Synthesis And Antitumor Activity Of Monofunctional Trinuclear Platinum (Ⅱ) Complexes

The study of platinum anticancer complexes plays an important role in the medicinal inorganic chemistry. Monofuncational multinuclear platinum complexes have a lot of DNA bingding modes which are different from that of cisplatin due to its non-classic structure. In addition, they often show the potential to overcome shortcomings of cisplatin, such as drug resistance and severe side effects. Therefore, we designed and synthesized a monofunctional trinuclear platinum anticancer complex and studied its antitumor activity and biological mechanism.In this study, a monofunctional trinuclear platinum complex (MTPC) with 1,3,5-tris(pyridin-2-ylmethoxy)benzene, ammine and chloride as the ligands was synthesized and characterized by 1H NMR and electrospray mass spectrometry. MTPC shows good solubility in water due to the flexible linker. In order to study the anticancer mechanism and bioreactivity of MTPC. circular dichroism spectroscopy and gel electrophoresis were used to investigate the DNA binding mode of MTPC. The results showed that MTPC can transfer the conformation of CT-DNA from B-to Z-type conformation significantly, which is completely different from that of cisplatin. At the same time, MTPC can unwinding the helix of pUC 19 plasmid at a concentration much lower than cisplatin. MTPC tends to form 1,4-GG rather than 1,2-GG intrastrand crosslinks, which are different from the case of cisplatin. The reactivity of MTPC towards glutathione was studied by electrospray mass spectrometry and 1H NMR spectra. The results show that MTPC reacts with glutathione quite slowly because of the steric hindrance. These characters may have an important meaning to overcome the cisplatin resistance and reduce side effects.The cytotoxicity of MTPC was tested on the human breast cancer cell line MCF-1, the human non-small-cell cancer cell line A549, and the human ovarian cancer cell line Skov-3 by the MTT assay. MTPC is more potent than or comparable to cisplatin. The cellular inhibition mode of MTPC was examined by flow cytometry using MCF-7 cells. MTPC arrests the cell cycle mainly in G2 or M phase, while cisplatin arrests the cell cycle in S phase. Similar to cisplatin, MTPC kills the cells predominantly through an apoptotic pathway. Considering the characters of chemical structure and biochemical reactivity, the mechanism of action for MTPC should be different from that of cisplatin. With these properties and good biological activity, the study of MTPC may offer some useful suggestion for designing new monofunctional mutinuclear platinum anticancer complexes.