Smyth M S, Stefanova I, Horak I D, Burke T R
Laboratory of Medicinal Chemistry, National Institutes of Health, Bethesda, Maryland 20892.
J Med Chem. 1993 Oct 1;36(20):3015-20. doi: 10.1021/jm00072a023.
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.
水杨基在几种有效的蛋白酪氨酸激酶（PTK）抑制剂中显著存在，包括发酵产物拉文达斯汀A（3）、水杨基磺酰硝基苯乙烯30，以及我们最近报道的含水杨基的芪7。以化合物7和异构体8作为先导结构，制备了双环核9 - 12作为构象受限的模拟物，其中7和8的羟基苯环与芪乙烯桥共面。先前对结构1的基于苯乙烯基的PTK抑制剂采用类似方法得到了活性增强的类似物2。然而，在本研究中，当针对免疫沉淀的p56lck PTK制剂的自磷酸化进行检测时，所得的含水杨基双环化合物表现出极低的抑制活性。讨论了这些结果的意义，因为它们涉及含水杨基芪相对于1型基于苯乙烯基的抑制剂以及以化合物31为代表的一类新兴的有效芳基取代双环抑制剂可能的取向方式。
