Design Of Platinum Anti-tumor Complexes With Mitochondria-Targeting Property

Platinum anti-tumor drugs have gained a great success during their history over four decades. However, the problem of drug resistances has always been a huge barrier for the improvement of their clinical efficiency. Drug resistances can be mainly attributed to two major reasons:the decrease of drug accumulation and the increasing cellular self-repair mechanisms in cancer cells. The problem is universal and lasting because of the similarity of the mechanisms between these traditional platinum anti-tumor drugs. It is generally accepted that traditional platinum complexes can cause damage to nuclear DNA and then inhibit the gene transcription and DNA replication processes of cells, and apoptosis comes at last. Therefore, searching for some new therapeutic targets could bring a potential to overcome the drug resistances of traditional platinum anti-tumor drugs.Mitochondria, as the power house in cells to keep their function, also act as a kind of vital organelles during cell apoptosis. In addition, mitochondria contain their own circular DNA, which can be treated as a therapeutic target in chemotherapy of cancer. Based on these knowledge, this work design a series of Pt complexes with Triphenylphosphonium (TPP) as a targeting group to the mitochondria. We synthesize three complexes with different sterical hindrance:[Pt(2-PPh3CH2Py)(NH3)2Cl](NO3)2, [Pt(3-PPh3CH2Py)(NH3)2Cl](NO3)2 and [Pt(4-PPh3CH2Py)(NH3)2Cl](NO3)2, namely 2-Pt,3-Pt and 4-Pt. The difference of structure leads to quite different biological activities. MTT assay shows that 2-Pt and 4-Pt are more active than 3-Pt. Then we use ICP-MS to determine the quantity of platinum in the mitochondria, all the three complexes show higher uptake of Pt in mitochondria to different extents. Mito-Stress test finds that 2-Pt can strongly decrease the efficacy of respiration of mitochondria. Besides, we also used gel electrophoresis and circular spectroscopy to determine the binding mode of the complexes to supercoiled DNA and the effect of DNA spatial conformation. These results are consistent with the cytotoxic properties of these complexes.These complexes can also hamper the gene transcription and DNA replication process by inhibiting the activity of an important enzyme:Human Topoisomerase â… , which is a kind of key enzyme during the process of the transformation of the topology of DNA during replication process. Gel electrophoresis showed that complexes 2-Pt and 4-Pt can strongly inhibit the activity of this enzyme, but 3-Pt did not show evident inhibition ability.Above all, this work synthesized and investigated a series of new platinum complexes with mitochondria-targeting ability. This series of complexes showed different mechanisms comparing to traditional platinum anti-tumor drugs. So there is a great potential for these complexes to overcome the drug resistance caused by platinum anti-tumor drugs.