Design,Synthesis And Immunosuppression Activity Evaluation Of Pseudolaric Acid B Derivatives

Objective Immunosuppressants is a kind of drug that can inhibit the abnormal immune response,and is mainly used for the treatment of autoimmune diseases and the rejection during organ transplantation in clinical.But the traditional immunosuppressants have the disadvantages,such as weak immunosuppressive activity,strong side effects,high price,so the development of new immunosuppressants with high efficiency and low toxicity,high selectivity,treatment window width,is still an arduous task placed for the medical workers.Cortex Pseudolaricis came from the dried root bark or the root bark of Pinaceae plant（Pseudolarix kaempferi）,which were used for the treatment of tinea disease in the early.The study shows that Pseudolaric acid B（PAB）which is the main active ingredient that have some immunosuppressive activity.Because of its greater cytotoxicity of Pseudolaric acid B,this paper takes PAB as the lead compound to obtain immunosuppressive derivatives with high efficiency,low toxicity,good solubility,easy absorption for oral administration.Methods 1.Pseudolaric acid B were transformed into intermediates Pseudolaric chloride by chloride method,and reducted it into pseudolaric acetaldehyde by using the tri-butoxy lithium aluminum hydride.Finally,pseudolaric acetaldehyde reacted with the corresponding primary amine through the"one-pot"reaction to reduce imines.2.Pseudolaric acid B reacted with methanol sodium to obtain deacetyl Pseudolaric acid B by ester exchange.Then the target compounds were synthesized by C-18 carboxyl reacting with small molecule amine.3Pseudolaric acid ester derivatives were synthesized by the reaction of small molecule heterocyclic alcohols with Pseudolaric acid.4 MTT method was used to test the proliferation inhibition activity on T,B cells and the toxicity on normal cells respectively.Results 31 Pseudolaric acid derivatives were designed and synthetized,including three series:（A）C-18 methylene Pseudolaric acid derivatives,14compounds;（B）amide derivatives of C-4 deacetyl Pseudolaric acid,5 compounds;（C）ester derivatives of C-18 Pseudolaric acid B,13 compounds.All the compounds were confirmed by ¹H-NMR,¹³C-NMR and HR-ESI-MS,and 28 compounds were not reported in the literature.Conclusion According to the pharmacological activity results,18-methylene aliphatic pseudolaric acid have better immunosuppressive activity,among them,A-1,A-13 and A-14 is particularly obvious.The activities of amide derivatives of deacetyl pseudolaric acid were reduced or lost,suggesting that 4-acetyl group is necessary for the activities.Ester derivatives of Pseudolaric acid with heterocyclic have certain activity,especially for the substituents with the indole ring.