| This thesis consists of four parts:(1)SARs study of active compounds-SP1601,SP2343,vincamine that protect beta-cell from STZ-induced apoptosis in MIN6 cells;(2)SARs study of active compounds-SP1178,SP2343 that protect nerve-cell from STZ-induced apoptosis in SH-SY5 Y cells;(3)study of FAP?-activated BF211prodrug;(4)palladium-catalyzed carbonylation methodology research.Diabetes is a metabolic disease which causes serious damage to the human life and health.More than 90% of the patients were diagnosed with type 2 diabetes.It was found that islet beta cell function obstacle is the core of type 2 diabetes onset and progression.The protection and restoration of pancreatic islet beta cell function could be the key for the treatment of type 2 diabetes,which provides a new direction to the development of diabetes drugs.During our course of work,the preliminary HTS results showed that compounds SP2343,SP1610 and vincamine exhibited good protective activities against STZ-induced apoptosis in pancreatic islet beta cells.Not only they had good activites in the cellular level,but also they could reduce blood glucose level and glycosylated hemoglobin level,improve oral glucose tolerance and the damaged condition of the islet beta cells on STZ/HFD diabetes mice.Based on their in vivo and vitro efficacy,relatively clear molecular mechanism of action,and simple structures,they were determined as hit compounds for further SARs studies.More than two hundred derivatives were designed,synthesized,and evaluated.From this study,we found SP2343 derivative C7 showed the best activity in vitro,and was effective at a low dose in vivo,but toxic at a high dose;and found vincamine derivative V9 was 50-fold more potent than vincamine.Alzheimer's disease(AD)is one of the most challenged threats to the public health all over the world.There is no effective drug for the treatment of AD at present,and marketed drugs can only relieve symptoms for AD patients.The development of effective drugs for AD therapy is difficult mainly because of its complex pathogenesis.Nerve fiber tangles and damaged nerve cells apoptosis is the primary cause of exacerbating the symptoms.So the protection and restoration of nerve cell function could be an important breakthrough for curing AD.During our course of work,the preliminary HTS results showed that compounds SP2343 and SP1178 exhibited goodprotective activities against STZ-induced apoptosis in nerve cells.Not only they had good activites in the cellular level,but also they could repair the damaged nerve cells,reduce A? production,and alleviate tau hyperphosphorylation on ICV-STZ induced AD rat,which improved the cognitive dysfunction.Meanwhile the molecular mechanism of SP2343 was studied in detail.Therefore,they were chosen as hit compounds for further research and development.According to the evaluation of the prepared SP2343 derivatives in vitro,the preliminary SARs was summarized,C50 and C52 were found to exhibit better activity nearly 80-fold than that of SP2343.Then the following fifty derivatives were synthesized and evaluated,but their activities were not improved further.Similarly,SP1178 derivatives did not exhibit better activities than that of SP1178,which was terminated for further research.During our course of work,bufalin,which is a major component of ChanSu,as an antitumor lead compound was structurally modified to provide a preclinical candidate compound with higher antitumor activity,lower toxicity and better druggability,named BF211.However,the toxicity test in dog indicated that BF211 still showed certain cardiac toxicity with the same mechanism as antitumor activity,thus it could not work by using the method of structural modifications to reduce toxicity.Current,enzyme-activated targeting antitumor prodrugs have already obtained remarkable positive results.Its core idea is to use specific targeting group to modify the toxic drug,in order to block the active group and form the prodrug with low activity.In vivo,prodrug could be delivered to the target site and hydrolyzed to release the parent drug in tumor tissue using the specific expression enzymes.Fibroblasts are mesenchymal cells mainly in tumor microenvironment,which are activated by tumor cells to become carcinoma associated fibroblasts(CAF).CAF could highly express FAP? that belong to serine proteinases.FAP? expressed in more than 90% of the carcinoma could regulate the growth of tumor cells,and promote the invasion and metastasis of tumor.Base on the FAP? enzyme-activated targeting antitumor prodrug strategy successfully applied to Doxorubicin,we designed and synthesized fourteen BF211 prodrug compounds.According to the results of enzyme incubation,tissue incubation and cell proliferation inhibition,prodrug 03 was found to be an ideal compound with high activity but low toxicity.It achieved antitumor effect similar to BF211 as well as reduced toxicity in colon cancer transplantation tumor rat model.The research work on this section laid the foundation for the more systematic study of FAP? activated-prodrug.Palladium-catalyzed carbonylation reaction is a popular method to prepare amide,ester,acids,aldehyde,and ketone.How to introduce the carbonyl is the most critical step in the process.CO gas is a powerful method for constructing carbonyl,but its high pressure and toxicity have seriously limited the widespread application.Therefore,we developed two new procedures for constructing carbonyl without using CO gas directly.The first one is a new palladium-catalyzed carbonylation procedure for the synthesis of alkynones form aryl iodides and terminal alkynes.In this procedure,CHCl3-CsOH?H2O have been applied as the formyl source.The second one is that with the help of I2-PPh3,arylaldehydes were synthesized from aryl iodides by using HCOOH as the formyl source.The advantages of these two methods are inexpensive and less toxic formyl sources,mild reaction condition,high yields,and easy workup procedure.In addition,the reaction is suitable for a broad scope,which has been successfully used in a variety of natural products. |
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