TYROSINE KINASE INHIBITORS .4. STRUCTURE-ACTIVITY-RELATIONSHIPS AMONG N-SUBSTITUTED AND 3-SUBSTITUTED 2,2'-DITHIOBIS(1H-INDOLES) FOR IN-VITRO INHIBITION OF RECEPTOR AND NONRECEPTOR PROTEIN-TYROSINE KINASES
TYROSINE KINASE INHIBITORS .4. STRUCTURE-ACTIVITY-RELATIONSHIPS AMONG N-SUBSTITUTED AND 3-SUBSTITUTED 2,2'-DITHIOBIS(1H-INDOLES) FOR IN-VITRO INHIBITION OF RECEPTOR AND NONRECEPTOR PROTEIN-TYROSINE KINASES
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DOI：
10.1021/jm00001a011
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发表时间：
1995-01-06
影响因子：
7.3
通讯作者：
DENNY, WA
中科院分区：
文献类型：
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作者：
PALMER, BD;REWCASTLE, GW;DENNY, WA
合成了一系列S取代的2，2‘-二硫代双(1H-吲哚)化合物，并评价了它们对表皮生长因子受体(EGFR)和非受体pp60(v-src)酪氨酸激酶活性的抑制作用，以扩展该系列化合物的构效关系。大多数化合物是通过2-氯-1-甲基吲哚-3-甲酰氯与胺反应，然后硫甲基化、脱甲基、氧化二聚，或异氰酸酯与1-甲基-2-吲哚硫酮的阴离子反应，然后二聚得到的。总体而言，具有多种侧链的类似物仍具有抑制活性。一系列3-甲酰胺类似物对S(IC(50)1-20 mU M)具有中等至良好的抗表皮生长因子受体活性，其中单烷基取代的效果最好。极性侧链一般不如亲脂性侧链有效，尤其是苯基。然而，N，N-二取代是抑制pp60(v-src)的最有效方式。多种取代的N-苯基甲酰胺对EGFR的抑制活性低于母体衍生物，N-亚硫基甲酰胺的活性也较低。一系列3-酮，包括甲基、苯基和呋喃衍生物，对pp60(v-src)激酶显示出中等的活性，但对EGFR的效果较差。这两种药物抑制这两种酶的机制对ATP和多肽底物都是非竞争性的。筛选出的化合物可抑制瑞士3T3细胞的生长，IC(50)S在低微摩尔范围内，并抑制碱性成纤维细胞生长因子介导的细胞内酪氨酸磷酸化。硫醇抑制了化合物的作用，这表明抑制作用的一个可能机制是硫醇-二硫键与催化位上的硫醇残基进行交换。两个具有代表性的化合物的晶体结构显示为折叠的V形结构，二硫键暴露，与这一假说一致。
A series of S-substituted 2,2'-dithiobis(1H-indoles) were synthesized and evaluated for their ability to inhibit the tyrosine kinase activity of both the epidermal growth factor receptor (EGFR) and the nonreceptor pp60(v-src) tyrosine kinase, to extend the available structure-activity relationships for this series. The majority of the compounds were prepared either by reaction of 2-chloro-1-methylindole-3-carbonyl chloride with amines, followed by thiomethylation, demethylation, and oxidative dimerization, or by reaction of isocyanates with the anion of 1-methyl-2-indolinethione followed by dimerization. Overall, inhibitory activity is retained by analogues having a wide variety of side chains. A series of 3-carboxamide analogues had moderate to good activity against isolated EGFR (IC(50)s 1-20 mu M), with monoalkyl substitution of the carboxamide being optimal. Polar side chains were generally less effective than lipophilic ones, with benzyl being particularly effective. However, N,N-disubstitution was the most effective pattern for inhibition of pp60(v-src). A variety of substituted N-phenylcarboxamides had lower activity against EGFR than the parent derivative, and a N-thienylcarboxamide also had low activity. A series of 3-ketones, including methyl, phenyl, and furyl derivatives, showed moderate activity against the pp60(v-src) kinase, but were less effective against EGFR. The mechanism of inhibition of both kinases by these drugs was shown to be noncompetitive with respect to both ATP and peptide substrate. Selected compounds inhibited the growth of Swiss 3T3 cells with IC(50)s in the low micromolar range and inhibited bFGF-mediated intracellular tyrosine phosphorylation in the same cell line. Thiol inhibits the effects of the compounds, suggesting that one possible mechanism of inhibition is thiol-disulfide exchange with thiol-containing residues in the catalytic sites. Crystal structures of two representative compounds show a folded, V-shaped structure, with the disulfide bridge exposed, consistent with this hypothesis.