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The Development of New Drugs Possessing New Concept to Treat in Rheumatoid Arthritis Disease

治疗类风湿性关节炎疾病新概念新药的开发

基本信息

批准号：
05558082
负责人：
TAKAISHI Yoshihisa
金额：
$ 11.2万
依托单位：
University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1995
项目状态：
已结题

项目摘要

Tripterygium wilfordii Hook (Celastraceae) has been used as anticancer drug and an insecticide by the Chinese for hundreds of years. Recently, this plant has been used to treat rheumatoid arthritis and spondy litis in some Chinese clinics. We started the study of isolation of the active priciples from T.wilfordii Hook fil var. regelii. For the in vitro assay system, we used the inhibition effects of interleukin-1 (IL-1) release.In rheumatoid arthritis, it is reported that there is a strong relationship between production of IL-1 by the synovium and degree of inflammation of the arthricular synovial membrane.It is therefore considered that the inhibition of excessive IL-1 release from cell could block various physiological activities. Bioassay-guided exploration led to the isolation of several structurally novel diterpenoid quinones. These quinones (we named triptoquionones A-G) proved to markedly inhibit the release of IL-1alpha and -1beta from lipopolysaccharide stimulated human peripheral mononuclear cells. The structures of these compound were elucidated on the basis of spectroscopic and chemical evidence.The most promising of these diterpenoids, from the standpoint of potential utility for treatment of rheumatoid arthritis, is triptoquinone A,which has progressed to further biological tests in vitro. So, we attempted the total synthesis of thriptoquinone A (TQA) and succeed an efficient first total synthesis.A significant inhibitory activity of TQA for adjuvant-induced arthritis was confirmed in rat. TQA did not show serious poisoning. TQA inhibited NOs induction primed by LPS.We isolated seven new triterpenoids from T.wilfordii, some of which showed the inhibition of IL-1 release. We attempted the preparation of callus and hairly root from T.wilfordii, and studied the constituents of callus.

雷公藤（雷藤科）被中国人用作抗癌药物和杀虫剂已有数百年的历史。最近，这种植物在一些中国诊所被用来治疗类风湿关节炎和脊柱炎。我们开始了从黄芪中分离活性成分的研究。对于体外检测系统，我们使用了白细胞介素-1 （IL-1）释放的抑制作用。在类风湿性关节炎中，据报道滑膜分泌IL-1与关节滑膜的炎症程度有很强的关系。因此认为抑制细胞过量的IL-1释放可以阻断多种生理活动。生物检测引导下的探索分离出了几种结构新颖的二萜类醌。这些醌类（我们命名为雷公醌A-G）被证明能显著抑制脂多糖刺激的人外周血单核细胞il -1 α和-1 β的释放。根据光谱和化学证据对这些化合物的结构进行了分析。从治疗类风湿性关节炎的潜在效用的角度来看，这些二萜中最有希望的是雷丙醌A，它已经进展到进一步的体外生物学试验。为此，我们尝试了四苯醌A （TQA）的全合成，并成功进行了高效的首次全合成。TQA对大鼠佐剂性关节炎有明显的抑制作用。TQA未显示严重中毒。TQA对LPS诱导的NOs有抑制作用。从雷公藤中分离到7个新的三萜类化合物，其中部分化合物具有抑制IL-1释放的作用。本研究尝试了从雷公藤中制备愈伤组织和毛状根，并对愈伤组织的成分进行了研究。