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.
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.
Carraro
Fabio
F
Dipartimento di Fisiologia, Sezione di Neuroimmunofisiologia, Università degli Studi di Siena, Via Aldo Moro, I-53100, Siena, Italy.
Naldini
Antonella
A
Pucci
Annalisa
A
Locatelli
Giada A
GA
Maga
Giovanni
G
Schenone
Silvia
S
Bruno
Olga
O
Ranise
Angelo
A
Bondavalli
Francesco
F
Brullo
Chiara
C
Fossa
Paola
P
Menozzi
Giulia
G
Mosti
Luisa
L
Modugno
Michele
M
Tintori
Cristina
C
Manetti
Fabrizio
F
Botta
Maurizio
M
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D016213:Cyclins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D019061:src-Family Kinases / Q000378:metabolism*
D000970:Antineoplastic Agents; D016213:Cyclins; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D019061:src-Family Kinases