Design, synthesis, and biological evaluation of pyrazolo[3,4-d]pyrimidines active in vivo on the Bcr-Abl T315I mutant (Articolo in rivista)

Type
Label
  • Design, synthesis, and biological evaluation of pyrazolo[3,4-d]pyrimidines active in vivo on the Bcr-Abl T315I mutant (Articolo in rivista) (literal)
Anno
  • 2013-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1021/jm400233w (literal)
Alternative label
  • Radi M, Tintori C, Musumeci F, Brullo C, Zamperini C, Dreassi E, Fallacara AL, Vignaroli G, Crespan E, Zanoli S, Laurenzana I, Filippi I, Maga G, Schenone S, Angelucci A, Botta M. (2013)
    Design, synthesis, and biological evaluation of pyrazolo[3,4-d]pyrimidines active in vivo on the Bcr-Abl T315I mutant
    in Journal of medicinal chemistry (Online)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Radi M, Tintori C, Musumeci F, Brullo C, Zamperini C, Dreassi E, Fallacara AL, Vignaroli G, Crespan E, Zanoli S, Laurenzana I, Filippi I, Maga G, Schenone S, Angelucci A, Botta M. (literal)
Pagina inizio
  • 5382 (literal)
Pagina fine
  • 5394 (literal)
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  • http://www.scopus.com/inward/record.url?eid=2-s2.0-84880165965&partnerID=q2rCbXpz (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 56 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
  • 13 (literal)
Note
  • Scopu (literal)
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  • Dipartimento di Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Farmacia, Università Degli Studi di Parma, Viale delle Scienze 27/A, 43124 Parma, Italy; Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, 16132 Genova, Italy; Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, 00185 Roma, Italy; Istituto di Genetica Molecolare, IGM-CNR, Via Abbiategrasso 207, 27100 Pavia, Italy; Laboratory of Preclinical and Translational Research, IRCCS, Referral Cancer Center of Basilicata (CROB), Rionero in Vulture (PZ), Italy; Dipartimento di Medicina Molecolare e dello Sviluppo, Università degli Studi di Siena, Via Aldo Moro 2, 53100 Siena, Italy; Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, Via Vetoio, 67100 Coppito, L'Aquila, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, BioLife Science Building, Temple University, 1900 North 12th Street, Philadelphia, PA 19122, United States (literal)
Titolo
  • Design, synthesis, and biological evaluation of pyrazolo[3,4-d]pyrimidines active in vivo on the Bcr-Abl T315I mutant (literal)
Abstract
  • Starting from our in-house library of pyrazolo[3,4-d]pyrimidines, a cross-docking simulation was conducted on Bcr-Abl T315I mutant. Among the selected compounds (2a-e), the 4-bromo derivative 2b showed the best activity against the Bcr-Abl T315I mutant. Deeper computational studies highlighted the importance of the bromine atom in the para position of the N1 side chain phenyl ring for the interaction with the T315I mutant. A series of 4-bromo derivatives was thus synthesized and biologically evaluated. Compound 2j showed a good balance of different ADME properties, high activity in cell-free assays, and a submicromolar potency against T315I Bcr-Abl expressing cells. In addition, it was converted into a water-soluble formulation by liposome encapsulation, preserving a good activity on leukemic T315I cells and avoiding the use of DMSO as solubilizing agent. In vivo studies on mice inoculated with 32D-T315I cells and treated with 2j showed a more than 50% reduction in tumor volumes. © 2013 American Chemical Society. (literal)
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