Million M E, Boiziau J, Parker F, Tocque B, Roques B P, Garbay C
Département de Pharmacochimie Moléculaire et Structurale U266 INSERM, Paris, France.
J Med Chem. 1995 Nov 10;38(23):4693-703. doi: 10.1021/jm00023a009.
Several series of hydroxybiphenyl compounds substituted by a hydrophobic group (tert-butyl or phenyl) and bearing a free or protected carboxylic moiety were synthesized. The compounds were tested for their ability to inhibit the intrinsic tyrosine protein kinase activity of the EGF-receptor in vitro and the EGF-stimulated DNA-synthesis by ER 22 cells. Although the compounds of each series had poor in vitro inhibitory potencies (IC50 >> 100 microM), most of them inhibited the EGF-dependent cellular proliferation of ER 22 cells at relatively low doses (IC50 = 1.1 microM for compound 14). Structure-activity studies based on the cellular results showed that the most interesting series was the linear terphenyl series B of 2'-hydroxy-1,1':4',1"-terphenyl-4-carboxylates. The availability of the hydroxyl group, either protected or unprotected, the linear arrangement of the hydrophobic moiety, the biphenyl skeleton, and the carboxylic group seem to be essential for the activity of the compounds.
合成了几个系列的被疏水基团（叔丁基或苯基）取代且带有游离或受保护羧基部分的羟基联苯化合物。测试了这些化合物在体外抑制表皮生长因子（EGF）受体的内在酪氨酸蛋白激酶活性以及抑制ER 22细胞中EGF刺激的DNA合成的能力。尽管每个系列的化合物体外抑制效力较差（半数抑制浓度[IC50] >> 100微摩尔），但它们中的大多数在相对低剂量下就能抑制ER 22细胞的EGF依赖性细胞增殖（化合物14的IC50 = 1.1微摩尔）。基于细胞实验结果的构效关系研究表明，最有意思的系列是2'-羟基-1,1':4',1''-三联苯-4-羧酸盐的线性三联苯系列B。羟基无论是被保护还是未被保护的状态、疏水部分的线性排列、联苯骨架以及羧基似乎对化合物的活性至关重要。
