Burke T R, Lim B, Marquez V E, Li Z H, Bolen J B, Stefanova I, Horak I D
Laboratory of Medicinal Chemistry, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.
J Med Chem. 1993 Feb 19;36(4):425-32. doi: 10.1021/jm00056a001.
A study was undertaken to prepare inhibitors of the lymphocyte protein-tyrosine kinase p56lck. Using the known p56lck inhibitor 3,4-dihydroxy-alpha-cyanocinnamamide (4) as a lead compound, bicyclic analogues were designed as conformationally constrained mimetics in which the phenyl ring and vinyl side chain of the cinnamamide are locked into a coplanar orientation. Such planarity was rationalized to be an important determinant for binding within a putative flat, cleftlike catalytic cavity. Bicyclic analogues were prepared using the naphthalene, quinoline, isoquinoline, and 2-iminochromene ring systems and examined for their ability to inhibit autophosphorylation of immunopurified p56lck. The most potent analogues were methyl 7,8-dihydroxyisoquinoline-3-carboxylate (12) (IC50 = 0.2 microM) and 7,8-dihydroxyisoquinoline-3-carboxamide (13) (IC50 = 0.5 microM). Inhibition by 12 was not competitive with respect to ATP. These compounds may represent important new structural motifs for the development of p56lck inhibitors.
开展了一项研究以制备淋巴细胞蛋白酪氨酸激酶p56lck的抑制剂。以已知的p56lck抑制剂3,4 - 二羟基 -α- 氰基肉桂酰胺（4）作为先导化合物，设计了双环类似物作为构象受限的模拟物，其中肉桂酰胺的苯环和乙烯基侧链被锁定在共面取向上。这种平面性被认为是在假定的扁平、裂隙状催化腔中结合的重要决定因素。使用萘、喹啉、异喹啉和2 - 亚氨基色烯环系统制备了双环类似物，并检测了它们抑制免疫纯化的p56lck自磷酸化的能力。最有效的类似物是7,8 - 二羟基异喹啉 - 3 - 羧酸甲酯（12）（IC50 = 0.2 microM）和7,8 - 二羟基异喹啉 - 3 - 甲酰胺（13）（IC50 = 0.5 microM）。12的抑制作用对ATP而言不是竞争性的。这些化合物可能代表了开发p56lck抑制剂的重要新结构基序。
