Non-Amine Based Analogues of Lavendustin A as Protein-Tyrosine Kinase Inhibitors

Article abstract of DOI:10.1021/jm00072a022

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 p56^lck, epidermal growth factor receptor (EGFR), and c-erb B-2/HER 2/neu PTK preparation showed that compound 12 (IC50=60 nM)was one of the most potent p56^lek 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 constuction of extremely potent PTK inhibitors.