Synthesis And Evaluation Of Immunosuppressive Activity Relationships Of Pseudolaric Acids B Derivatives

Objective:Immune diseases mainly include autoimmune diseases and organ rejection,which are caused by the over-reaction of the body's immune system to the body,which caused a lot of pain for the patients.Therefore,The advent of immunosuppressor which are drugs that inhibit the proliferation and function of T lymphocytes and B lymphocytes,takes the gospel for the patients.However,there are some problems that the current immunosuppressive drugs exist such as poor activity,large toxic and side effects and narrow therapeutic window.Thus,it has been a difficult task to research and develop a more efficient and low-toxic new immunosuppressive drugs.Pseudolaric acid B is a new diterpene acid compound,which is extracted from pseudolarix.The basic structure of pseudolaric acid B is a special azulenesmoiety,which both has lactone ring structure and conjugated diene acid side chain.The special structure of pseudolaric acid B determines its special functions.It has been found that pseudolaric acid B has a strong antifungal,antifertility and antitumor activity.In the previous studies,our group discovered that Pseudolaric acid B shows a special immunosuppression for lymphocytes,and synthesized series of derivatives with better activities,particularly for alcohol esters and amide derivatives.On the basis of previous studies,we choose a more easier way to compound series alcohol esters and amide derivatives,expecting to obtain a series of compouds which is high efficiency,low toxicity and high selectivity.And we further study the conditions of selective reduction of a conjugated diene side chain of pseudolaric acid B to obtain a series of selective reduction derivatives with good immunosuppressive activity.Content:In this paper,three series of target compounds were synthesized from pseudolaric acid B under the guidance of the principle of drug combination and“Lipinski's rule of five”.Effects of target compounds on immunosuppressive activity and toxicity of T and B lymphocytes in mice through pharmacological experiments,and discuss structure-activity relationship,and then The partial Pseudolaric acid B derivatives three double bonds were hydrogenated and get the all reduction products.The last,The selective reduction conditions of diene side chains conjugated by Pseudolaric acid B were studied.And selective reduction or hydrogenation reduction derivatives,expecting selective reduction products.Methods:1.Pseudolaric acid B which is taken as the raw material was condensed with the condensation agent and then reacted with alcohol to obtain pseudolaric acetic ester derivatives.2.It takes pseudolaric acid B as raw material,and was directly reacted with amine compound through a condensing agent to obtain pseudolaric acid B amide derivatives.3.Three of the double bonds in the molecule of pseudolaric acid B derivatives were reduced.4.Using sorbic acid as the lead compound,the selective reduction conditions of selective conjugated dienes were explored and applied to the selective reduction of pseudolaric acid B.5.Inhibiting effect on the proliferation and toxicity of pseudolaric acid B derivatives were tested by MTT.Results:Three series of compounds of pseudolaric acids B were synthesized,including seven pseudolaric acetic ester derivatives and pseudolaric acid B amide derivatives.The structures of these compounds that none of the eighteen compounds are reported,were identified by analysis of 1H-NMR,HR-ESI-MS and ¹³C-NMR.The toxicity activity had no obviously correlation with the anti-proliferation activity.In vitro immunosuppressive activity screening showed that the target compounds which are A3,A4,B2,B6 and B9 showed good inhibitory activity against proliferation of T and B lymphocytes in mice,and low toxicity to normal cells.Six derivatives of pseudolaric acid B which were hydrogenated and reduced,and the structures of the target compounds were preliminary confirmed by 1H-NMR,ESI-MS.The selective reduction condition of the conjugated diene side chain of acetic acid was selected.In the ionic liquid,using Pd?acac?₂ to catalyze hydrogenation,which has the ability to selectively reduce the final double-bonds in the conjugated double bonds of sorbic acid?sorbic acid?can be selectively reduced and try to reduce the double-bonds in the13th and 14th positions of pseudolaric acids B.Conclusion:Three series and twenty-four pseudolaric acids B derivatives were synthesized and none of compounds are reported up to now.Among the ester derivatives of series A,A3 and A4 have better inhibitory activity against T and B lymphocyte proliferation and lower toxicity to normal cells,and A2,A5 and A7 also have a better inhibitory activity against T lymphatic cell proliferation than pseudolaric acids B's,and A5,A6 and A7 also have significant inhibitory effects on B lymphocyte proliferation.B series amide derivatives,among which B2,B6 and B9 are ideal derivatives with high efficiency,low toxicity and high selectivity.B1,B5 and B7derivatives also have a better inhibitory activity against T lymphatic cell proliferation than pseudolaric acids B's and B8,B9 also have significant inhibitory effects on B lymphocyte proliferation.For ester derivatives and amide derivatives containing F substitution,their immunosuppressive activities on T and B lymphocytes were significantly increased,and more side chain substitution containing F could be considered in the next experiment.Conjugated dienes side chains can be selectively reduced in ionic liquids using palladium acetone as catalyst.