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 NI side chain phenyl,ring for the interaction with the T315I mutant. A series of 4;bromo derivatives was thin 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.

Design, Synthesis, and Biological Evaluation of Pyrazolo[3,4-d]pyrimidines Active in Vivo on the Bcr-Abl T315I Mutant / Radi, Marco; Cristina, Tintori; Francesca, Musumeci; Chiara, Brullo; Claudio, Zamperini; Elena, Dreassi; Anna Lucia, Fallacara; Giulia, Vignaroli; Emmanuele, Crespan; Samantha, Zanoli; Ilaria, Laurenzana; Irene, Filippi; Giovanni, Maga; Silvia, Schenone; Adriano, Angelucci; Maurizio, Botta. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 56:(2013), pp. 5382-5394. [10.1021/jm400233w]

Design, Synthesis, and Biological Evaluation of Pyrazolo[3,4-d]pyrimidines Active in Vivo on the Bcr-Abl T315I Mutant

RADI, Marco;
2013-01-01

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 NI side chain phenyl,ring for the interaction with the T315I mutant. A series of 4;bromo derivatives was thin 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
Design, Synthesis, and Biological Evaluation of Pyrazolo[3,4-d]pyrimidines Active in Vivo on the Bcr-Abl T315I Mutant / Radi, Marco; Cristina, Tintori; Francesca, Musumeci; Chiara, Brullo; Claudio, Zamperini; Elena, Dreassi; Anna Lucia, Fallacara; Giulia, Vignaroli; Emmanuele, Crespan; Samantha, Zanoli; Ilaria, Laurenzana; Irene, Filippi; Giovanni, Maga; Silvia, Schenone; Adriano, Angelucci; Maurizio, Botta. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 56:(2013), pp. 5382-5394. [10.1021/jm400233w]
File in questo prodotto:
File Dimensione Formato  
2013_JMC.pdf

non disponibili

Tipologia: Documento in Post-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 4.84 MB
Formato Adobe PDF
4.84 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2650664
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 40
  • ???jsp.display-item.citation.isi??? 42
social impact