Investigation Of The Interactions Between Photoactive Pt(Ⅳ) Antitumor Metallodrug And Model DNA By Mass Spectrometry

This thesis focuses on the application of mass spectrometry to study the mechanism of action of photoactive Pt（Ⅳ）metal anti-tumor complexes,and explores the synthesis of new drugs,the interaction with biological targets,and the imaging of drug distribution in tumor tissues.Firstly,the most active anti-tumor diazidodihydroxido Pt（Ⅳ）complex of trans,trans,trans-[Pt（N₃）₂（OH）₂（py）₂]（1）was synthesized as the reference,and further trials to synthesize of the similar series of platinum complex containing heterocyclic ligands（pyridazine,pyrimidine and pyrazine）with two nitrogen atoms in one aromatic ring was conducted to help understand the structure-activity relationship of this kind of complexes.Next,we selected Pt（Ⅳ）complex 1 to interact with different mononucleosides,and characterized their photochemical products by high resolution electrospray ionization mass spectrometry.The results showed that the photoactivatable diazidodihydroxido Pt（Ⅳ）complex 1 could coordinate with all four nucleosides and induce their oxidation.In particular,the double coordination of adenine/cytosine base of Pt and the oxidation of the two bases were found for the first time.For comparisone with cisplatin,three classical DNA model sequences（5′-AGA-3′,5′-TGGT-3′,5′-TGTGT-3′）were also selected and their photochemical products by complex 1 after light irradiation were also analyzed by mass spectrometry.The results showed that the main reaction products of complex 1 with three DNA sequences were all mono-platinated DNA（[DNA+1′]（1′=[Pt（N₃）（py）₂]⁺））with 1,3-AA and 1,3-GG intrastrand crosslinks formed in AGA and TGTGT detected,respectively,while none1,2-GG intrastrand crosslink found in TGGT.These were in line with the binding styles of cisplatin and transplatin.Guanine was identified as the main platination site on these three model sequences by tandem mass spectrometry,however,binding to A or T base were also observed.In addition,we have cooperated with other research groups to carry out a number of imaging studies on the distribution of Pt and other metal elements in tumor tissues of model mice after intravenous injection of cisplatin and other Pt（Ⅳ）complexes by laser ablation-inductively coupled plasma-mass spectrometry（LA-ICP-MS）,the imaging results were analyzed and compared between cisplatin and other Pt（Ⅳ）complexes.