Design,Synthesis And Anti-inflammatory Activity Of Costunolide Derivatives

Ulcerative colitis(UC)is a chronic,refractory disease with a large number of patients and lack of specific drugs.Traditional Chinese medicine Saussurea costus C.B.Clarke and its formulations are widely used in the treatment of gastrointestinal diseases.This research found that costunolide(Cos),the main ingredients of Saussurea costus,has good anti-UC activity:Pharmacodynamic experiments show that Cos can significantly inhibit Dextran sulphate sodium(DSS)induced mouse colitis,reduce myeloperoxidase(MPO)activity,improve colon tissue pathological damage,and decreased the levels of proinflammatory cytokines in colons of colitis mice when administered intragastrically at 25 mg/kg.Although Cos has a significant role in the treatment of UC,it has problems such as poor water solubility,poor stability,and low oral bioavailability.By analyzing the structure of Cos,it is found that the double bond in the ring is the main reason for its poor stability.At the same time,the use of prodrug strategy can significantly improve the water solubility of the compound.Based on the above analysis,on the one hand,it is designed to introduce an electron withdrawing group at the allylic position of the double bond in the ring to reduce the electronegativity of the double bond,and the two double bonds are respectively reduced,epoxidized,and difluorocyclopropanation to improve the stability of the compound.On the other hand,it is designed to introduce a dimethylamino group at the C13 position to make aprodrug and it is expected to improve its water solubility and bioavailability.Based on the above structural modification strategy,a total of 25 compounds in 6 categories were designed and synthesized.By testing their inhibitory effects on lipopolysaccharide(LPS)stimulated B cells,a highly active compound 1r(IC50=0.11 μM)was finally obtained.Compared with Cos(IC50=1.77 μM),the activity of 1 r increased by 16 times.The most active compound 1r was further evaluated on physical and chemical properties.The results showed that the chemical stability of 1r was greatly improved compared with Cos(in the artificial gastrointestinal fluid,the compound degradation ratio was<3%within 8 hours).After modification of compound 1r into a prodrug 1y,the water solubility increased by 150 times(the solubility of 1r is 56.50 μg/mL,and the solubility of 1y is 8.58 mg/mL).In mouse plasma,1y can release 70%of the original drug 1r within 2 h.The above results fully prove that the stability of the product 1r,which is modified by the structure of the double bond in the ring,is improved.The physicochemical properties of the prodrug 1y is greatly improved.In the future,the mechanism of action of compound 1r will be confirmed,and the metabolic stability,in vivo pharmacokinetics and in vivo pharmacodynamics will be evaluated.It is hoped that an anti-UC drug candidates with novel mechanisms of action will be developed.