Synthesis,Characterization And Antitumor Activity Of A New Type Of Platinum Complexes With Ammonia/Cyclohexylamine As Carried Group

Classical platinum drugs such as carboplatin,cisplatin and oxaliplatin have received wide attentions due to their unique antitumor mechanism and broad-spectrum antitumor effect in the treatment of some malignant tumors.Among them,oxaliplatin has become the mainstay of clinical chemotherapy for the treatment of carcinoma of the rectum.However,the efficacy of classical platinum drugs is often limited by a series of toxic side effects such as severe gastrointestinal reactions,nephrotoxicity,ototoxicity,neurotoxicity and cross-resistance between platinum drugs.Therefore,the development of better therapeutic effects,less toxic side effects and low cross-resistance,which is the direction for the development of antitumor drugs.It has been found that the amino group and cyclohexylamine,the asymmetric carried groups,are important pharmacophores which play an role in affecting their antitumor activity,and because of their asymmeytric carried groups structure,which are different from the symmetric amines in the classic platinum-listed drugs.So,there are some differences in the mechanism of action.Comparing the adducts of classical platinum drugs with tumor cell DNA,Satraplatin induced adduct does not bind to high mobility group protein 1,which recognizes DNA damage caused by cisplatin and inhibits trans-lension replication by certain DNA polymerases.These differences may provide a mechanism by which some classical platinum resistance can be overcome by satraplatin.Furthermore,in contrast to cisplatin and carboplatin,Satraplatin-induced adduct is not recognized by the DNA mismatch repair protein,resulting in the absence of DNA mismatch repair and avoiding the resistance of classical platinum drugs.Base on the above considerations,This thesis is mainly divided into two parts,which for the discovery of new platinum drugs with better efficacy,low toxicity and low cross-resistance:Part one:Synthesis,Characterization and Antitumor Activity of Novel Pt(?)Complexes with Ammonia/Cyclohexylamine as Carrier GroupA new class of divalent platinum complexes have been designed and synthesized based on the asymmetric amine ligand of satraplatin and the classical platinum drugs cisplatin,carboplatin and oxaliplatin leaving groups.The structures of the novel divalent complexes C1-C3 were determined by platinum content determination,nuclear magnetic resonance spectroscopy,infrared spectroscopy,elemental analysis and elemental analysis and electrospray ionization mass spectrometry.The results showed that the C1 and C2 complexes showed better antitumor activity to the selected four cell lines,and increased by about 2~7 times comparing with cisplatin.Therefore,platinum complexes C1 and C2 are expected to become several potential lead complex in the development of future platinum-based antitumor drugs.Part two: Synthesis,Characterization and Antitumor Activity of Novel Pt(?)Complexes with Ammonia/Cyclohexylamine as Carrier Group(1)Novel Pt(?)complexes as targeted cytostatic drug against breast cancer cellsThe novel Pt(?)platinum complexes with targeted cytostatic agent what can not only target specific tumor cells,but also reduce damage to normal cells,reduce toxic effects,and make it more effective in treating tumor cells.Based on the novel Pt(?)C1-C2,a new type of Pt(?)complexes C4-C7 with targeting what effect were designed and synthesized by introducing the hydroxyl group or the chlorine atom and the targeting biotin ligand on the axis,which for the treatment of breast cancer cells.(2)Novel Pt(?)complexes with lipophilic ligandsA novel Pt(?)complexes with a lipophilic ligand could prevent it from reacting pre-reactively in the digestive tract,and which could improve transmembrane efficiency and bioavailability.Therefore,it can reduce the side effects and enhance cytotoxicity.Based on the novel Pt(?)C1-C3,a new type of Pt(?)complexes C8-C10 with lipophilic ligands were designed and synthesized by introducing the chlorine atom and the ligand with lipophilic groups with acetic anhydride on the axis.The means for determining the structure of two major Pt(?)complexes and the evaluation of cytotoxicity are consistent with the method of divalent platinum complexes.Platinum complexes C5,C8 and C9 all contain a chloride in the axial direction,showed outstanding antitumor activity against the four cancer cell lines,especially the platinum compound C9 is 2~8 times more cytotoxic than cisplatin and satraplatin,and it is expected that the complex be orally active and expected to be an antitumor drug candidate.