Synthesis Of Marine Natural Product HKS And Bromophenol And Their SAR Study As New Thrombin Inhibitor

Of the world's population aging in modern society, the morbidity and mortality of thrombosis disease appeared an increasing tendency. Anticoagulant drugs play an important role in the prevention and treatment of thrombosis disease by interfering with coagulation factor or thrombin. How to obtain an ideal anticoagulant with potential benefits including high efficacy, safety, low levels of bleeding, fixed dosing, rapid onset of action, wide therapeutic range and no requirement for therapeutic monitoring is becoming the highlight in the research of pharmaceutical chemistry.Marine natural products have various structurally unique and pharmacologically active metabolites, and have become foundation for new drugs exploitation. As a kind of new bromophenol compound, (+)-3-(2,3-dibromo-4,5-dihydroxyphenyl)-4-bromo-5,6-dihydroxy-l,3-dihydroisobenzofuran (HKS) has been isolated from Brown Alga Leathesia nana by our group and shown good anticoagulation activities. The dissertation focuses on the synthesis of this lead compound and the investigation on the new anticoagulant compounds. Meantime, we established some better ways of preparing bromophenol compounds which is beneficial to the constructing their compound libraries for the purpose of their bio-functions studies.1. From the starting materials vanillin, the first synthesis of racemic natural product HKS has been achieved (12.36% yields of ten steps).2. Research on the preparation of bromides for several arenes such as vanillin, isovanillin, vertraldethyde, veratric acid, bis(3,4-dimethoxyphenyl)methanone and bis(3,4-dimethoxyphenyl)methane was carried out. Synthetic route with good selectivity and high yield was obtained through the optimization of reaction.3. The coupling reaction of some veratrolelike-aryl bromides with bromoveratric acid was investigated. Mixed anhydride obtained by in situ reaction of aromatic acid and TFAA (trifluoroacetic anhydride) was used as acylating agent, and Friedel-Crafts acylation reaction was carried out by a one pot procedure. Thus, the use of acyl chloride and aluminium trichloride were eliminated. One pot reaction avoids tedious separation and purification process of the intermediates, which can save time and resources while increasing chemical yield.4. Other reactions or methods such as oxidation reaction, reduction reaction, free radical bromination reaction, protection and deprotection of phenolic hydroxyl group and the construction of dihydroisobenzofuran skeleton involved in the synthesis of target product HKS was investigated systematically.5. For better understanding structure-activity relationship,50 new polybromoarenes were designed and synthesized using bis(3,4-dimethoxyphenyl) methanone as basic scaffold. Among of them,36 compounds were screened for the anticoagulation activities in vitro and 5 compounds with preferable activity were obtained. The preliminary structure-activity relationships show that anticoagulation activity is closely related to bromo and phenolic hydroxyl group. Anticoagulation activity enhanced with the increasement of bromo group. Meanwhile, phenolic hydroxyl group is essential for the coagulation activity. The coagulation activity would reduce if the phenolic hydroxyl group was shielded. When carbonyl group between two aromatic rings was reduced to methylene or hydroxyl group, no change was observed about the anticoagulation activity.