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.
Wilson
Lawrence J
LJ
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
Malaviya
Ravi
R
Yang
Cangming
C
Argentieri
Rochelle
R
Wang
Bingbing
B
Chen
Xin
X
Murray
William V
WV
Cavender
Druie
D
D000818:Animals; D003500:Cyclization; D004353:Drug Evaluation, Preclinical; D006967:Hypersensitivity / Q000188:drug therapy*; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors*; D008407:Mast Cells / Q000187:drug effects; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D019311:Staurosporine / Q000138:chemical synthesis*; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000201:enzymology
D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D053616:Janus Kinase 3; D019311:Staurosporine