Optimization Design And Antitumor Activity Of Arenobufagin Derivatives

Arenobufagin is one of the effective active ingredients of traditional Chinese medicine,and it has excellent anti-tumor activity,but it has obvious cardiotoxic side effects and poor water solubility,which makes it necessary to carry out structural optimization research.The current research mainly focuses on the hydroxyl group at the 3 position of Arenobufagin,and forms a prodrug by introducing an ester group and a peptide bond to reduce the toxicity of the scorpion venom.In order to find highly active and less toxic Arenobufagin derivatives,this paper carried out research on the natural active product Arenobufagin,optimization and anti-tumor activity,and preliminary discussion of its structure-activity relationship.Twenty-two 3-position ester-substituted Arenobufagin derivatives were designed and synthesized.Cell Titer^TM Blue method was used to select human breast cancer cell line MCF-7,human liver cancer cell line Bele7404and human colon cancer cell line HCT116,and 22 Arenobufagin derivatives.In vitro anti-tumor activity tests were performed.Except the compound ZM 235,the other compounds showed excellent anti-tumor activity,and the activity of the three tumor cell lines reached nanomolar level,and some Arenobufagin derivatives reached several nanomolar.In vivo anti-tumor activity study found that the derivative ZM 226 inhibited the human liver cancer Bel7404xenograft model in nude mice with a dose of 2.5 mg/Kg,which was 49%（tumor weight）,which was superior to the positive control drug 5-fluorouracil.The acute toxicity study found no death in mice administered intraperitoneally at 80 mg/Kg,indicating that the toxicity of compound ZM 226 was relatively low.