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Combretastatin A-4(CA-4)是一个天然的秋水仙碱结合位点的微管蛋白抑制剂,具有抗肿瘤活性。PI3K信号通路是细胞内重要的信号转导通路之一,也是癌细胞中常见的异常表达信号通路。微管蛋白抑制剂和信号通路激酶抑制剂均为抗肿瘤药物研发的热点。设计、筛选并合成了具有秋水仙碱和PI3K双靶点的CA-4衍生物。利用SBDD技术,采用活性基团协作的方法,对CA-4进行秋水仙碱和PI3K双靶点结构改造。结合CA-4的构效关系,保留A环及3个甲氧基,以羰基取代连接双键碳以保证顺式构型,苯并呋喃环取代B环,B环侧链引入卤素增效,依据结合活性自由能打分值筛选出9种靶点活性高的衍生物进行分子对接分析及可视化分析,并通过碘代、溴代、Rap-Stoermer偶联反应和Heck偶联反应合成目标化合物CA-4,其结构经1H NMR、13C NMR和MS确证。活性测试结果表明:目标化合物对乳腺癌MCF-7和MDA-MB-231 2种肿瘤细胞具有抑制作用。 相似文献
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The title compound,1-(2-(1 H-indol-3-yl)ethyl)-3-(2-methoxyphenyl)urea(C_(18)H_(19)N_3O_2,M_r = 309.36) has been synthesized,and its structure was characterized by ~1H-NMR,~(13)C-NMR,ESI-MS and single-crystal X-ray diffraction.It crystallizes in the monoclinic space group P2_1/c with a = 16.2774(15),b = 11.1082(10),c = 9.0819(3) ?,β = 103.09(9)°,V = 1599.5(3) ?~3,Z = 4,T = 293(2) K,μ(MoKα) = 0.086 mm~(-1),D_c = 1.285 g/cm~3,F(000) = 656 and GOOF = 0.981.5973 reflections were measured(7.04≤2θ≤52.04°),and 3143 were unique(Rint= 0.0393,Rsigma = 0.0546) and used in all calculations.The final R = 0.0756(I 2σ(I)) and w R = 0.1976(all data).The antitumor activity of the title compound was analyzed by MTT assay.Meanwhile,to rationalize its potencies in the CDK4 target,the title compound was docked into CDK4 protein and the interactions with the active site residues were analyzed. 相似文献
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The title compound,ethyl(R)-2-(biphenyl-4-carbonyl)-2,3,4,9-tetrahydro-1H-pyri do-[3,4-b]indole-1-carboxylate(C_(27)H_(24)N_2O_3) has been synthesized,and its structure was charac-terized by ~1H-NMR,~(13)C-NMR,ESI-MS and single-crystal X-ray diffraction.It crystallizes in the orthorhombic system,space group Pbca with a = 16.9950(8),b = 9.5445(4),c = 28.3188(3) ?,V = 4593.6(3) ?~3,Z = 8,T = 294.64(10) K,μ(MoKα) = 0.08 mm~(-1),Dc = 1.228 g/cm~3,F(000) = 1792 and GOOF = 1.036.11836 reflections were measured(7.04≤2θ≤52.04°),and 4506 were unique(R_(int)= 0.0393,R_(sigma )= 0.0546) and used in all calculations.The final R = 0.0576(I 2σ(I)) and wR = 0.1563(all data).The preliminary biological tests show that the title compound has a good antitumor activity against Hela in vitro with the IC_(50) value of 4.71 μmol/L. 相似文献
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