Synthesis,Characterization,and Biological Activity Of Novel Platinum Anticancer Drugs Containing Active Functional Groups

Classic platinum drugs have achieved great success in the current treatment of cancer,but their application has been limited by toxic side effects and drug resistance.Fluorine has unique physical and chemical properties and biological activities and exhibits the advantages of changing the lipophilicity of drugs and improving drug efficacy.Currently,nearly 40%of FDA-candidate drugs contain fluorine atoms or fluorine-containing groups in their structure.The non-psychoactive substance cannabinoid(CBD)has excellent potential applications in the fields of analgesia,anti-inflammatory,and anticancer.The combined use of CBD with classic platinum drugs not only plays a synergistic anticancer effect but also reduces the generation of drug resistance and toxic side effects.Therefore,it aims to improve the efficacy and reduce the side effects of platinum drugs by modifying the structure of classical platinum drugs through fluorinated groups and CBD.The main research contents of this paper are as follows:In the first part,eight novel fluorinated sterically hindered platinum complexes P1-P8 were designed and synthesized based on the modification of the structures of novel fluorinated sterically hindered groups and targeted biotin groups.The chemical structures of the complexes were characterized by a series of testing methods such as~1H NMR,IR,and ESI-MS.The features of the complexes were studied through stability and log P(o/w)tests,and the complexes P1-P8 exhibited good stability under dark and DMSO conditions.At the same time,introducing lipophilic fluorine atoms and biotin can improve the lipid solubility of the complex to a certain extent.Subsequently,the antiproliferative activity of the target complexes P1-P8 was determined by MTT assay,and it was found that the highly lipophilic Pt(Ⅳ)complex P8 exhibited good tumor cell selectivity and antiproliferative activity.In SW480,HCT116,and A549 cancer cells,its activity was twice that of cisplatin,and three times that of picoplatin.At the same time,complexes P3 and P6 also showed better cytotoxic activity than picoplatin.Finally,the binding characteristics of the complexes to DNA were determined by UV titration and fluorescence quenching,complexes P8,P6,and P3 also showed high binding efficiency with DNA.In the second part,the CBD structure was introduced into the departure group of classical platinum drugs,and three novel bifunctional Pt(Ⅱ)complexes M1-M3 containing CBD active groups were designed and synthesized.Their structures were characterized by ~1H NMR,IR,and ESI-MS.According to the stability and log P(o/w)experiments,the results show that the three complexes are stable and have lipophilicity.Subsequently,the antiproliferative activity of the target complexes M1-M3 was measured by MTT method.The results showed that the antiproliferative activity of the complexes M1-M3 in different cancer cell lines(Hela,HCT116,and HepG2)was higher than that of the positive controls(cisplatin,carboplatin,and oxaliplatin),and its toxicity to normal cells LO2 was low,thereby demonstrating its good tumor selectivity and safety,especially the activity of the complex M1 in Hela and He PG2 was three times higher than that of carboplatin.The activity of complex M2 in HCT-116 is four times that of carboplatin.The binding ability of the target complexes to DNA was determined by UV titration and fluorescence quenching experiments,and it was found that the complexes M1-M3 also had a high binding efficiency with DNA in vitro,and the binding efficiency of the complex M2 was higher.In summary,the introduction of fluorinated steric hindrance groups and active CBD leaving groups is of great significance in improving the selectivity and safety of platinum complexes against cancer cells.The latter can also play a good role in synergistic anticancer cells,which also provides a new direction for the design of new platinum drugs.