The Synthesis Of Droandrographolide Derivatives And Their Biological Activities

Andrographolide, molecular formula C20H30O5, is a kind of diterpene lactones extracted from Acanthaceae Andrographis, and shows many activites such as anti-inflammatory, anti-viral, anti-tumor effect, immune regulation, liver-protective and choleretic for the treatment of cardiovascular and cerebrovascular diseases,anti-diabetic, antifertility and so on.Organic phosphorus compounds are extremely important substances in life process and they largely exist in nature and living organism. Many endogenous active substances in living organisms contained phosphate structure unit, such as, adenosine triphosphate(ATP) involved in the energy conversion, various functional enzymes involved in metabolism in vivo, nucleic acid participated in the genetic expression and so on. Therefore, phosphate ester structure unit can be found in almost every life process. Long time ago, organ ophosphorus compounds were important antitumor drugs and widely used in clinical medicine, such as cyclophosphamide, chlorine phosphoramide and a double dimethyl phosphate amide ethyl ester were used as broad-spectrum anti-tumor drugs. According to the activity of many anti-cancer drugs may increase after the introduction of organic phosphorus, phosphate ester structure was introduced in the 3- bit and 19- bit of andrographolide to enhance its antitumor activity. In addition, the introduction of phosphate increased the solubility of andrographolide, and prolonged the reserved time in vivo. In fact, many chemotherapy effects of organophosphorus compounds are due to the organic phosphorus participated in the metabolism.Recent reports indicated that vast andrographolide derivatives have good bi ological activity because of the lactone ring five membered structure and diol st ructure. In this paper, andrographolide was used as the lead compound, a serie s of the andrographolide derivatives were designed and synthesized through tw o kinds of structure modification. A total of 16 compounds, eight of them wer e new compounds.Firstly, modificating mother ring structure of andrographolide.Secondly, phosphate ester structure was introduced in the 3- bit and 19- bit ofandrographolide. Structure modification can improve liposolubility and selectivi ty of drugs, reduce side effects and enhance biological activity. In addition, the structure of andrographolide derivatives were confirmed by IR, MS, 1H-NMR,and their antiinflammatory, antipyretic, antibacterial, immunity and anti-tumor a ctivity were studied, and the structure-activity relationship was also preliminarily analyzed in this paper. From the preliminary pharmacological studies, We can conclude that the anti-inflammatory and the antibacterial effect are dependent of the five number lactam ring. It has an effect on antipyretic. It has nothing to do with the immune function. 8-bit methylene is the antibacterial activity of related groups. 14-OH is the bacteriostatic activity of the existence of enhanc ement effect. 3,12-bit-introduction of sulfonicacid,phosphate greatlyenhance the understanding of anti-inflammatory, antipyretic, antibacterial, immunity and anti-tu mor activity.