The Synthesis, Characterization And Antitumor Activity Of New Binuclear Platinum(Ⅱ)Complexes Containing DNA Intercalator

The cancer is one of the diseases of serious threat to human’s health and life nowadays,and there are more than seven million are found died of cancer each year in the world.In recent years,the incidence and mortality of cancer have been rising sharply as a result of the changes in people’s quality of life and the environmental deterioration.Platinum drugs become one of the most frequently used metal-containing drugs in the clinical treatment of malignancy because of their good antitumor activity.However,severe side effects,including ototoxicity,nephrotoxicity and gastrointestinal reactions,and intrinsic resistance has become major drawbacks of platinum-based drugs which have limited its clinical effectiveness.Therefore,it is an important developing direction of the development of platinum drugs with equal or high antitumor activity but lower toxicity.Previous research found that Trans-(1R,2R)-cyclohexanediamine,the chiral ligands of oxaliplatin,is a component which plays an important role in affecting its biological effects.Meanwhile,Polynuclear platinum complexes represent a novel class of prospective anticancer agents that possess distinctive cytotoxic activities as compared with mononuclear platinum compounds,which have broken the "classical" cisplatin structure for platinum anticancer agents.Polynuclear platinum complexes,structurally different from cisplatin,contain two or more reactive platinum coordination spheres.In all cases the platinum coordination centers are linked by aliphatic polyamines.Unlike the mononuclear cisplatin and its analogues that predominantly form 1,2-interstand cross-links with DNA,polynuclear platinum complexes could span over several base pairs and form long-distance intra-and inter-strand cross-links.Meanwhile,planar aromatic ring small molecule compounds with a rigid structure can be inserted into the groove of base and double stranded DNAthrough π-π stacking and dipole-dipole interactions,and which not only make the closer the alignment of platinum drugs to the DNA of tumor cell,but overcome cisplatin resistance and enhance anticancer activity of platinum drugs in tumor cell lines.Based on above considerations,my master’s thesis is divided into two parts:1.The synthesis,characterization and antitumor activity of new binuclear platinum complexes containing DNA intercalator.A new chiral binuclear platinum ligands HL were synthesized based on Trans-(1R,2R)-cyclohexanediamine of oxaliplatin and terephthalaldehyde of planar aromatic moleculues with inserted effects.With HL as the carrier ligand,six chiral binuclear platinum complexes were designed and synthesized with six leaving groups which can alter the ipid/water partition coefficients.The structure of L1-L6 were charactered by IR,1H NMR and ESI-MS,and their in vitro antitumour activity has been evaluated by MTT assay using HepG-2,A549,HCT-116 and MCF-7 cancer cell lines.The results showed that all the complexes exhibited antitumour activity to the four cancer cell lines,Particularly,L2,bearing ClCH2COO-as the leaving group,not only showed higher cytotoxic activity than carboplatin against HepG-2 and A549 cell lines but also showed a comparable activity against HCT-116.Consequently,the synthesized dinuclear platinum compounds L1 and L2,especially L2,seem to be promising leading compounds for further biological evaluations.2.Design,synthesis and characterization of novel chiral polyamine ligand with alkyl chain as the bridge.Polynuclear platinum-based complexes,with flexible alkyl chains,can predominantly form 1,2-interstand cross-links with DNA,polynuclear platinum complexes could span over several base pairs and form long-distance intra-and inter-strand cross-links,and it’s may also form a winding pattern to enhance anticancer activity.Consequently,these unconventional DNA adducts could overcome cisplatin resistance in tumor cell lines.Therefore,a new chiral trinuclear amine ligand was synthesized based on Trans-(1R,2R)-cyclohexanediamine of oxaliplatin and used six carbon chain long flexible alkyl chains as the bridge.The structure of ligand was charactered by 1H NMR and ESI-MS.The novel trinuclear amine ligand has three Trans-(1R,2R)-cyclohexanediamine and an alkyl chain as the bridge,which would probably be developed as a potential platinum intermediate.