title: Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors.
abstract: A series of SAHA-like molecules were prepared introducing different lactam-carboxyamides in position 7 of the suberoylanilide skeleton. The activity against different HDAC isoforms was tested and the data compared with the corresponding linear products, without substituent in position 7. In general, this modification provided an effective reinforcement of in vitro activity. While the lactam size or the CO/NH group orientation did not strongly influence the inhibition, the contemporary modification of the suberoylamide fragment gave vary active variants in the lactam series, with compound 28 (ST8078AA1) that showed IC50 values between 2 and 10nM against all Class I HDAC isoforms, demonstrating it to be a large spectrum pan-inhibitor. This strong affinity with HDAC was also confirmed by the value of IC50=0.5μM against H460 cells, ranking 28 as one of the most potent HDAC inhibitors described so far.
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: maurizio.taddei@unisi.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taddei
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cini
authors.affiliation: Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Giannotti
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Roma, Italy. Electronic address: giuseppe.giannini@sigma-tau.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giannini
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Roma, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Battistuzzi
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Roma, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Vignola
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Roma, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Vesci
authors.affiliation: R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Roma, Italy.
authors.forename: Walter
authors.initials: W
authors.lastname: Cabri
mesh_terms: D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007769:Lactams / Q000737:chemistry*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007769:Lactams; D006655:Histone Deacetylases
keywords: Anticancer; HDAC; Heterocycles; Hydroxamic acid; Pan-inhibitor