| For a long time,natural products have been the important source of innovative drug development because of its novel skeleton type and unique pharmacological activity;In the long history,Chinese herbal medicine has also made important contributions to the prosperity of the Chinese nation.Deepening the development of medicinal plant resources will not only help the satisfaction of clinical needs,but also contribute to the promotion of Chinese traditional culture.However,in the practical application of natural products,there are also exist many shortcomings,such as unclear mechanism of action,poor water solubility,weak activity,and difficulty in modification,which seriously restricts the use and development of these natural compounds.Therefore,this thesis attempts to reflect our thoughts and answers to these questions through three natural product-related topics.This thesis consists of three parts:(1)Study on the structure-activity relationship and mechanism of anti-tumor activity of Carpesium abrotanoides L.;(2)Development of cholic acid derivatives in the treatment of nonalcoholic steatohepatitis with multiple function;(3)Exploration of the preparation of ?-iodocarboxylates from epoxy compounds and their application in the modification of natural products;C.abrotanoides L.is a kind of common Chinese herbal medicine with a long history.It has a history of folk medicine for hundreds of years,and has multiple pharmacological activities such as swelling,pain relief,heat-clearing and detoxification.However,the anti-tumor activity relationship,specific targets and mechanisms of the active ingredients in this plant had not been reported yet.Therefore,in the second chapter of this thesis,this traditional Chinese medicine was selected as the research target,the chemical research and mechanism exploration of the anti-tumor active ingredients were also been carried out.First of all,extraction and separation had been carried out on this plant,and six kinds of natural products were obtained.PL-01 was selected as hit after preliminary pharmacological evaluation,and the inhibition activity of STAT3 pathway,HCT116 and HT-29 tumor were selected as indicators.And then,more than 140 derivatives,with different structure types,were obtained through structure modification and transformation,and structure-activity relationship was established.More than 70 compounds with enhanced in vitro activity were obtained,the activity of these compounds was enhanced by 2~8 times compared with PL-01.From overall view,most of the esters,benzenesulfonates,and carbamate derivatives have increased activity,while amides and ethers have decreased activity;we have also found that,the double bond in ?,?-unsaturated ketones was a good modification site,since both the anti-tumor activity and water solubility of amine prodrugs had been greatly improved at the same time.And then,the possible mechanisms of action and targets of these compounds were studied.By the solution of probes,protein mass spectrometry,virtual docking,etc.,it was first reported that these compounds could covalently bind to the non-ATP binding pocket site on the JAK2 protein,at Cys 452.It was also found that this compound could affect the three-dimensional structure of JAK2 protein as an allosteric inhibitor,which could also inhibit JAK2-STAT3 pathway and blocks G2/M phase.Finally,several compounds with good activity in vitro had been chosen to carried out further in vivo experiments.The results of the evaluation showed that these compounds can achieve a tumor inhibition rate of 42-50%,while the safety was good as well,which deserved further study.Recently,with the changes in people's eating habits and lifestyles,the incidence of nonalcoholic steatohepatitis(NASH)has increased,seriously threatening people's health.However,until now,the FDA has not approved any drugs for NASH treatment.Therefore,the development of new NASH therapeutic drugs not only has far-reaching clinical use value,but also has broad market prospects.Considering the development of NASH research field,in the third chapter of this thesis,we put forward the hypothesis that "the treatment of NASH requires both the symptoms and the root causes",and tried to find out the multi-functional cholic acid derivatives.This will lay the foundation for the research and development of new NASH therapeutic drugs.A variety of cholic acids,ursodeoxycholic acid included,had been used as substrates,and more than 230 compounds were obtained through structure modification and transformation.Many kinds of pharmacological activities evaluation were carried out on them.In the evaluation of lipid-lowering activity,we conducted a screening of Di I-LDL phagocytosis experiments and found that,the lipid-lowering activity of cholic acid derivatives could be effectively improved after structural transformation and modification.Nearly 60 compounds had potential lipid-lowering activity(with LDL-Uptake rates over 1.2),of which 28 derivatives had strong lipidlowering activity(with LDL-Uptake rates over 1.3);In the evaluation of antiinflammatory activity,some compounds were selected and the inhibition test of NO formation tests were carried out.28 compounds found to have stronger activity than indomethacin,while 5 compounds were even more active than dexamethasone,showing very good anti-inflammatory potential;In terms of energy metabolism,some compounds were selected and TGR5 agonistic activity had been tested,more than 20 derivatives,were better than the positive control drug INT-777.The EC50 of some compounds,CA-E11-8 included,could increased by more than 15 times,reaching a level below 10 n M;finally,the liver-protected activity of these compounds had been tested as well.On this basis,the structure-activity relationship of these cholic acid derivatives had been summarized in different pharmacological activities.Compounds with multiple activities,such as liver protection,anti-inflammatory and lipid-lowering activity,were found,which laid the foundation for the research and development of new NASH therapeutic drugs.Finally,considering that the carboxylic acid fragments and epoxy fragments are common or potential functional groups in the structure of natural products,and based on the fact that ?-halocarboxylates are an important class of organic synthetic building blocks.We have developed a new reaction under the Ph3P/I2 system,carboxylic acid was used as a carbon source,which could prepare stereo selective ?-iodocarboxylates through epoxy compounds.The reaction condition was mild,the yield was high,and the substrate had wide adaptability,and had been practiced and popularized on many complex natural product substrates such as Isosteviol and Vincamine.The discovery of the reaction not only improved the construction of the relevant system for the ring opening reaction of epoxy compounds,but also provided a new way for the further structural modification,development and application of some natural products. |
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