Study On The Metabolism Of 'Liang Relationship' Compound Bornyl Caffeate In Vivo

With the aggravation of aging population and the increase in the number of people suffering Alzheimer disease(AD).Development of effective and innovative drugs treating AD has been a hot issue in the field of medicine.Molecular drug design adheres from the theory of traditional Chinese medicine and integrates modern multi-disciplinary,which has become an important way in today's new drug research and development.Also,drug metabolism plays a vital role in the preclinical safety assessment of new drug.With the guidance of the strategy of ‘Combination of Traditional Chinese Medicine and Molecular Chemistry',the core effective molecules of ‘Liang' relationship herb pair Salvia miltiorrhiza and Borneolum Syntheticum(SM-BS)was conbined by chemical reaction and ‘Liang' relationship compound bornyl caffeate with potential anti-AD was synthesized.Meanwhile,from the angle of pharmacokinetics,metabolic profile of bornyl caffeate in vivo was obtained by using HPLC-Q-TOF/MS,which providing the experiment data to support the druggability of bornyl caffeate reference and idea for the exploration of anti-AD new drugs.The paper is divided into four chapters;the main contribution was as follows:1.Caffeic acid and borneol,the core effective compound of ‘Liang' relationship herb pair SM-BS,was conbined by chemical reaction,‘Liang' relationship compound bornyl caffeate was synthesized based on the strategy of ‘Combination of Traditional Chinese Medicine Molecular Chemistry' The structural characterization and determination of purity of the target compound was conducted by analytical methods such as HPLC,IR,HPLC-Q-TOF/MS and NMR.The results indicated that the structure of the target compound was consistent with bornyl caffeate,the purity is 99.736%.The results accord with the requirement of the investigation of drug metabolism and lay foundation for the following research of metabolism in vivo.2.Thirteen metabolites in rat plasma,urine,feces after oral administration of bornyl caffeate were identified by HPLC-Q-TOF/MS and metabolic profile of bornyl caffeate was acquired.It involves the metabolic pathways of hydrolysis,methylation,sulfation and glucuronidation.3.Tissue distribution of bornyl caffeate in rats was performed by HPLC-Q-TOF/MS method above.The components absorbed in organs such as heart,brain,liver and kidney were recognized and twelve metabolites were identified.Among these,the metabolites in heart and brain included caffeic acid,m-coumaric acid,dihydrocaffeic acid,caffeic acid glucuronidation conjugation.The metabolic pathways contained hydrolysis,glucuronidation and methylation.Isopropyl caffeate was firstly discovered.The results showed that isopropylated metabolic form might be a characteristic metabolic pathway of ‘Liang' relationship compound bornyl caffeate.Fourteen metabolites in rat plasma,urine,feces,tissue after oral administration of bornyl caffeate were identified by HPLC-Q-TOF/MS and metabolic profile of bornyl caffeate was acquired.The study showed that caffeic acid and related metabolites were main forms of metabolites of bornyl caffeate in vivo.4.The synthesis and structural characterization of isopropyl caffeate was accomplished,the preparation process was optimized,t with purity of 99.9%.,the product was separated and characterized.