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Synthesis, characterization, and evaluation of a novel inhibitor of WNT/β-catenin signaling pathway

机译：新型WNT /β-catenin信号通路抑制剂的合成，表征和评价

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Background Wnt/β-catenin signaling is a highly conserved pathway in organism evolution and is important in many biological processes. Overactivation of Wnt/β-catenin signaling is closely related to tumor development and progression. To identify potent small molecules that can fight aberrant Wnt/β-catenin-mediated cancer, we synthesized a novel pyrazoline derivative (N-(4-hydroxybenzyl)-1,3,4-triphenyl-4,5-dihydro-1 H -pyrazole-5-carboxamide, BHX) to block Wnt signaling, and determined the absolute configuration of its precursor (ethyl 1,3,4-triphenyl-4,5-dihydro-1 H -pyrazole-5-carboxylate). We then evaluated the inhibitory effect of BHX in vitro and in vivo . Results Cell proliferation was assessed in three human cancer cell lines (A549, HT29, and MGC803) in the presence and absence of BHX using MTS assays. BHX effectively inhibited A549, HT29, and MGC803 cell proliferation with IC50 of 5.43?±?1.99, 6.95?±?0.24, and 7.62?±?1.31?μM, respectively. BHX significantly induced apoptosis and G1 phase arrest in A549 and MGC803 cells. The β-catenin protein level was markedly reduced in A549 and MGC803 cells under BHX treatment. The inhibitory effect of BHX in vivo was investigated using a mouse xenograft model. A549 xenograft growth was suppressed by 50.96% in nude mice treated continuously with 100?mg/kg BHX for 21 d. Weight remained almost unchanged, which indicates the low toxicity of the compound. Conclusions Our data suggest that BHX is a new drug candidate for cancer treatment because of its potent effect on the Wnt/β-catenin pathway and low toxicity.
机译：背景Wnt /β-catenin信号传导是生物进化中高度保守的途径，在许多生物学过程中都很重要。 Wnt /β-catenin信号的过度激活与肿瘤的发生和发展密切相关。为了鉴定可对抗Wnt /β-catenin介导的异常癌症的有效小分子，我们合成了一种新型吡唑啉衍生物（N-（4-羟基苄基）-1,3,4-三苯基-4,5-二氢-1 H-吡唑-5-羧酰胺，BHX）阻断Wnt信号传导，并确定其前体的绝对构型（1,3,4-三苯基-4,5-二氢-1 H-吡唑-5-羧酸乙酯）。然后我们评价了BHX在体外和体内的抑制作用。结果在存在和不存在BHX的情况下，使用MTS分析评估了三种人类癌细胞系（A549，HT29和MGC803）中的细胞增殖。 BHX有效抑制A549，HT29和MGC803细胞的增殖，IC 50 为5.43？±1.99、6.95？±？0.24和7.62？±？1.31？分别为μM。 BHX显着诱导A549和MGC803细胞凋亡和G1期阻滞。在BHX处理下，A549和MGC803细胞中的β-catenin蛋白水平显着降低。使用小鼠异种移植模型研究了BHX在体内的抑制作用。在以100？mg / kg BHX连续治疗21 d的裸鼠体内，A549异种移植的生长被抑制了50.96％。重量几乎保持不变，表明该化合物的毒性低。结论我们的数据表明BHX因其对Wnt /β-catenin途径的有效作用和低毒性而成为治疗癌症的新药。

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