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

Lawrence J Wilson; Ravi Malaviya; Cangming Yang; Rochelle Argentieri; Bingbing Wang; Xin Chen; William V Murray; Druie Cavender

doi:10.1016/j.bmcl.2009.04.039

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

Bioorg Med Chem Lett. 2009 Jun 15;19(12):3333-8. doi: 10.1016/j.bmcl.2009.04.039. Epub 2009 Apr 18.

Authors

Lawrence J Wilson¹, Ravi Malaviya, Cangming Yang, Rochelle Argentieri, Bingbing Wang, Xin Chen, William V Murray, Druie Cavender

Affiliation

¹ High Throughput Chemistry Department, Johnson & Johnson Pharmaceutical Research & Development L.L.C. 920 Route 202, PO Box 300, Raritan, NJ 08869, USA. wilsonlarr@gmail.com

PMID: 19427203
DOI: 10.1016/j.bmcl.2009.04.039

Abstract

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.

MeSH terms

Animals
Cyclization
Drug Evaluation, Preclinical
Hypersensitivity / drug therapy*
Janus Kinase 3 / antagonists & inhibitors*
Mast Cells / drug effects
Mice
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemical synthesis*
STAT5 Transcription Factor / metabolism
Staurosporine / chemical synthesis*
Structure-Activity Relationship
T-Lymphocytes / enzymology

Substances

Protein Kinase Inhibitors
STAT5 Transcription Factor
Janus Kinase 3
Staurosporine