Total Synthesis Of Crotontomentosin D And Sinopyrine B And Construction And Application Of High-throughput Drug Screening System

This thesis is divided into three parts:(1)Synthesis of crotontomentosin D;(2)Synthesis of sinopyrine B;(3)Construction and application of high-throughput drug screening system.Part Ⅰ : Natural products with pharmacological activity are an important source of small molecule drugs.Total synthesis of natural products not only provides a large number of active molecules,but also facilitates the modification of active natural products to discover new drug active molecules.Crotontomentosin D extracted from Croton plants has antiproliferative activity against Hela,Hep G2,MDA-MB-231 and A549 cell lines.However,there is no report on the synthesis of this compound.Based on the gold-catalyzed 1,3-acyloxy migration/cyclization/electrophilic aromatic substitution cascade reaction strategy,we quickly constructed the key tricyclic skeleton in one step.The first total synthesis of crotontomentosin D was completed in 8 steps with a total yield of 25%,which provided strong support for the subsequent biological activity screening.Part Ⅱ: Pyrrolo [2,1-a]isoquinoline molecules combine the two key skeletons of pyrrole and isoquinoline,and have a wide range of biological activities,such as antitumor activity,HIV-1 integrase inhibition,reversal of multidrug resistance.Sinopyrine B extracted from Sinomenium acutum is a typical pyrrolo [2,1-a]isoquinoline compound,but no related biological activity has been reported.In order to study the activity of sinopyrine B and explore the active relationship between natural products containing pyrrolo [2,1-a]isoquinoline skeleton,we successfully constructed the key pyrrole ring by using the copper-catalyzed tandem cyclization reaction of aminomalononitrile.The first total synthesis of sinopyrine B was completed in 10 steps with a total yield of 7 %.The preliminary activity test of sinopyrine B was performed using a high-throughput screening system.Part Ⅲ : Preliminary screening of bioactive molecules is the basic method and basic means in the process of new drug research and development.Through reasonable experimental design in the early stage and the establishment of appropriate experimental methods and screening models in the later stage,compounds with corresponding biological activities can be efficiently screened out,paving the way more efficiently for drug development from basic research in the laboratory to clinical practice.Pancreatic cancer is known as the king of cancer,with the characteristics of ’three high and four low ’.The efficacy of existing treatments has reached a bottleneck,and the 5-year survival rate is only 10 %.Pancreatic cancer is a complex multigenic disease,and KRAS mutation is the most common type.KRAS G12 D mutation accounts for 40% of all KRAS mutations.If small molecule compounds targeting KRAS G12 D can be found,it is of great significance for the prevention and treatment of pancreatic cancer through appropriate structural modification.Toward the screening of bioactive molecules for pancreatic cancer,we established a high-throughput screening system for KRAS G12 D mutant small molecule compound inhibitors,and made some progress.Through the subsequent improvement and optimization of the screening model,it is expected to use this method to screen out more new drug lead compounds.