Pd(II) and Pt(II) saccharinate complexes with two phosphine derivatives: Synthesis, anticancer and antiangiogenic activities

Abstract

As clinically used anticancer Pt(II) drugs have severe side effects, there is a growing interest for new metal complexes with great potential for cancer therapy. The current work aimed to prepare and characterize new Pd(II) and Pt(II) saccharinate (sac) complexes bearing pyridyl‐ and benzyldiphenylphosphines (PPh2Py and PPh2Bz, respectively), cis‐[Pd(sac)2(PPh2Py)2] (1), cis‐[PtCl(sac)(PPh2Py)2]·0.5DMF (2), cis‐[Pd(sac)2(PPh2Bz)2]·DMF (3) and trans‐[PtCl(sac)(PPh2Bz)2] (4) as promising anticancer and antiangiogenic drugs. The anticancer activity of the complexes was screened against seven cancer cell lines including HCT116 (colon), HepG2 (liver), MDA‐MB‐231 (breast), PANC‐1 (pancreatic), A549 (lung), C6 (glioma), DU145 (prostate) and normal human lung epithelial cells (BEAS‐2B). 1 and 2 did not show biological activity below 20 μM at 48 h, whereas 3 and 4 displayed significant cytotoxic effect on the cancer cells. 4 was the most potent complex (IC50 = 2.2–12.1 μM) and displayed much greater cytotoxicity than cisplatin in all the cancer cell lines. 4 caused apoptosis in HCT116 cells as evidenced by annexin V positivity and caspase 3/7 activity assays. Furthermore, the inhibition of antiapoptotic Bcl‐2 proteins by the complex suggested the intrinsic apoptosis. In addition, 4 greatly enhanced generation of intracellular reactive oxygen species (ROS) and consequently caused remarkable DNA double‐strand breaks in HCT116 cells. Moreover, the chick chorioallantoic membrane (CAM) assay was used to evaluate antiangiogenic potential of 4. The complex effectively inhibited angiogenesis at a dose of 50 ng, suggesting it as a promising multi‐targeted agent for antiangiogenic cancer treatment.