Synthesis Of Andrographolide Derivatives And Study Of Their Anti-tumor Activity

Cancer is major disease which threats health and life.Every year about 1.25 million people occurr tumor in our country,.Approximately 0.9 million persons died of tumor, so the study of antineoplastic drug is the top priority in which the pharmaceutical sciences workers will study.As one of the three means of cancer treatment,chemotherapy treatment in a variety of tumor play a very important role.A recent study found that the microenvironment of inflammation has a positive impacts on producing and developing of tumor,at the same time,Many member signal paths and targets that inducing inflammation play an important role in producing of tumor.The relevance of inflammation and tumor prompts that we should have studied painstakingly new antineoplastic drugs which are specific for the target of inflammation member.Traditional Chinese Medicines contains many preparations and monomers which having strong anti-inflammatory activity.Andrographolide is one of them.Andrographis panniculata(Burm.f.)Nees was found in India and planted in east,middlesouth and southwest China.Test is bitter,nature is cold,returning heart,lung,large intestine,bladder.Possessing the effect of clearing away heat and toxic material and cooling blood detumescence Recently,pharmacologicalactivities study proclaims,excepting it is used extensively to anti-inflammatory therapy,it's newly pha-rmacological activities is rich,such as antibacterial,antivirus effect,antitumor effect, inhibitory effect on plateletag gregation,antihypotensive effect,antifertility activity, hepatoprotective activity,antihyperglycemic effect,immune activity,hepatic protectant cholagogic activity.Its anti-tumor activity has aroused widespread concern in scientific research personnel.。In view of these facts,In this paper,sixteen andrographolide deri vatives were synthesized from andrographolide.Nine of them are new,seven of them have been already reported.The new compounds are 3-keto-14-deoxyandrographolide(Ⅰ-5),3-keto-19-formyl-14-deoxyandrographolide(Ⅰ-10),3-keto-19-formyl-dehydroandrogra -pholide(Ⅰ-12),8-methyl-8,9-didehydrodehydroandrographolide(Ⅰ-17),8-methyl-7,8-didehydro-3-keto-19-formyl-14-deoxyandrographolide(Ⅰ-18),2,3-dehydro-8-methyl -8,9-didehydro-19-formyldehydroandrographolide(Ⅰ-19),potassium salt of 14-deoxy -andrographolide acid(Ⅱ-2),potassium salt of dehydroandrographolide acid(Ⅱ-3); The others arel4-deoxyandrographolide(Ⅰ-1),dehydroandrographolide(Ⅰ-2),isoandrographolide(Ⅰ-3),potassium salt of andrographo-lidic acid(Ⅱ-1),andrographolide acid(Ⅱ-5),triacetyl andrographolide(Ⅳ),diacetyl-14-deoxyand -rographolide(Ⅳ-1).We used MTT method conducted a study of anti-tumor activity of the above compounds,The results show that nucleus compound were synthesized from the andrographolide 14-deoxyandrographolide,dehydroandrographolide,isoandrographolide have varying degrees of anti-tumor activity on the tumor cells. Among of the derivatives synthesized from the andrographolide,hydroxy ester derivatives triacetyl andrographolide is the best on anti-tumor,its open loop acid and its acid potassium salt and sodium bisulfite adduct of the double bonds are lower than andrographolide itself.on the anti-tumor effect.We got hydroxy esterification,oxidation derivatives from dehydroandrographolide inhibit growth of tumor cells are superior to their raw materials dehydroandrographolide.Among of the hydroxy ester-modified derivatives,diacetyldehydroandrographolide is the best on anti-tumor;Among its hydroxy oxidized derivatives,the 3-keto-19-formyl -dehydroandrographolide is the best on anti-tumor,it's dual-hydroxy-oxide derivatives of dehydroandrographolide,intensity of its anti-tumor activity after diacetyldehydroandrographolide,the result shows that increasing carbonyl ketone and aldehyde carbonyl in the mother nucleus will be beneficial to improve anti-tumor activity of the nucleus compounds.Among of we received hydroxy esterification derivatives from isoandrographolide,second acid monoester isoandrographolide and diacetyl isoandrographolide on tumor cell growth inhibition rate are better than isoandrographolide,but 3,19-disuccinate monoester isoandrographolide tumor cell growth inhibition is lower than isoandrographolide,this may be related to longer acyl branched-chain.We got hydroxy esterification and oxide derivatives from 14-deoxyandrographolide are less than 14-deoxy andrographolide on anti-tumor effects.We got open loop acid and its acid potassium salt respectively from andrographolide,14-deoxyandrographolide,dehydroandrographolide and andrographo -lide sodium bisulfite adduct of the double bonds are poor on the anti-tumor effect,on the one hand,may be related to the more polarity and difficult through the membrane, but also show that the 5 yuan lactone ring is necessary group.for the anti-tumor activity...