An in vivo active 1,2,5-oxadiazole Pt(II) complex: A promising anticancer agent endowed with STAT3 inhibitory properties.
New Pt(II) complexes (Pt-1-3) bearing 1,2,5-oxadiazole ligands (1-3) were synthesized, characterized and evaluated for their ability to disrupt STAT3 dimerization. Ligand 3·HCl showed cytotoxic effects on HCT-116 cells (IC50= 95.2 μM) and a selective ability to interact with STAT3 (IC50= 8.2 μM) versus STAT1 (IC50> 30 μM). Its corresponding platinum complex Pt-3 exhibited an increased cytotoxicity (IC50= 18.4 μM) and a stronger interaction with STAT3 (IC50= 1.4 μM), leading to inhibition of its signaling pathway. Pt-3 was also evaluated in cell-based assays for its action on p53 expression and on STAT3 phosphorylation. In syngeneic murine Lewis lung carcinoma (LLC) implanted in C57BL/6 mice, Pt-3 showed a higher antitumor activity with fewer side effects than cisplatin.
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
Federica
F
Porta
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
Giorgio
G
Facchetti
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via Marzolo 5, 35131, Padova, Italy. Electronic address: nicola.ferri@unipd.it.
Nicola
N
Ferri
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy. Electronic address: arianna.gelain@unimi.it.
Arianna
A
Gelain
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
Fiorella
F
Meneghetti
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
Stefania
S
Villa
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
Daniela
D
Barlocco
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy.
Daniela
D
Masciocchi
Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
Akira
A
Asai
Center for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan.
Nao
N
Miyoshi
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milano, Italy.
Silvia
S
Marchianò
Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, 125 Gwahakro Yoosunggu, Daejeon 34141, Republic of Korea.
Byoung-Mog
BM
Kwon
Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, 125 Gwahakro Yoosunggu, Daejeon 34141, Republic of Korea.
Yena
Y
Jin
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via Marzolo 5, 35131, Padova, Italy.
Valentina
V
Gandin
Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via Marzolo 5, 35131, Padova, Italy.
Cristina
C
Marzano
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133 Milano, Italy. Electronic address: isabella.rimoldi@unim.it.
Isabella
I
Rimoldi
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D010984:Platinum / Q000737:chemistry / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D010069:Oxadiazoles; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D010984:Platinum
Antitumor agents; Cytotoxic activity; DNA-interaction; Platinum diamine complex; Protein–protein interactions