Design,synthesis And Anticancer Activity Of Targeted Anticancer Prodrugs Based On Organic Cation Transporters

In order to realize the targeted therapy of cancer,the prodrug modification strategy has gradually become a research hotspot.The prodrug strategy is mainly to functionally modify anticancer drugs to improve the pharmacokinetics of these drugs and reduce damage to normal cells and tissues.Novel organic cation transporter 2（OCTN2,SLC22A5）is abundantly expressed in small intestinal cells and is an important nutrient transporter for carnitine transport into cells.In recent years,several studies have shown that oral prodrug strategies targeting OCTN2 are feasible for improving certain antitumor drugs.Therefore,it is a great significance to study the anticancer oral prodrugs targeting OCTN2 and their anticancer properties based on small carnitine molecules.In order to improve the antitumor effects of cisplatin and doxorubicin,the synthesis and anticancer activities of carnitine-targeted anticancer prodrugs derived from these two broad-spectrum anticancer drugs were studied in detail.The main work of this thesis is as follows:1.Using cisplatin as the parent,three carnitine-cisplatin prodrugs linked by fatty acids were obtained by esterification,namely carnitine-glutaric acid-Pt（IV）,carnitine-suberic acid-Pt（IV）,carnitine-sebacic acid-Pt（IV）,three prodrug molecules were successfully synthesized by ¹H NMR,¹³C NMR and electrospray mass spectrometry,respectively.The inhibitory rate of complexes 1-3 on HCT116,LOVO,He La,A549 and Hep G-2 cells was determined by MTT method,and the half-inhibitory concentration was calculated.The results showed that:carnitine-suberic acid-Pt（IV）and carnitine The inhibitory effect of carnitine-sebacic acid-Pt（IV）on the proliferation of these cancer cells is obvious,and the inhibitory effect of complex 3 is more in line with expectations.In addition,these Pt（IV）prodrugs were excellent in inhibiting tumor cell proliferation after co-culture with these cancer cells for 48 and 72 hours,and the half-inhibition could also be reduced when the drug and cancer cells were interacted for a longer period of time.concentration,which is closely related to its faster intracellular targeted trafficking and responsive cleavage of sensitive bonds.2.Using doxorubicin as the parent,the DOX-PEG nanoparticles were first synthesized by Schiff base reaction,and then connected with L-carnitine-suberic acid,and finally the p H-sensitive nanoparticles coupled with doxorubicin-carnitine were obtained.The successful synthesis of doxorubicin prodrug was confirmed by ¹H NMR,and its stable existence in normal physiological environment was proved by dynamic light scattering test,and the particle size distribution of its nanoparticles showed that the nanoparticles could be taken up by cells.Preliminary experiments show that the nanomicelles are less toxic to normal cells.