Two novel platinum(II) complexes with sorafenib and regorafenib: Synthesis, structural characterization, and evaluation of in vitro antitumor activity

摘要

Two new Pt(II) complexes with sorafenib (SRFN) and regorafenib (RGFN), having the general formulae [Pt (SRFN)(DMSO)Cl-2] (SRFN-Pt) and [Pt(RGFN)(DMSO)Cl-2] (RGFN-Pt), were prepared and characterized by ESI-MS, IR, UV-Vis spectroscopy, elemental analyses, and H-1 and C-13 NMR, respectively. The anticancer activities of SRFN-Pt and RGFN-Pt were evaluated by MTT assay with NCI-H460 (human non-small cell lung cancer NCI-H460 cell line), SK-OV-3 (ovarian cancer cell line), SK-OV-3/DDP (cisplatin-resistant SK-OV-3 cell line), T-24 (human bladder cancer cell line), HeLa (cervical cancer cell line), A549/DDP (cisplatin-resistant A549/DDP non-small cell lung cancer cell line) cancer cells and in the normal HL-7702 cells. The results suggested that SRFN-Pt and RGFN-Pt were more effective against the A549/DDP tumor cells (IC50 = 1.18 +/- 0.15 mu M and 0.13 +/- 0.03 mu M) than SRFN (45.03 +/- 0.79 mu M), RGFN (40.11 +/- 2.15 mu M), and cisplatin (97.63 +/- 1.06 mu M), respectively, and RGFN-Pt was more effective than SRFN-Pt. In addition, SRFN-Pt and RGFN-Pt induced G2/M and S phase arrest. Cytotoxic mechanism studies revealed that SRFN-Pt and RGFN-Pt triggered mitochondria-mediated apoptotic cell death at low concentration. RGFN-Pt exhibited obvious priority on the in vitro antitumor activity than SRFN-Pt, which should be undoubtedly correlated with the key roles of the fluoro substituted groups in the RGFN ligand of RGFN-Pt. The in vitro anti-tumor activity studies suggested that RGFNPt pointed to a new direction in developing Pt(II) drugs as anti-cancer agent.