Synthesis,Characterization And Antitumor Activity Of Novel Chiral Binuclear Platinum(?)Complexes

Cancer is a disease which has serious threat to human beings,and China has the largest number of cancer patients in the world.Cancer is not only a serious threat to the life and health of people but also represents a tremendous burden on patients,families,and societies,which is a very prominent social public health problem that may hinder economic and society development.Platinum antitumor drugs have been extensive applied in chemotherapy because of their excellent clinical results.Currently,cisplatin,carboplatin,and oxaliplatin are widely used due to their own advantage among the approved Pt-based antitumor drugs in the world.However,platinum antitumor drugs possess serious gastrointestinal reaction,nephrotoxicity,ototoxicity,neurotoxicity and cross resistance in clinical treatment that limit their applications.Therefore,developing new platinum drugs which have few side effects and little drug resistance is a direction of the development of antitumor drugs.Previous study indicated that trans-1R,2R-cyclohexanediamine,the chiral ligands of oxaliplatin,is an important component which plays the antitumour role.Moreover,multinuclear platinum-based drugs can form multipoint bonding with DNA.This bonding force makes DNA more devastating and more difficult repaired due to the multinuclear platinum drugs' non-classical structure-activity relationship.This kind of function may avoid the drug resistance.In addition,many planar aromatic molecules with inserted DNA effect can form hydrogen bonding with DNA,thereby increasing interactions between drugs and DNA.In combination with the mechanism of multinuclear platinum drugs and the structure of DNA,binuclear platinum complexes with alkyl chain may be intertwine with DNA chain besides multipoint bonding with DNA which makes them integrated tightly with DNA.This effect may enhance the cytotoxicity and reduce drug resistance.Even compared to cisplatin,A2 demonstrated comparability in HepG-2 cancer cell line.Based on above considerations,my master's thesis is divided into two parts:Part one:Based on trans-1R,2R-cyclohexanediamine of chiral ligand of oxaliplatin,terephthalaldehyde of planar aromatic molecules with inserted effects as well as six leaving groups which can alter the ipid/water partition coefficients,we designed and synthesized seven binuclear platinum complexes and tested cell cytotoxicities in vitro by MTT assay.Their structures were charactered by IR,1H-NMR,and ESI-MS,and their in vitro cytotoxicity have been evaluated by MTT assay using HepG-2,A549,HCT-116 and MCF-7 cell lines.The results showed that six compounds showed antitumor activity to the selected four cell lines.Particularly,The cytotoxicities of compounds A2 is significantly higher than that of carboplatin and oxaliplatin against the four cell lines.Even compared to cisplatin,A2 demonstrated comparability in HepG-2 cancer cell line.Compound A2 may beome a very promising lead compounds in the future.Part two:Design,synthesis and characterization of five dinuclear platinum(II)complexes with alkyl chain as bridgeBased on trans-1R,2R-cyclohexanediamine of chiral ligand of oxaliplatin,a chiral tetradentate ligand with a six-carbon alkyl chain as bridge as well as five leaving groups which can alter the ipid/water partition coefficients,we designed and synthesized five binuclear platinum complexes.Their structures were charactered by 1H-NMR,and ES-MS.