| Cisplatin drugs have achieved great success in clinic since they came into the market.At present,one of the key problems to be solved is to develop new derivatives with low toxicity,high efficiency and drug resistance.In this paper,Pt（Ⅱ）complexes with photoactivity were designed and synthesized.Taking Caenorhabditis elegans as the biological model,molecular sensitized oxygen was produced into reactive oxygen species（ROS）by applying light,trying to reduce the drug resistance of cisplatin and make it a potential high-efficiency antitumor drug,which provides a certain method to solve the defects of platinum drugs.This paper has completed the following three aspects:1、The toxicity of monofunctional Pt（Ⅱ）complexes（mCBP and dCBP）containing photosensitive group（BODIPY）to Caenorhabditis elegans in dark and light was explored.The results showed that dCBP showed high toxicity to N2（wild-type,cisplatin resistant）and ok938（asna-1 deficient,cisplatin sensitive）Caenorhabditis elegans under light conditions（the longevity,body length and spawning rate of nematodes were reduced）.RNA sequencing experiments confirmed the expression changes of related genes in several key cancer related pathways JNK and Wnt/β-Catenin,such as JNK-1,wrm-1,Oct-1 and gst-4,in the dark and under light conditions.These expression changes can explain the changes of nematode physiological indexes,and reveal how the complexes of these two Pt（Ⅱ）affect some cancer related pathways.Among these genes,oct-1 and gst-4 were reported to be related to the production of platinum drug resistance.The expression of these genes changed significantly in the presence of dCBP and light,which can reduce the possibility of drug resistance to a certain extent.2、A bifunctional Cis-Pt（Ⅱ）complex（cBBP）modified with BODIPY,a control compound containing pyridine group（cBPP）,and two trans-Pt（Ⅱ）complexes（tBPP and tBBP）were designed and synthesized.The structure of the complex was verified by NMR,IR,UV and high-resolution flight mass spectrometry.The prepared complexes were characterized by photophysical and chemical properties,including absorption and emission spectra and the ability to sensitize reactive oxygen species.Circular dichroism spectra were measured to characterize the damage ability of the complexes to the three-dimensional structure of DNA.The results showed that both cBBP and tBBP had significant ability to sensitize the production of reactive oxygen species,and cBBP also showed high ability to destroy the threedimensional structure of DNA.3、We evaluated the effects of the above complexes on the physiological indexes of Caenorhabditis elegans.The results showed that the polar toxicity order of the complexes under dark or light conditions was cBBP>cisplatin>tBBP>cBPP>tBPP and anti transplatin.Compared with dark conditions,light conditions can significantly improve the toxicity of photosensitizer（BODIPY）modified complexes（significantly affect the physiological indexes such as LC50 value,body length,number of eggs and life span of Caenorhabditis elegans）.CBBP has high toxicity in Caenorhabditis elegans under dark and light conditions.Topo-i enzyme has been proved to be the target of a variety of anticancer drugs with clinical significance,and topoisomerase I is the potential binding substrate of BODIPY molecules.Therefore,in order to explore the potential mechanism of the complex,we verified the binding of the prepared complex with TOPO-Ⅰ.the results showed that only cBBP had good binding ability with TOPO-Ⅰ.we further verified the above research results through simulation calculation.The above research results showed that the significant biological toxicity of CBBP may be due to its ability to sensitize reactive oxygen species（ROS）efficiently,And good combination ability with TOPO-Ⅰ. |
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