Nussbaumer P, Winiski A P, Cammisuli S, Hiestand P, Weckbecker G, Stütz A
Department of Dermatology, SANDOZ Research Institute, Vienna, Austria.
J Med Chem. 1994 Nov 25;37(24):4079-84. doi: 10.1021/jm00050a005.
The active partial structure of the potent tyrosine kinase inhibitor lavendustin A was derivatized in the search for novel agents against cellular proliferation. The antiproliferative potential of the new derivatives was determined using the human keratinocyte cell line HaCaT as the primary test system. Whereas the lavendustin A partial structure is ineffective in inhibiting cell proliferation, esterification of its carboxylic acid function leads to measurable antiproliferative activity. Additional O-methylation of the 2,5-dihydroxyphenyl moiety yields activity in the micromolar range. Further substantial increases in activity are achieved by replacing the nitrogen with oxygen and carbon within the 2,5-dimethoxyphenyl series (but not within the 2,5-dihydroxyphenyl analogs) leading to 5-[2-(2,5-dimethoxyphenyl) ethyl]-2-hydroxybenzoic acid methyl ester (13) as the most potent analog identified to date. These increases in antiproliferative activity are paralleled, however, by the disappearance of activity against the epidermal growth factor receptor-associated tyrosine kinase, suggesting another mechanism of action.
强效酪氨酸激酶抑制剂拉文杜斯汀A的活性部分结构经衍生化处理，以寻找针对细胞增殖的新型药物。使用人角质形成细胞系HaCaT作为主要测试系统，测定了新衍生物的抗增殖潜力。拉文杜斯汀A的部分结构在抑制细胞增殖方面无效，但其羧酸官能团的酯化导致可测量的抗增殖活性。2,5-二羟基苯基部分的额外O-甲基化产生了微摩尔范围内的活性。通过在2,5-二甲氧基苯基系列（但不是在2,5-二羟基苯基类似物中）用氧和碳取代氮，可进一步大幅提高活性，从而得到5-[2-(2,5-二甲氧基苯基)乙基]-2-羟基苯甲酸甲酯（13），这是迄今为止鉴定出的最有效的类似物。然而，抗增殖活性的这些增加与针对表皮生长因子受体相关酪氨酸激酶的活性消失同时出现，这表明存在另一种作用机制。
