Hydroxylated 2-(5'-salicyl)naphthalenes as protein-tyrosine kinase inhibitors.
The salicyl group figures prominently in several potent protein-tyrosine kinase (PTK) inhibitors, including the fermentation product lavendustin A (3), the salicylsulfonyl nitrostyryl 30, and our recently reported salicyl-containing stilbene 7. Taking compound 7 and the isomeric 8 as lead structures, bicyclic nuclei 9-12 were prepared as conformationally constrained mimetics in which the hydroxyphenyl rings of 7 and 8 are held coplanar with the stilbene ethylene bridge. A similar approach with styryl-based PTK inhibitors of structure 1 previously yielded analogues 2 with enhanced potency. In the present case, however, the resulting salicyl-containing bicyclics exhibited extremely poor inhibitory potency when examined against autophosphorylation of immunoprecipitated p56lck PTK preparations. The implications of these results are discussed as they relate to the potential ways in which salicyl-containing stilbenes may be oriented relative to styryl-based inhibitors of type 1 and to an emerging class of potent aryl-substituted bicyclic inhibitors exemplified by compound 31.
Smyth
M S
MS
Laboratory of Medicinal Chemistry, National Institutes of Health, Bethesda, Maryland 20892.
Stefanova
I
I
Horak
I D
ID
Burke
T R
TR
D006900:Hydroxylation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012459:Salicylates / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D009281:Naphthalenes; D012459:Salicylates; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)