Smyth M S, Stefanova I, Hartmann F, Horak I D, Osherov N, Levitzki A, Burke T R
Laboratory of Medicinal Chemistry, National Institutes of Health, Bethesda, Maryland 20892.
J Med Chem. 1993 Oct 1;36(20):3010-4. 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 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.
发酵产物拉文杜斯汀A（1）是一种蛋白酪氨酸激酶（PTK）抑制剂，其活性药效基团先前已被证明存在于更简化的含水杨酰基苄胺2中。胺2与另外两种天然产物PTK抑制剂，即埃布他汀（3）和白藜芦醇（4）在结构上有一些相似之处。因此，合成了2的不含胺的类似物，这些类似物结合了埃布他汀或白藜芦醇的其他方面。在免疫沉淀的p56lck、表皮生长因子受体（EGFR）和c-erb B-2/HER 2/neu PTK制剂中对这些抑制剂进行检测，结果表明化合物12（IC50 = 60 nM）是迄今为止报道的最有效的p56lck抑制剂之一。这些结果表明，氮不是拉文杜斯汀A药效基团2的必需组成部分，并且带有水杨酰基部分的1,2-二芳基乙烷和-乙烯似乎是构建极其有效的PTK抑制剂的有价值的结构基序。
