133651&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77249133651&partnerID=8YFLogxK

U2 - 10.1021/jm901502p

DO - 10.1021/jm901502p

M3 - Article

C2 - 20017493

AN - SCOPUS:77249133651

VL - 53

SP - 822

EP - 839

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 2

ER -