Design,synthesis And Bioactivity Study Of Lycorine And Tanshinone Derivatives

Natural products with unique chemical structure and broad biological activities are treasury of drug discovery.Lycorine and tanshinone are two natural products with small molecular weight but novel skeletons.Both of them,with diverse bioactivities and certain medicinal properties,are rich in relevant plants and easy to be obtained.Among them,lycorine has a unique structure with a five-ring structure containing four consecutive chiral carbons,however,which brings the problem of poor solubility.Lycorine exhibits an extensive range of biological activities,including anti-tumor,anti-bacterial and anti-inflammatory.Because of the high toxicity of lycorine,it's hard to develop its use in other ways as a lead compound.Compared with lycorine,the advantages and disadvantages of tanshinone is more distinct.Tanshinone was extracted from traditional Chinese medicine named salvia miltiorrhiza,which can promote blood circulation,relieve uneasiness of mind and body tranquilization and has been widely used in the treatment of cardiovascular diseases such as atherosclerosis.Especially,tanshinone IIA-sulfonic sodium injection has already been approved in China for the treatment of cardiovascular disease such as coronary heart disease,angina and myocardial infarction.In recent years,there have been lots of reseaches on tanshinone,but its poor water solubility,low activity as anti-cancer drug,instability in liver microsomes,low bioavailability and unclear mechanism remain great challenges for researchers.As discussed above,this thesis is aimed to explore interaction of natural product with the relevant targets and to solve the problems of solubility and explore the mechanism of action by diversity derivatization.On the one hand,in order to further study the anti-inflammatory activity of lycorine,we tried to reduce the toxicity of lycorine derivatives through rational structure optimization.On the other hand,we developed molecularly targeted anti-inflammatory lycorine derivatives with unusual fragments,of which inhibitory activity against the hot target NLRP3 were improved.As for tanshinone,based on our previous research about anti-tumor activity of tanshinone derivatives,we focused on the problems of low bioavailability and unstable metabolism.We designed and synthesized more than one series of novel compounds according to the special structure of tanshinone.Then we further explored the relationship between tanshinone derivatives and IDO1.Therefore,the research work of this thesis is divided into two parts:Part I:Construction of lycorine derivative compound library and study of cytotoxicity and inhibitory activity against NLRP3To get novel compounds with good bioactivities,we proposed to construct lycorine library on the basis of the ring-opening modification strategy.During the ring opening reaction,we found that the C-ring-opening product can be obtained following the E-ring-opening product.This is a safer and more effective reaction method we found than that reported in literatures using cyanide bromide.We also explored how to obtain the different ring-opening products by changing the reaction conditions.Moreover,the derivatives 1-20a containing ethyl chloride and 3-5 containing benzyl chloride had been obtained though the above reaction.First,we synthesized a series of triazole derivatives by azidation reaction and Click reaction.However,from the result of anti-tumor activity test,we found that all the ring-opening compounds had poor anti-proliferation effect against KB cells with IC₅₀ values more than 20?M.Therefore,we introduced the active fragment of CY-09,a selective NLRP3 inflammasome inhibitor,into the ring-opening structure of lycorine with lower toxicity.It turned out that compounds 3-24 and 3-25 had potent inhibitory activity of NLRP3 inflammasome.Interestingly,compound 3-25 showed better inhibitory activity than positive compound CY-09,which provided us with a new idea of research on NLRP3 inflammasome inhibitors.Part II:Design,synthesis and antitumor activity of tanshinone derivativesAiming at the problem of poor metabolic stability of tanshinone skeleton,we explored the carbonyl difluorination method and modified the warning structure of o-quinone.We designed and synthesized three series of compounds:the difluorinated derivatives of tanshinone I skeleton,the difluorinated derivatives of tanshinone IIA skeleton and the difluorinated derivatives of tanshinone azacyclic skeleton.In the synthesis of these compounds,we have further explored and optimized the fluorination conditions,and successfully constructed a difluorinated derivatives library based on tanshinone skeleton.The results of anti-tumor activity of the above-mentioned difluorinated derivatives showed that the difluorinated modification of tanshinone I and tanshinone IIA skeleton decreased cytotoxicity,while the difluorinated modification of tanshinone azacyclic skeleton remained activity with IC₅₀ values less than 5?M.The difluorinated derivatives of compound 4-52,which we expect to modify,achieved the effect of maintaining activity,but unfortunately,without improvement of metabolic stability.It has been reported that tanshinone has a certain inhibitory activity against IDO1,we screened the IDO1 activity of our compounds from tanshinone difluoride derivative library and the previous tanshinone IIA derivative library.The results proved the key role of o-quinone structure in the activity against IDO1 and we got the lead compound4-53 from the tanshinone IIA derivative library.We modified a series of compounds with Michael receptor from the lead compound 4-53 to get several tanshinone derivatives.Among them,compounds 4-56 and 4-57 got potent activities with IC₅₀ranging from 0.3 to 0.8?M.