【摘要】：基于藥效團(tuán)拼合的設(shè)計(jì)原理,以4-羥基苯乙酮為原料,通過加成、環(huán)化、取代、肼解和縮合等多步反應(yīng)構(gòu)建了兩類含有靛紅結(jié)構(gòu)的吡唑衍生物,共計(jì)12個(gè)目標(biāo)產(chǎn)物,其結(jié)構(gòu)經(jīng)~~1H NMR,~(13)C NMR和HRMS確證.采用細(xì)胞計(jì)數(shù)試劑盒-8(CCK-8)法測(cè)試目標(biāo)產(chǎn)物對(duì)人非小細(xì)胞肺癌細(xì)胞A549的體外抑制作用,部分化合物顯示出一定的抗增殖活性,其中N'-(3-亞氨基-6-氯吲哚-2-酮)-1-苯甲基-3-(4-甲氧基苯基)-1H-吡唑-5-甲酰肼(7e)和N'-(3-亞氨基-6-溴吲哚-2-酮)-1-苯甲基-3-(4-甲氧基苯基)-1H-吡唑-5-甲酰肼(7f)的IC_(50)值分別為30.41和29.69μmol/L.流式細(xì)胞術(shù)檢測(cè)表明,化合物7f能夠劑量依賴性地誘導(dǎo)A549細(xì)胞凋亡,并降低線粒體膜電位,但對(duì)細(xì)胞周期沒有影響.上述研究證明,目標(biāo)產(chǎn)物7f能夠通過線粒體途徑誘導(dǎo)A549細(xì)胞凋亡,從而發(fā)揮抗腫瘤活性.
[Abstract]:Based on the design principle of pharmacophore assembly, two kinds of pyrazole derivatives with indirubin structure were synthesized from 4-hydroxyacetophenone by multi-step reactions such as addition, cyclization, substitution, hydrazine hydrolysis and condensation. Its structure was confirmed by 1H NMR,~ (13) C NMR and HRMS). The inhibitory effect of the target product on human non-small cell lung cancer cell line A549 in vitro was tested by cell count kit 8 (CCK-8). Some of the compounds showed certain antiproliferative activity. The IC_ (50) values of N- (3-Imino-6-chlorindole-2-one) -1-phenyl-methyl-3- (4-methoxyphenyl) -1H-pyrazolyl hydrazide (7e) and N- (3-imino-6-bromoindole -2-one) -1-phenylmethyl-3- (4-methoxyphenyl) -1H-pyrazole-5-formyl hydrazide (7f) were 30.41 渭 mol/L. and 29.69 渭 mol/L., respectively. Flow cytometry showed that compound 7f could induce apoptosis of A549 cells in a dose-dependent manner and decrease mitochondrial membrane potential, but had no effect on cell cycle. These results suggest that target product 7f can induce apoptosis of A549 cells through mitochondrial pathway, thus exerting antitumor activity.
【作者單位】： 遵義醫(yī)學(xué)院藥學(xué)院;成都大學(xué)四川抗菌素工業(yè)研究所;
【基金】：貴州省科技廳(Nos.[2014]7565,[2014]7557,[2015]6010) 遵義醫(yī)學(xué)院博士科研啟動(dòng)基金(No.F-631);遵義醫(yī)學(xué)院大學(xué)生創(chuàng)新創(chuàng)業(yè)(Nos.[2014]5811,[2014]2918);遵義醫(yī)學(xué)院學(xué)科建設(shè)(藥物化學(xué))資助項(xiàng)目 國(guó)家級(jí)大學(xué)生創(chuàng)新創(chuàng)業(yè)(No.201510661009)~~
【分類號(hào)】：O626;TQ460.1

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