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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and Structure-Activity Studies on N-[5-(1H-Imidazol-4-yl)-5,6,7,8-tetrahydro-l-naphthalenyl]methanesulfonamide,an Imidazole-Containing alpha_1A-Adrenoceptor Agonist
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Synthesis and Structure-Activity Studies on N-[5-(1H-Imidazol-4-yl)-5,6,7,8-tetrahydro-l-naphthalenyl]methanesulfonamide,an Imidazole-Containing alpha_1A-Adrenoceptor Agonist

机译：含咪唑的α_1A-肾上腺素受体激动剂N- [5-（1H-咪唑-4-基）-5,6,7,8-四氢-1-萘]甲磺酰胺的合成及结构活性研究

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Indigoids,a class of bis-indoles,represent a promising protein kinase inhibitor scaffold.Oxidation of indole by cytochrome P450(P450)has been shown to generate species(indoxyl,isatin)that couple to yield indigo and indirubin.Escherichia coil-expressed human P450 2A6 mutants isolated from a randomized library were incubated with 27 substituted indole derivatives.Extracts of the cultures were screened for inhibition of human cyclin-dependent kinases(CDK)-l and -5 and glycogen synthase kinase-3(GSK3).The extracts from cultures incubated with 5-methoxyindole were the most inhibitory.High-performance liquid chroma-tography(HPLC)separation yielded a mixture of seven colored indigoids.These indigoids included indigo,indirubin,the di(5-methoxy)derivatives of indigo and indirubin,and both of the possible mono 5-methoxy derivatives of indirubin,which were all identified by visible,mass,and NMR spectra.Cultures with 5-methylindole added to the media also yielded inhibitory material,and 5-and 5'-methylindirubin were characterized.The most inhibitory of these indigoids were the monosubstituted indirubins and 5,5'-dimethoxyindirubin,which was>=10X more active than indirubin.Thus,the overall approach involves the use of a library of randomized enzyme mutants to activate component moieties of a desired set of larger molecules,thus yielding a library of drug candidates that can be screened and characterized.The general strategy may have additional applications.
机译：吲哚类是一类双吲哚，代表了一种有前途的蛋白激酶抑制剂支架。已证明，细胞色素P450（P450）对吲哚的氧化作用会产生几类物质（吲哚酚，伊斯汀），它们会产生靛蓝和靛玉红。从随机库中分离出的P450 2A6突变体与27种取代的吲哚衍生物孵育，筛选培养液中抑制人细胞周期蛋白依赖性激酶（CDK）-1和-5和糖原合酶激酶-3（GSK3）的提取物。用5-甲氧基吲哚培养的细菌具有最大的抑制作用。高效液相色谱（HPLC）分离得到七种有色靛蓝的混合物。这些靛蓝包括靛蓝，靛蓝红素，靛蓝的二（5-甲氧基）衍生物和靛红红素。 ，以及靛蓝红素的两种可能的单5-甲氧基衍生物，都通过可见，质谱和NMR谱鉴定。加入5-甲基吲哚的培养基也产生抑制物质，以及5-和5'-m表征了乙基靛玉红。对这些靛蓝的抑制作用最大的是单取代的靛玉红和5,5'-二甲氧基靛蓝红，其活性高于靛蓝红10倍。因此，总体方法涉及使用随机酶突变体文库来活化组分所需的一组较大分子的部分，从而产生可以筛选和表征的候选药物库。一般策略可能会有其他应用。

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