The Synthesis And Biological Research Of Andrographolide Devivatives

In this article, 16 andrographolide derivatives were synthesized from andrographolide and characterized by spectral analysis, 10 of them have been already reported, 6 of them are new. We also studied the anti-inflammtory effect, the immune activity, antitumor activity of them and the SAR of the andrographolide derivatives.There are 3 parts in this article, As follows:Part one: The chemical components of Andrographis panniculata (Burm.f.)Nees and pharmacological activities research of Andrographoli- de derivatives. Andrographis panniculata (Burm.f.) Nees was found in India and planted in east, middlesouth and southwest China. It is used extensively as an antipyretic, anti-inflammtory and antivirus medicine for a long time.Recently, it's newly pharmacological activities were found, such as immune activity, antitumor effect, hepatoprotective activity, inhibitory effect on platelet aggregation, antihypotensive effect, antifertility activity and antihyperglycemic effect. It's main component is diterpene lactams which is represented by andrographolide.Part two: The synthetic strategy and route of the andrographolide derivatives. 16 andrographolide derivatives were synthesized from andrographolide, The compounds are 14-deoxyandrographolide(2), dehydr- oandrographolide(4), isoandrographolide(59) andrographolidic acid(60), triacetyl andrographolide(32), trifloroacetyl andrographolide(61), androgra- pholide trimaleic acid monoes-ter(62), diacetyl dehydroandrographolide (63), dehydroandrographolide disuccinic acid monoester(35), dehydroandr- ographolide-3,19-cyclophosphate(64), adduct of andrographolide and NaHSO3(47), diacetyl-14-Deoxyandrogra- pholide(58), diacetyl isoandrogra-pholide (65), isoandrographolide disuccinic acid monoester(66), isoandrographolide dioxalochlolide monoester(67) and isoandrographolide dioxalic acid monoester(68).Part three: We also studied the anti-inflammtoryeffect, the immune activity, antitumor activity of them and the SAR of the andrographolide derivatives.The preliminary pharmacological studies indicated that the five-number lactam ring of the andrographolides is necessary for antitumor activities Andrographolide, dehydroandrographolide via condensation can boost up antitumor activities in different level. The number and site of the double bonds and hydroxy might be related to antitumor activities. Andrographolide with–F can improve tumor grow up, Just only isoandrograph-olide dioxalochlolide monoester with isoandrographolide as the basic structure is more improve than isoandrographolide in antitumor activitiesFrom the preliminary pharmacological studies, We can conclude that the anti-inflammatory effect are independent of the five-number lactam ring opened or not. Andrographolide, dehydroandrographolide, 14-deoxyandrographolide and isoandrographolide via condensation can decrese anti-inflammatory effect in different level. Anti-inflammatory activities of andrographolide derivatives have relations with the site of double bonds. The anti-inflammatory effect of andrographolide derivatives with encircle double bond are much stronger than that with outer circle double bond. THF rings of isoandrographolide can boost up the anti-inflammatory activity possibly.We study the effect of the andrographolide derivatives on T-cell indicated that the immune activity of andrographolide derivatives have relations with the five-number lactam ring of the andrographolides. The opened five-number lactam ring compound can strongly improve that drug inhibit the delayed type hypersensitivity effect. Dehydroandrographolide and via condensation cyclophasphate derivatives can also improve improve that drug inhibit the delayed type hypersensitivity effect. The immune effect of andrographolide derivatives have relation to the number and site of the double bonds. To improve number of the double bonds, the immune effect will be depression. The compounds with outer circle 12,13-double bonds are stronger in immune effect. Isoandrographolide without immunodepression activity has relation to the THF ring possibly.We study the effect of the andrographolide derivatives on peritoneal macrophages. The five-number lactam ring is not necessary for the immunodepression. Andrographolide, dehydroandrographolide and isoandrographolide via condensation can boost up the immunodepression in different level. The immunodepression of andrographolide derivatives have relation to the site of double bond, the immunodepression of andrographolide derivatives with outer circle double bond are much stronger than that with encircle double bond. To improve number of the double bonds, the immunodepression will be decline; Andrographolide derivatives with -F, -Cl and the THF rings, the immunodepression will be decline. Andrographolide derivatives with–SO3Na can strongly boost the immunodepression.