Studies On The Synthesis Of Natural Product Dolastatin 10 And Its Analogues

The marine natural product dolastatin 10 was originally isolated from the Indian Ocean sea hare Dolabella auricularia.Dolastatin 10 is a highly cytotoxic peptide which shows remarkable inhibition ability against a variety of tumor cell lines.Despite satisfactory preclinical results,dolastatin 10 as a single agent has been dropped from Phase II clinical trials due to toxic side effects.Afterwards,a series of dolastatin 10 analogues have been developed and led to clinical trials.The antibody-drug conjugates Adcetris which was used to treat Hodgkin's lymphoma was developed from one of the dolastatin 10 analogues MMAE and has been approved by FDA in 2011.Moreover,nearly half of the ADC drugs in clinical research are developed on the basis of dolastatin 10 analogues and it holds tremendous promise to become a new antineoplastic agent.On the other hand,the complex structure of dolastatin 10 made it very challenging for the synthesis.So it is of great significance for further study of dolastatin 10 and its analogues either from the perspective of pharmaceutical chemistry or organic synthesis.Recent progress of the synthesis of pepetides was reviewed in the preface.Focusing on the marine natural peptides those with antineoplatic activity,and the discovery,synthesis and development of dolastatin 10 and its analogues.The paper is consisting of the following parts.In the first section,in-depth research has been made for the synthesis of the three key intermediates Dil,Dap and Doe of dolastatin 10 respectively.After the optium of synthetic route and screening of reaction conditions,the three key intermediates can be obtained in large quantities.Subsequently,dolastatin 10 and three chiral isomers have been synthesized under solution phase conditions.In the.second section,on the basis of existing literatures about the SAR study,N-terminal modifications of dolastatin 10 was studied based on the known compound MMAF.With replacement of the terminal tertiary amine by a primary amine and by varying the substituent at the a-carbon atom of the N-terminal amino acid,13 new analogues of dolastatin 10 have been synthesized.By cyclization of the linear peptides,12 new cyclic peptides analogues were also synthesized for the studies on the influence of biological activity of dolastatin 10 with conformation changes.In the third section,for the feature of toxic side effects,dolastatin 10 has been designed as a prodrug.This purpose was achieved by the transformation of the linear dolastatin 10 into depsipeptide or the introduction of enzymatic cleavage dipeptide linker.In the fourth section,by measuring the half-maximal inhibitory concentration(IC50)values against the HCT-116 tumor cell line,the in vitro antitumor activity of the new dolastatin 10 analogues was evaluated.Ten compounds with N-terminal modifications showed enhanced activity in comparison with MMAF,and compound 37f exhibited the most effective potency with an IC50 value of 0.07 ?M.Generally,the cyclic peptides showed lower potency in comparison with the corresponding linear peptides because of the the conformation changes.However,compounds 40m and 401 showed enhanced activity with IC50 value of 0.03 ?M.