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

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.