Non-amine based analogues of lavendustin A as protein-tyrosine kinase inhibitors.
The fermentation product lavendustin A (1) is a protein-tyrosine kinase (PTK) inhibitor whose active pharmacophore has previously been shown to reside in the more simplified salicyl-containing benzylamine 2. Amine 2 bears some structural resemblance to two other natural product PTK inhibitors, erbstatin (3) and piceatannol (4). Non-amine containing analogues of 2 were therefore synthesized which incorporated additional aspects of either erbstatin or piceatannol. Examination of these inhibitors in immunoprecipitated p56lck, epidermal growth factor receptor (EGFR), and c-erb B-2/HER 2/neu PTK preparations showed that compound 12 (IC50 = 60 nM) was one of the most potent p56lck inhibitors reported to date. These results demonstrate that nitrogen is not an essential component of the lavendustin A pharmacophore 2 and that 1,2-diarylethanes and -ethenes bearing a salicyl moiety appear to be valuable structural motifs for the construction of extremely potent PTK inhibitors.
Smyth
M S
MS
Laboratory of Medicinal Chemistry, National Institutes of Health, Bethesda, Maryland 20892.
Stefanova
I
I
Hartmann
F
F
Horak
I D
ID
Osherov
N
N
Levitzki
A
A
Burke
T R
TR
D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism; D007163:Immunosorbent Techniques; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D015394:Molecular Structure; D010636:Phenols / Q000737:chemistry* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases; D013329:Structure-Activity Relationship
D066246:ErbB Receptors; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D010636:Phenols; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; C062898:lavendustin A