2. Academic Validation
  3. Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors

Lactam based 7-amino suberoylamide hydroxamic acids as potent HDAC inhibitors

  • Bioorg Med Chem Lett. 2014 Jan 1;24(1):61-4. doi: 10.1016/j.bmcl.2013.11.072.
Maurizio Taddei 1,  Elena Cini 2,  Luca Giannotti 2,  Giuseppe Giannini 3,  Gianfranco Battistuzzi 4,  Davide Vignola 4,  Loredana Vesci 4,  Walter Cabri 4
Affiliations

Affiliations

  • 1 Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy. Electronic address: maurizio.taddei@unisi.it.
  • 2 Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy.
  • 3 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.
  • 4 R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., Via Pontina Km 30,400, I-00040 Pomezia, Roma, Italy.
PMID: 24345446 DOI: 10.1016/j.bmcl.2013.11.072
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.

Keywords

Anticancer; HDAC; Heterocycles; Hydroxamic acid; Pan-inhibitor.

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