The Design And Synthesis Of The Tumor-targeted Drug, Bufalin’s Derivatives

Molecular-targeted therapy is an important method for recent scientific researchers in the treatment of cancer. It uses the carrier, which can specifically bind to tumor cells, to transport the cytotoxin to the tumor cells and kill them while does no harm to the normal cells. Antibody-drug conjugates (ADCs) are one of the important kinds of molecular-targeted drugs, which use linkers to combine cytotoxity and antibody. ADCs have the advantages of both high bioactivity and high selectivity.BF211, a cardiac glycoside compound, was originally used to treat congestive heart failure, arrhythmia and heart disease. Later, scientists discovered when the blood concentration is lower than the required in the treatment of heart disease, it can induce apoptosis of tumor cells, reflecting the anti-tumor effect. However, BF211 also have toxic effects on normal cells and tissues, which has limited its application.The chemical linkers have a crucial effect on the research of ADCS. They not only need to complete the task of "missile carrier", which can transport and release the cytotoxicity effectively. But also should be biocompatible, with no influence on tumor-targeting groups. The main content of this thesis is to find a suitable chemical linker, which is combined with the BF211 to lower the cytotoxicity and release BF211 effectively.The chapter one introduces the background of molecular targeted drugs and antibody-drug conjugates. We also give a brief introduction of BF211 and C-A54. Then we propose our project ideas based on the literature.In the chapter 2, we designed and synthesized the compound MC-GFLG-BF211 and MC-GFLG-PABC-BF211, which were synthesized on the basis of GFLG linker. However, the bioactivity of these two compounds is too low to satisfy the expectations.The chapter 3, introduces the synthesis of MC-Val-Cit-PABC-BF211 and MC-Val-Cit-BF211 on the basis of Val-Cit linker. After testing their bioactivity, we found the bioactivity of MC-Val-Cit-PABC-BF211 is much better, which met our requirement of linking a carrier in the further research. Then we combined C-A54 with MC-Val-Cit-PABC-BF211 and constructed the compound A54-C-MC-Val-Cit-PABC-BF211. We found its bioactivity is higher than MC-Val-Cit-PABC-BF211 and it could effectively release the BF211 molecule. Therefore, Val-Cit-PABC can be better applied to the design and synthesis of ADCs, which provides a strong basis for the study of ADCs in the future. The further research is ongoing and we hope to improve the selectivity of the targeting peptides.