Synthetic staurosporines via a ring closing metathesis strategy as potent JAK3 inhibitors and modulators of allergic responses

被引：19

作者：

Wilson, Lawrence J. ^{[1
]}

Malaviya, Ravi ^{[3
]}

Yang, Cangming ^{[1
]}

Argentieri, Rochelle ^{[3
]}

Wang, Bingbing ^{[1
]}

Chen, Xin ^{[2
]}

Murray, William V. ^{[1
]}

Cavender, Druie ^{[3
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev LLC, High Throughput Chem Dept, Raritan, NJ 08869 USA

[2] Johnson & Johnson Pharmaceut Res & Dev LLC, Comp Aided Drug Design Dept, Raritan, NJ 08869 USA

[3] Johnson & Johnson Pharmaceut Res & Dev LLC, Inflammat Therapeut Dept, Raritan, NJ 08869 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 12期

关键词：

Staurosporine; Protein kinases; Natural products; Ring closing metathesis; Immune system; CRYSTAL-STRUCTURE; NATURAL-PRODUCTS; KINASE DOMAIN; ASTHMA; CELLS;

D O I：

10.1016/j.bmcl.2009.04.039

中图分类号：

R914 [药物化学];

学科分类号：

100705 [微生物与生化药学];

摘要：

The synthesis and biological evaluation of JAK3 based staurosporine compounds is described. The compounds are constructed completely de novo, and a ring closing metathesis strategy is used to assemble the sugar mimetic portion. These analogs show potent JAK3 activity against isolated enzyme and in T-cells. One analog (32) showed unique biological effects during in vitro and in vivo tests including inhibition of STAT5 phosphorylation, blockade of mast cell responses, and reduction of JAK3 based effects in mice models of allergic disease. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：3333 / 3338

页数：6

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