The Research Of A New Cancer Targeted Drug Conjugate Of Bufalin Derivative And The Anti-tumor Effect Research Of Compounds Acting On Mitochondria

Part 1 The research of a new cancer targeted drug conjugate of bufalin derivativeAntibody-drug conjugates(ADCs) are monoclonal antibodies designed to deliver cytotoxic drugs selectively to antigen expressing cells. Several components of an ADCs including the antibody, the cytotoxic drug payload and the linker. Antibody-drug conjugates (ADCs) combine the targeted monoclonal antibody (mAb) arid the highly active cell-killing drugs, thereby taking advantages of the best characteristics of both components, are emerging as a powerful new anticancer agents. Up to now, two ADCs (Mylotarg and Adcetris) have been approved by FDA and more ADC candidates are in clinical trials which show significantly clinical effects at home and abroad.BF211 is a bufatoxin derivative that has good anti-cancer effects in vitro and vivo,but it lakes of targeting ability that limiting its application. We design it links with antibody/Tumor homing peptide by right linker,increasing the targeting ability while decrease the toxic and side effect.In these studies, we combine BF211 with different linkers like thioether bond,PEG, dipeptide, andtetrapeptide,and choosing the linker that can linking with BF211 and doesn’t influence the effect of BF211,and proving that adding a PABC would has greater efficacy on release and cytotoxicity.Then we combine BF211 with a polypeptide witch can targeting liver cancer that get the conjugates CXM-03035, Enzyme-digestion test proving that CXM-03035 can be cutted off by cathepsin and releasing BF211 that exerting toxic effects, We proving that BF211 can be engineered as cytotoxic drug directly to tuMor cells by suitable methods with enzyme and cell level experiment, It will provide reference for researching and applying ADCs.Part 2 The anti-tumor effect research of compounds acting on mitochondriaMitochondria, as the center of the cell metabolic and signal transduction networks, exhibit various physiological functions,like cell signal transduction,storing calciumit, cell growth and differentiation, cell autophagy and cell apoptosis, participates and plays a central role in many apoptotic pathway. The research on mitochondria has become one of the hotpots for new drug research and development of drug targeting. Mitochondrial membrane potential (MMP) can directly measure the energy state of mitochondrion and its functions directly, The MMP of tumor cells are higher than normal cells,so it’s capable that destructing of mitochondrial membrane potential thereby causing cell apoptosis consequently resulting in cell death.Based on high-throughput screening model, the hit compound LGH00278 was gained from 4000 compounds by Li Jia’s research group of national center for pharmaceutical screening,which can reduce MMP in muscle cells with low concentration. Be based on the structural modification of LGH00278, a series of novel compounds were designed and synthesized by Tang Jie’s research group of ECNU,we evaluate the compounds’effects of cell cytotoxicity inhibiting tumor cell proliferation and reducing the MMP, and find they can inhibiting tumor cell proliferation and reducing the MMP, which have a positive correlation. Further research of compounds having research value showed that they can destruct of MMP thereby causing cell apoptosis. Through above work, we got some new compounds having research value and these research will provide reference for researching of the anti-cancer by destructing of MMP.