4,5,6,7-Tetrahydro-isoxazolo-[4,5-c]-pyridines as a new class of cytotoxic Hsp90 inhibitors

  • Eur J Med Chem. 2014 Apr 9:76:53-60. doi: 10.1016/j.ejmech.2014.01.056.
Riccardo Baruchello  1 ,  Daniele Simoni  2 ,  Paolo Marchetti  1 ,  Riccardo Rondanin  1 ,  Stefania Mangiola  1 ,  Cristiana Costantini  1 ,  Maria Meli  3 ,  Giuseppe Giannini  4 ,  Loredana Vesci  5 ,  Valeria Carollo  5 ,  Tiziana Brunetti  5 ,  Gianfranco Battistuzzi  5 ,  Manlio Tolomeo  6 ,  Walter Cabri  5
Affiliations
  • 1. Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, I-44121 Ferrara, Italy.
  • 2. Dipartimento di Scienze Chimiche e Farmaceutiche, Università degli Studi di Ferrara, I-44121 Ferrara, Italy. Electronic address: [email protected].
  • 3. Dipartimento di Scienze per la Promozione della Salute e Materno Infantile, Sezione di Farmacologia, Università di Palermo, Italy.
  • 4. R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., I-00040 Pomezia, Roma, Italy. Electronic address: [email protected].
  • 5. R&D Sigma-Tau Industrie Farmaceutiche Riunite S.p.A., I-00040 Pomezia, Roma, Italy.
  • 6. Centro Interdipartimentale di Ricerca in Oncologia Clinica e Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Malattie Infettive, Università di Palermo, Palermo, Italy.
PMID: 24565573 DOI: 10.1016/j.ejmech.2014.01.056
Abstract

HSP90 is considered an interesting therapeutic target for Anticancer drug development. Here we describe a new class of 4,5,6,7-tetrahydro-isoxazolo-[4,5-c]-pyridine compounds. A small library of derivatives has been synthesized and investigated. Some reported compounds show interesting properties combining both notable binding to HSP90 and potent cell growth inhibitory activity. N-5 substitution with a 2,4 resorcinol carboxamide appears crucial for activity. Moreover, a derivative bearing a hydroxamic acid residue bound to C-3 amide portion was found to inhibit both HSP90 and HDAC6.

Keywords
4,5,6,7-Tetrahydro-isoxazolo-[4,5-c]-pyridines; Anti-cancer drugs; Heat shock protein 90.