| 查看: 358 | 回复: 1 | |||
yaoguiyang木虫 (小有名气)
|
[求助]
求助构效关系的翻译
|
|
Traditionally, the immunosuppressive potential of cyclosporin derivatives was tested in isolated T-cell assays. In this context, the immunosuppressive activity of cyclosporins largely correlates with the ability of cyclophilin A−cyclosporin complexes to inhibit the activity of calcineurin. However, as described above, cyclophilins appear to be involved in other immune response processes such as innate immunity and inflammation. In order to explore the potential of cyclophilin inhibitors to act as inhibitors of leukocyte trafficking by inhibiting extracellular cyclophilins, a series of impermeable cyclosporins were prepared.83 The benzimidazole derivative 15 (Figure 9) was determined to have a similar affinity to cyclophilin A as 1 in an in vitro proline isomerase binding assay. A cellular cyclophilin binding assay developed using a fluorescently labeled cyclophilin derivative revealed that 15 is at least 50-fold less permeable than 1. As expected, despite its significant restriction to the extracellular space, 15 inhibits leukocyte migration toward cyclophilin A. This inhibitor also reduces leukocyte activation in a mouse model of allergic contact hypersensitivity. Although detailed data are not available, in a patent filing Scynexis explored the potential for alkylation at P5 to influence the immunosuppressive activity and antiviral potency of 1.119 Earlier, chemists at Sandoz had demonstrated that alkylation of the free NH at this position can influence the conformation and immunsuppressive activity of cyclosporin derivatives.120 Compound 16 (Figure 10) was prepared via alkylation of [(D)- MeAla]3-CsA with dimethylallyl bromide. This analogue was reported to bind to cyclophilins A and D with good (<60 nM) potency and to have an EC50 in the replicon assay of less than 200 nM. Furthermore, in a standard stimulated T-cell assay, 12 was found to be at least a 40-fold less potent inhibitor of IL-2 release than 1. |
回复此楼» 猜你喜欢
职称评审没过，求安慰
已经有41人回复
-
回收溶剂求助
已经有7人回复
-
硝基苯如何除去
已经有3人回复
-
A期刊撤稿
已经有4人回复
-
垃圾破二本职称评审标准
已经有17人回复
-
投稿Elsevier的Neoplasia杂志，到最后选publishing options时页面空白，不能完成投稿
已经有22人回复
-
EST投稿状态问题
已经有7人回复
-
毕业后当辅导员了，天天各种学生超烦
已经有4人回复
-
求助文献
已经有3人回复
-
三无产品还有机会吗
已经有6人回复
yaoguiyang
木虫 (小有名气)
 |
2楼2014-11-30 11:06:32