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

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.

Graphical abstractThe synthesis and biological evaluation of JAK3 based staurosporine compounds is described. The compounds are constructed using a ring closing metathesis strategy to assemble the sugar mimetic portion (I). These analogs show potent JAK3 inhibitory activity against isolated enzyme and in IL-2 stimulated 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 degranulation, and reduction of JAK3 effects in mouse models of allergic disease.Figure optionsDownload full-size imageDownload as PowerPoint slide