Synthesis,Characterization And Activity Of A Class Of Fluorine-Containing Antitumor Platinum(Ⅳ)Complexes

Platinum-based anticancer drugs are important clinical drugs for cancer treatment.However,due to the poor specificity of anticancer chemotherapy,severe side effects,cross-resistance and acquired resistance of various cancers limit the efficacy of platinum drugs.Therefore,the research and development of platinum drugs with good therapeutic effect,low toxicity and side effects and overcoming drug resistance is an important focus in the screening of platinum antitumor drugs.Kinetically inert Pt(Ⅳ)complexes can be reduced in vivo by glutathione and ascorbic acid to a toxic Pt(Ⅱ)complexes.The Pt(Ⅳ)complexes contain two axial ligands that can regulate the reduction kinetics,lipophilicity and tumor selectivity of platinum drugs and chemical structures with central coordination saturation that limit the interaction with biomolecules before reaching the target in vivo,which can reduce the occurrence of related side reactions and side effects.Biotin is absorbed by cancer cells mainly through the sodium-dependent multi-vitamin transporter(SMVT),which is overexpressed in a variety of cancer cells.Biotin-conjugated drug delivery systems not only increase the cellular uptake of drugs but also enable safer,targeted delivery of drugs to tumor tissues.In the design of new drugs,fluorination of bioactive molecules is a well-established strategy to improve drug efficacy,biological half-life,and bioabsorption.Fluorine-containing drug molecules can regulate acidity and lipophilicity and control conformational bias by properly replacing hydrogen atoms or functional groups with fluorine,which may eventually lead to improvements in pharmacological properties,such as lipophilicity,solubility,pharmacokinetic parameters,bioavailability,etc.Therefore,in order to improve the defects of classical platinum antitumor drugs,we synthesized a class of fluorine-containing and antitumor Pt(Ⅳ)complexes S1-S7 by integrating the excellent properties of Pt(Ⅳ)complexes and introducing fluorine-containing groups,and using biotin as active targeting groups.First,we determined the structures of the new Pt(Ⅳ)complexes S1-S7 by the determination of Pt content,the proton nuclear magnetic resonance,IR and mass spectrum.Then,the cell activity of S1-S7 in five tumor cell lines SW480(human colon cancer cells),HCT116(human colon cancer cells),MCF-7(human breast cancer cells),A549(human non-small cell lung cancer cells),and Hep G2(human liver cancer cells)were evaluated by cell activity assay in vitro.The results of MTT assay showed that:(1)The cytotoxic activity of Pt(Ⅳ)complexes S5-S7 was better than that of S1-S4,possibly because the axial bond of S5-S7 complexes was chlorine.Chlorine is easier to be reduced than hydroxyl,and the compounds that are easier to be reduced are easier to bind to DNA and increase their antitumor activity.(2)Pt(Ⅳ)complex S6 showed superior cellular activity to cisplatin and picoplatin on SW480,HCT116 and Hep G2 cancer cell lines.The introduction of fluorine atom and biotin ligand had the potential to increase its antitumor activity.(3)Pt(Ⅳ)complex S6 has better cellular activity than S5 and S7,probably because the leaving group of S6 is oxalic acid.The oxalate ligand has a moderate chelating strength with platinum units,that is,after entering tumor cells,it is relatively easy to dissociate into bivalent Pt ions to form adducts with DNA,thus increasing its antitumor activity.In conclusion,the fluorine-containing tetravalent platinum complex S6 designed and synthesized in this paper is a leading anti-tumor platinum complex with further research value.