title: Phenylpyrrole-based HDAC inhibitors: synthesis, molecular modeling and biological studies.
abstract: Histone deacetylases (HDACs) regulate the expression and activity of numerous proteins involved in the initiation and progression of cancer. Currently, three hydroxamate-containing HDAC pan-inhibitors have been approved as antitumor agents.
  
  
  
  We herein present the development of a series of novel phenylpyrrole-based derivatives stemmed from combined computational and medicinal chemistry efforts to rationally modulate HDAC1/6 isoform selectivity. In vitro activity on HDAC1 and HDAC6 isoforms and the effects of selected analogs on histone H3 and α-tubulin acetylation levels were determined. Cell-based data evidenced, for selected compounds, a promising antitumor potential and low toxicity on normal cells.
  
  
  
  The newly developed compounds represent a valuable starting point for the development of novel anticancer agents.
authors.affiliation: European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Margherita
authors.initials: M
authors.lastname: Brindisi
authors.affiliation: European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Cavella
authors.affiliation: European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Brogi
authors.affiliation: Department of Biochemistry, Biophysics & General Pathology, Second University of Napoli, Vico Luigi De Crecchio 7, 80138 Napoli, Italy.|Institute of Genetics and Biophysics Adriano Buzzati-Traverso, IGB-CNR, Via Pietro Castellino 111, 80131 Napoli, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Nebbioso
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104 Freiburg, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Senger
authors.affiliation: European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: Maramai
authors.affiliation: Department of Biochemistry, Biophysics & General Pathology, Second University of Napoli, Vico Luigi De Crecchio 7, 80138 Napoli, Italy.|Institute of Genetics and Biophysics Adriano Buzzati-Traverso, IGB-CNR, Via Pietro Castellino 111, 80131 Napoli, Italy.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Ciotta
authors.affiliation: Department of Biochemistry, Biophysics & General Pathology, Second University of Napoli, Vico Luigi De Crecchio 7, 80138 Napoli, Italy.|Institute of Genetics and Biophysics Adriano Buzzati-Traverso, IGB-CNR, Via Pietro Castellino 111, 80131 Napoli, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Iside
authors.affiliation: European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Butini
authors.affiliation: European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Lamponi
authors.affiliation: Department of Pharmacy, University of Napoli Federico II, Via D. Montesano 49, 80131 Napoli, Italy.
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.affiliation: Department of Biochemistry, Biophysics & General Pathology, Second University of Napoli, Vico Luigi De Crecchio 7, 80138 Napoli, Italy.|Institute of Genetics and Biophysics Adriano Buzzati-Traverso, IGB-CNR, Via Pietro Castellino 111, 80131 Napoli, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Altucci
authors.affiliation: Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstraße 25, 79104 Freiburg, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Jung
authors.affiliation: European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Campiani
authors.affiliation: European Research Centre for Drug Discovery & Development (NatSynDrugs), University of Siena, via Aldo Moro 2, 53100 Siena, Italy.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gemma
mesh_terms: D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D056572:Histone Deacetylase Inhibitors; D011758:Pyrroles; C110550:HDAC1 protein, human; C433811:HDAC6 protein, human; D056284:Histone Deacetylase 1; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: HDAC; antitumor agents; bioinformatics; drug design; enzyme inhibitors; epigenetics