| Base on the discovery of lead compounds which have therapeutic value from the traditional Chinese herb, then modify them to enhance its curative effect is an important way to gain candidate drugs which have China's own intellectual property rights.Arthritis is a common disease, and rheumatoid arthritis is the most common and difficult to cure. The ratio of disability is quite high. Traditional drugs which are used to treatment rheumatoid arthritis are most of NSAIDs and COX-2 selective inhibitors. However, the serious gastrointestinal (GI) adverse reactions and the side effects of ardiovascular which are discovered limit their further application. In recent years, the advent of NO-NSAIDs to anti-inflammatory drugs brought significant progress. Such drugs can both inhibit COX to anti-inflammatory or analgesic and protect blood vessel by GI with NO-induced. So far, there are several NO-NSAIDs come into different stages of clinical research and the research of this area is becoming hotter.NO is a small molecule that found from endothelial vascular, it is synthesized by L-arg with NOS-induced. The structure of NO is simple but extremely unstable, easy to proliferation, easy to react and the biological half-life is only about 5s.The biosynthesis of NO in vivo is like this: by the catalytic of NOS the L-arg is oxidized and brings Citrulline, at the same time release NO. The research shows that there are relationships between acute or chronic inflammation and NO. The source of NO is not clear by now, may be from blood vessels, neutrophil or macrophage. The anti-inflammatory of NO is mainly in the following aspects: First, There is lot of NO in the host with inflammatory response and they can prevent the entrance of cells, viruses and parasites. Second, to inhibit inflammation, the NO maintain the integrity of BVE by adjusting the relationships between platelet - intramural vascular and inhibit the aggregation or depolymerization of platelet. Third, it can inhibit the proliferation of lymphocyte and at the same time stimulation many immune responses or immune pathological process including of rheumatoid arthritis.Siegesbeckiae orentalis(Compositae)is a herbaceous plant that can be used to treat rheumatism, inflammatory and other disease. Kirenol is a main active component of siegesbeckia orentalis, and it can be used to anti-rheumatism, anti-inflammatory and enhance immunity. It is a lead compound of anti-rheumatism which is used as a traditional Chinese herb.But the research of kirenol is most about its mechanism of anti-inflammatory, rarely about the modification of it.So, we modified it with the aim of gaining the compounds that has better liposolubility and better bioavailability than kirenol, and the inhibitory activity on nitric oxide (NO) production in LPS-activated macrophage were tested.First, we can see that the content of kirenol in different origin of Herba Siegesbeckiae is different from the articles before. Therefore, we test the content of kirenol by HPLC and selected the best one. By comparison, we selected 5kg Herba Siegesbeckiae from Longkou in Shandong province, and then isolated 4.208 kirenol. Then, we modified them. We design a series of acetal and ketal reaction on kirenol, because many drugs contain acetal or ketal groups which can significantly improve drug activity. By these, we got 23 compounds: Dimethyl-21-ethenetylene-kirenol, cyclohexyl-21- ethenetylene- kirenol,β-ethyl-α-methyl-21- ethenetylene- kirenol,α-ethyl-β-methyl-21- ethenetylene- kirenol,β-isopropyl-α-methyl-21- ethenetylene- kirenol,α-isopropyl-β-methyl-21- ethenetylene- kirenol,β-isobutyl-α-methyl-21- ethenetylene- kirenol,α-isobutyl-β-methyl-21- ethenetylene- kirenol, diphenyl-21- ethenetylene- kirenol,β- ( 3 , 4-dimethoxy ) benzyl-21- ethenetylene- kirenol,α-(3,4-dimethoxy)benzyl-21- ethenetylene- kirenol,β-p-hydroxy-benzyl -21- ethenetylene- kirenol,α- p-hydroxy -benzyl -21- ethenetylene- kirenol,β-(2-hydroxy)benzyl-21- ethenetylene- kirenol,α-(2-hydroxy)benzyl-21- ethenetylene- kirenol,β-(3-methoxy-4-hydroxy)benzyl -21- ethenetylene- kirenol,α-(3-methoxy-4-hydroxy)benzyl -21- ethenetylene- kirenol, 2,15,16,19- quadracetyl- kirenol,2,16,19- triacetyl- kirenol, 16 , 19- diacetyl- kirenol, 2,15,16-trimethoxy- kirenol, 15,16 ,19-trimethoxy- kirenol, 15,16-dimethoxy- kirenol, and 19 of them were first synthesized. There are several enantiomers. To establish the exact structure of them, two-dimensional NMR experiments including COSY, HSQC, and HMQC were carried out. Finally, their inhibitory activity on NO production in LPS-activated mouse macrophage was tested with the aim of gain lead compounds that more active than kirenol.The result shows that the activity of kirenol derivatives is nothing about molecular weight but the number of hydroxyl which is modified and the position of groups. The more the number of hydroxyl modified, the better the activity of the derivatives. When the position of groups on enantiomers is different, the activity of them is also different.In a word, modern pharmaceutical industry has become a major industry of the 21st century in China. So, the study of innovative drugs is of great social and economic benefit. We modified the kirenol and tested the inhibitory activity on nitric oxide (NO) production in LPS-activated macrophage. We have gotten some delectable result and established a good basis for further research of kirenol.
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