The Abietane Diterpenoids From Salvia Prattii And Their Antiplatelet Aggregation Activity

This dissertation mainly discussed the abietane diterpenoids from Salvia prattii and their antiplatelet activity,including four chapters.Chapter 1 presente the phytochemistry studies on the abietane diterpenoids of S.prattii.Chapter 2 is the antiplatelet and vasodilative activity of abietane diterpenoids.Chapter 3 is the synthetic study of abietane type platelet aggregation inhibitors.Chapter 4 is summary and future prospect.(1)S.prattii,belonging to the Labiatae family,is widely utilized in traditional Tibetan medicines as an alternative of“Danshen”(S.miltiorrhiza).Totally 74 abietane diterpenoids,including 42 new ones(2 new skeletons involving 4 compounds),were isolated from the roots of this plant.The classes of these compounds include tanshenones,seco-abietane,homo-abietane,nor-abietane,and icetexane diterpenoids.Their structures were determined by analyses of comprehensive NMR and MS spectroscopic data and single-crystal X-ray diffractions.It's noteworthy that salpratlactones A-B(51-52)are the first pair of cis-trans tautomeric abietane derivatives,characterized with an unprecedented 6/5 fused carbocyclic rings linked to a?-lactone ring by an exocyclic double bond.Significantly,the tautomers also stand for the first naturally occurring agonists of TTCCs.At the concentration of 10?M,51,52 and their mixture all obviously enhanced the peak currents of Ca_v3.1 TTCC by the same level(around 30%).Further studies revealed that 51 activated Ca_v3.1 TTCC in a dose-related manner(1?M to 100?M),with the EC₅₀ value of 12.48?M.In addition,salprattins K-L(35-36)are the first examples of1,10;4,5-bis-seco-abietane diterpenoids feature with a 6/6/6/6/3 ring system.While salpratlactones N-U(53-60)represent the first examples of4,5;11,12-bis-seco-abietane diterpenoids from the family Salvia.(2)In order to explore the potential cardiovascular activity of diterpenoids from this traditional medicinal plant,the antiplatelet aggregation,vasodilative,and hypolipidemic activity of abietane diterpenoids were tested.The antiplatelet aggregation activity of 100 abietane diterpenoids were evaluated,14 compounds possessed significant antiplatelet aggregation activity induced by arachidonic acid(AA).The arachidonic acid metabolic pathway is an important link in the process of antiplatelet aggregation,and it's regarded as an important antithrombosis target for the development of antiplatelet drugs.Significantly,Compounds 17,18 and 91 showed the most excellent antiplatelet aggregation activity,with IC₅₀ values 1.03,1.06,and2.05?g/ml,respectively,which were approximately 20-fold better than the positive control aspirin(IC₅₀ 27.69?g/ml).Compoured with aspirin,abietane diterpenoids have unique structures,which are potential to become novel antiplatelet lead compounds.(3)In order to elucidate the mechanism of antiplatelet and structure-activity relationship of active molecule,the synthetic and structural modification studies of1-keto-aethiopinone(91),one of the most potent platelet aggregation inhibitor,were carried out.Target molecule was abotined from benzocyclohexanone 3-19 through key reactions such as Friedel-Crafts alkylation,Wacker oxidation and alkylation reaction in a total yield of 2.8%in 9 steps.(4)The diversity and potential biological activity of abietane diterpenoids form S.prattii were summaried and prospected.