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Synthesis of imidazo-thiadiazole linked indolinone conjugates and evaluated their microtubule network disrupting and apoptosis inducing ability
Bioorganic Chemistry ( IF 5.1 ) Pub Date : 2017-12-07 , DOI: 10.1016/j.bioorg.2017.11.021
M.P. Narasimha Rao , Burri Nagaraju , Jeshma Kovvuri , Sowjanya Polepalli , Sateesh Alavala , M.V.P.S. Vishnuvardhan , P. Swapna , Vijaykumar D. Nimbarte , Jerripothula K. Lakshmi , Nishant Jain , Ahmed Kamal

A series of imidazo[2,1-b][1,3,4]thiadiazole linked indolinone conjugates were synthesized and investigated for antiproliferative activity in different human cancer cell lines by changing various substitutions at indolinone and phenyl ring systems. Among them conjugates 7, 14 and 15 were exhibited potent antiproliferative activity with GI50 values from 0.13 to 3.8 μΜ and evaluated for cell cycle analysis, tubulin polymerization assay and apoptosis. Treatment with 7, 14 and 15 were resulted in accumulation of cells in G2/M phase, inhibition of tubulin assembly, disruption of microtubule network. Inhibition of tubulin polymerization was further supported by Western blot analysis. In addition, the conjugates (7, 14 and 15) also showed apoptosis in HeLa cell line, detailed biological studies such as Hoechst 33,258 staining, DNA fragmentation and caspase-3 assays suggested that these compounds induce cell death by apoptosis. Docking studies revealed that these compounds (7, 14 and 15) bind with αAsn101, αThr179, αSer178, βCys241, βLys254 and βLys352 in the colchicine-binding site of the tubulin.



中文翻译:

咪唑并噻二唑连接的吲哚酮偶联物的合成及其微管网络破坏和凋亡诱导能力的评价

合成了一系列咪唑并[2,1- b ] [1,3,4]噻二唑连接的吲哚满酮缀合物,并通过改变吲哚满酮和苯环系统上的各种取代来研究其在不同人类癌细胞系中的抗增殖活性。其中缀合物71415分别表现出有效的抗增殖活性,GI 50个值从0.13到3.8μΜ并评价细胞周期分析,微管蛋白聚合测定法和细胞凋亡。治疗71415导致细胞在G2 / M期积累,抑制微管蛋白装配,破坏微管网络。蛋白印迹分析进一步支持了微管蛋白聚合的抑制。另外,该缀合物(71415)也显示在HeLa细胞系中的细胞凋亡,详细的生物学研究如Hoechst的33258染色,DNA片段化和胱天蛋白酶-3测定表明,这些化合物通过凋亡诱导细胞死亡。对接的研究显示,这些化合物(71415)与αAsn101,αThr179,αSer178,βCys241,βLys254和βLys352结合在微管蛋白的秋水仙碱结合位点。

更新日期:2017-12-07
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