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Pyrazolo[3,4-d]pyrimidines as potent antiproliferative and proapoptotic agents toward A431 and 8701-BC cells in culture via inhibition of c-Src phosphorylation.

Authors :
Carraro F
Naldini A
Pucci A
Locatelli GA
Maga G
Schenone S
Bruno O
Ranise A
Bondavalli F
Brullo C
Fossa P
Menozzi G
Mosti L
Modugno M
Tintori C
Manetti F
Botta M
Source :
Journal of medicinal chemistry [J Med Chem] 2006 Mar 09; Vol. 49 (5), pp. 1549-61.
Publication Year :
2006

Abstract

We report here the synthesis of new pyrazolo[3,4-d]pyrimidine derivatives along with their biological properties as inhibitors of isolated Src and cell line proliferation (A431 and 8701-BC cells). Such compounds block the growth of cancer cells by interfering with the phosphorylation of Src, and they act as proapoptotic agents through the inhibition of the anti apoptotic gene BCL2. Several of them were found to be more active than the reference compound (1-(tert-butyl)-3-(4-chlorophenyl)-4-aminopyrazolo[3,4-d]pyrimidine, PP2) in inhibiting cell proliferation and in inducing apoptosis, and as active as PP2 in the inhibition of the phosphorylation of isolated Src. Moreover, molecular modeling simulations have been performed to hypothesize the way, at the molecular level, by which the inhibitors were able to act as antiproliferative agents.

Details

Language :
English
ISSN :
0022-2623
Volume :
49
Issue :
5
Database :
MEDLINE
Journal :
Journal of medicinal chemistry
Publication Type :
Academic Journal
Accession number :
16509573
Full Text :
https://doi.org/10.1021/jm050603r