Total Synthesis Of Elongation Factor 1? Inhibitor Nannocystin A And Design,Synthesis And Biological Evaluation Of Nannocystin A Analogues

Natural products and their derivatives are important sources of leads and/or drug candidates in drug development as well as in the field of chemical biology.An analysis of the new drugs approved by the US Food and Drug Administration?FDA?in recent 30years suggested that more than 60%of those drugs were natural products or direct derivatives from natural products.Therefore,it is important to study the total synthesis and structure-activity relationship of natural products or their derivatives with significant bioactivities.Cancer is a huge threat to human health,studies have shown that tumors caused millions of human deaths every year,and the discovery of new anti-cancer drugs is urgent.Eukaryotic elongation factor 1??eEF1??,known as a potential anti-cancer drugs target,has attracted a lot of research interests in medicinal chemistry community.Transcription and translation of proteins is important in proteins synthesis.Eukary elongation factor 1?is an important protein factor that promotes the elongation of polypeptide chains during mRNA translation.Block this process can inhibit the growth of tumor cells or kill tumor cells.Currently,drug candidates for this target have entered into the clinical trials,but have not been successfully marketed yet.So,we conducted the total synthesis of elongation factor 1?inhibitor nannocystin A and design,synthesis and biological evaluation of nannocystin A analogues in this thesis.The first part of this thesis is the total synthesis of elongation factor 1?inhibitor nannocystin A.Nannocystin A is a novel 21-membered macrolactone isolated from myxobacterium Nanocystis sp.It is a potent elongation factor 1?inhibitor and inhibits cancer cell line growth at nanomolar concentrations(IC₅₀ values against PC3 and HCT116 cell line are 1 nM and 1.2 nM,respectively).Subsequent pharmacological studies cannot be performed due to the limited source of natural product,.Therefore,we started the total synthesis of nannocystin A.First,we proposed a Stille coupling ring close strategy based on the conjugated alkene moiety.Unfortunately,we faced unpredicted difficulties in synthesizing Stille ring close precursor 3-1.Then,we turned our attention to macrolactamization strategy.At last,a concise asymmetric total synthesis of nannocystin A has been developed,which features Sharpless epoxidation,Stille coupling and final macrolactamization.Overall,nannocystin A was prepared in 11longest linear steps and 5.3%overall yield.The second part of this thesis is the design,synthesis and biological evaluation of nannocystin A analogues.Herein,a series of nannocystin A analogues were synthesized and their structure–activity relationship?SAR?were established based on the MTT assay and western blotting analysis.The SAR enabled us to identify a structurally simplified nannocystin A analogue 4-N18,which exhibited potent antiproliferative activities with IC₅₀0 values ranging from 4.3 to 48 nM against the tested cell lines,and inhibited eEF1?expression in A549 cell line.4-N18 arrested cell cycle at G2 phase and induced A549 cell apoptosis via up-regulation of caspase-3,caspase-9 and bax protein expressions in a dose-dependent manner,while it significantly decreased the bcl-2expression.Collectively,these data demonstrated that 4-N18 could be a promising lead for the development of structurally novel eEF1?inhibitor for cancer treatment.