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

• Published in: Journal of medicinal chemistry Vol. 49; no. 5; pp. 1549 - 1561
• Main Authors: Carraro, Fabio, Naldini, Antonella, Pucci, Annalisa, Locatelli, Giada A, Maga, Giovanni, Schenone, Silvia, Bruno, Olga, Ranise, Angelo, Bondavalli, Francesco, Brullo, Chiara, Fossa, Paola, Menozzi, Giulia, Mosti, Luisa, Modugno, Michele, Tintori, Cristina, Manetti, Fabrizio, Botta, Maurizio
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 09.03.2006; Amer Chemical Soc
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Cell Line, Tumor; Chemistry, Medicinal; Cyclins - antagonists & inhibitors; Cyclins - biosynthesis; Cyclins - genetics; Drug Screening Assays, Antitumor; General aspects; Humans; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phosphorylation; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - biosynthesis; Proto-Oncogene Proteins c-bcl-2 - genetics; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; RNA, Messenger - biosynthesis; Science & Technology; src-Family Kinases - metabolism; SIGNAL-TRANSDUCTION; POLY(ADP-RIBOSE) POLYMERASE; ACTIVATION; CANCER METASTASIS; FAMILY KINASES; HUMAN-BREAST; KINASE INHIBITORS; TYROSINE KINASES; DUCTAL INFILTRATING CARCINOMA; HUMAN TUMORS; Antineoplastic agent; Human; Squamous cell carcinoma; Phosphorylation; Gene product; Malignant tumor; Organic chlorine compounds; In vitro; Modeling; Cell line; Structure activity relation; C-Onc gene; Molecular model; Mammary gland; Inhibition; Mechanism of action; Chemical synthesis; Tumor cell; Apoptosis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050603r

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.