4-Anilino-6,7-dialkoxyquinolime-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors
4-Anilino-6,7-dialkoxyquinolime-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors
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DOI：
10.1021/jm000206a
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发表时间：
2000-08-24
影响因子：
7.3
通讯作者：
Zhang, N
中科院分区：
文献类型：
--
作者：
Wissner, A;Berger, DM;Zhang, N
报道了一系列4-苯胺基-6，7-二烷氧基喹啉-3-腈类表皮生长因子受体激酶抑制剂的合成及构效关系。3，4-二烷氧基苯胺与（乙氧基亚甲基）氰基乙酸乙酯缩合，然后热环化，区域特异性地得到6，7-二烷氧基-4-氧代-1，4-二氢喹啉-3-腈。氯化（POCl 3），然后与取代苯胺反应，得到EGF-R激酶的4-苯胺基-6，7-二烷氧基喹啉-3-腈抑制剂。这些化合物的另一种合成方法是从3，4-二烷氧基苯甲酸甲酯开始。硝化后还原（Fe，NH 4Cl，MeOH-H2O）得到2-氨基-4，5-二烷氧基苯甲酸甲酯。用DMF-缩醛形成脒，然后用LiCH 2CN环化，得到6，7-二烷氧基-4-氧代-1，4-二氢喹啉-3-腈，将其如前所述转化。还制备了在喹啉环的3-位上含有酸、酯、酰胺、甲醇和醛基的化合物用于比较，以及几种1-苯胺基-6，7-二甲氧基异喹啉-4-碳腈。评价了化合物抑制EGF-R催化结构域自磷酸化的能力。这些抑制剂的SAR相对于6，7-烷氧基基团的性质，苯胺取代基，并在3-位的取代基进行了研究。进一步评价化合物抑制过表达EGF-R或HER-2的细胞系生长的能力。发现4-苯胺基喹啉-3-腈是EGF-R激酶的有效抑制剂，其活性与基于4-苯胺基喹唑啉的抑制剂相当。根据Hck和FGF受体-1激酶的X射线结构，建立了一个新的EG;F-R激酶的同源模型。该模型表明，与喹唑啉为基础的抑制剂，N3原子是氢键键合的水分子，这反过来又与Thr 830相互作用。有人提出，喹啉-3-腈结合在一个类似的方式，其中水分子被取代的氰基与相同的Thr残基相互作用。
The synthesis and SAR of a series of 4-anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor (EGF-R) kinase are described. Condensation of 3,4-dialkoxyanilines with ethyl (ethoxymethylene)cyano acetate followed by thermal cyclization gave, regiospecifically, 6,7-dialkoxy-4-oxo-1,4-dihydroquinoline-3-carbonitriles. Chlorination (POCl3) followed by the reaction with substituted anilines furnished the 4-anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors of EGF-R kinase. An alternate synthesis of these compounds starts with a methyl 3,4-dialkoxybenzoate. Nitration followed by reduction (Fe, NH4Cl, MeOH-H2O) gave a methyl 2-amino-4,5-dialkoxybenzoate. Amidine formation using DMF-acetal followed by cyclization using LiCH2CN furnished a 6,7-dialkoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile, which was transformed as before. Compounds containing acid, ester, amide, carbinol, and aldehyde groups at the 3-position of the quinoline ring were also prepared for comparison, as were several 1-anilino-6,7-dimethoxyisoquinoline-4-carbonitiriles The compounds were evaluated for their ability to inhibit the autophosphorylation of the catalytic domain of EGF-R. The SAR of these inhibitors with respect to the nature of the 6,7-alkoxy groups, the aniline substituents, and the substituent at the 3-position was studied. The compounds were further evaluated for their ability to inhibit the growth of cell lines that overexpress EGF-R or HER-2. It was found that 4-anilino quinoline-3-carbonitriles are effective inhibitors of EGF-R kinase with activity comparable to the 4-anilinoquinazoline-based inhibitors. A new homology model of EG;F-R kinase was constructed based on the X-ray structures of Hck and FGF receptor-1 kinase. The model suggests that with the quinazoline-based inhibitors, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 830. It is proposed that the quinoline-3-carbonitriles bind in a similar manner where the water molecule is displaced by the cyano group which interacts with the same Thr residue.