Study On Synthesis Technology Of Key Intermediate Of Dolastatin 10 And Synthesis Of Cyclic Peptide Analogues

A wide variety of terrestrial and marine organisms provide a broad source of anticancer drugs.The marine natural product,dolastatin 10,is a potent microtubule inhibitor isolated from the Dolabella auricularia.Preclinical studies have shown that it has a strong inhibitory effect on a variety of cancer cells.However,because of its strong toxicity,even if it is structurally modified,it cannot be directly applied to the clinic.Subsequently,the analogues of dolastatin 10 was applied to antibody-drug conjugations(ADC),and good results were obtained.At present,a number of ADC drugs with dolastatin 10 as a cytotoxin have been marketed,and part of it has entered the stage of clinical trials.Therefore,it is of great significance for the amplification synthesis,structure-activity relationship study and target research of the dolastatin 10 and its analogues.The first part of the preface of this paper describes the discovery history of dolastatin 10 and its application to clinical through structural modification.The second part introduces the synthesis method of the dolastatin 10,focusing on the existing synthetic routes of the two key intermediates Dil and Dap fragments.The third section describes anti-tumor cyclic peptide from natural products,including those already in clinical use and in clinical research.The second chapter begins with the research content of this paper.The second chapter and the third chapter respectively analyze the existing synthetic routes of the Dil fragment and Dap fragment the key intermediate of the dolastatin10,and try to optimize it to fit the amplification synthesis.Finally,the optimal route was selected and amplified,so that the synthesis scale reached 50 g and a good yield was obtained.By optimizing the post-treatment,high-purity end products could be obtained without column chromatography.In the fourth chapter,the cyclic peptide analogues of the dolastatin 10 were synthesized.Firstly,the synthesis process of the key intermediate tetrapeptide fragment was optimized.Then,based on the obtained tetrapeptide fragment,several dolastatin10 N-terminal modification analogues were synthesized.Thereafter,the pentapeptide cyclization conditions were further optimized,and the obtained linear pentapeptide compound was cyclized to synthesize a plurality of cyclic peptide analogs.All of the obtained linear peptide and cyclic peptide compounds were tested for biological activity.The structure-activity relationship of the dolastatin 10 cyclic peptide analogues and the linear peptide analogues was summarized by analyzing the biological activity results.The last chapter of this paper is the study of the dolastain 10 cyclic peptide analogues target.We compared the commonly used target finding methods and selected the fluorescent probe method to find the target of the dolastatin 10 cyclic peptide analogues.Based on the structure-activity relationship summarized above,the fluorescent probes of the dolastatin 10 cyclic peptides were designed and synthesized,but different problems were encountered,and the fluorescent probes of cyclic peptide compounds were not successfully synthesized..