title: 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.
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.
authors.affiliation: Dipartimento di Fisiologia, Sezione di Neuroimmunofisiologia, Università degli Studi di Siena, Via Aldo Moro, I-53100, Siena, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Carraro
authors.forename: Antonella
authors.initials: A
authors.lastname: Naldini
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pucci
authors.forename: Giada A
authors.initials: GA
authors.lastname: Locatelli
authors.forename: Giovanni
authors.initials: G
authors.lastname: Maga
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.forename: Olga
authors.initials: O
authors.lastname: Bruno
authors.forename: Angelo
authors.initials: A
authors.lastname: Ranise
authors.forename: Francesco
authors.initials: F
authors.lastname: Bondavalli
authors.forename: Chiara
authors.initials: C
authors.lastname: Brullo
authors.forename: Paola
authors.initials: P
authors.lastname: Fossa
authors.forename: Giulia
authors.initials: G
authors.lastname: Menozzi
authors.forename: Luisa
authors.initials: L
authors.lastname: Mosti
authors.forename: Michele
authors.initials: M
authors.lastname: Modugno
authors.forename: Cristina
authors.initials: C
authors.lastname: Tintori
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: 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*
chemical_list: D000970:Antineoplastic Agents; D016213:Cyclins; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D011743:Pyrimidines; D012333:RNA, Messenger; D019061:src-Family Kinases