Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors are drugs that are effectively used to treat breast cancer. We synthesized a novel bromophenol derivative ethyl (E)-4-(2-(2,3-dibromo-4,5-dimethoxybenzylidene)hydrazine-1-carbothioamido)benzoate (DDHCB) as a novel PARP-1 inhibitor. Our study found that DDHCB could inhibit PARP-1 activity with an IC₅₀ value of 58.3 nM. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphe-nyltetrazolium bromide (MTT) assay indicated that DDHCB could selectively inhibit proliferation of BRCA mutant cells and demonstrate the ability of synthetic lethality. DDHCB could also induce DNA double-strand breaks with the ability to increase the foci quantitation of γ-H2AX. Moreover, DDHCB could increase PARP-1-DNA trapping and inhibit PAR formation in HCC-1937 cells. Further investigation showed that DDHCB induced apoptosis and G2/M cycle arrest. Finally, we found that DDHCB inhibited the growth of HCC-1937 xenografts with low toxicity. In vivo mechanisms showed that the level of γ-H2AX was increased in the DDHCB-treated tumors, indicating the PARP-1 inhibition ability of DDHCB in vivo. Our study results indicated that the future development of DDHCB for the treatment of breast cancer is promising.

中文翻译：

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新型聚（ADP-核糖）聚合酶-1抑制剂DDHCB通过合成致死机制在体内和体外抑制BRCA突变乳腺癌细胞的增殖。

聚（ADP-核糖）聚合酶-1（PARP-1）抑制剂是有效用于治疗乳腺癌的药物。我们合成了一种新型的溴酚衍生物（E）-4-（2-（2,3-二溴-4,5-二甲氧基亚苄基）肼-1-碳硫代酰胺基）苯甲酸酯（DDHCB）作为新型的PARP-1抑制剂。我们的研究发现DDHCB可以通过IC ₅₀抑制PARP-1活性值为58.3 nM。3-（4,5-二甲基噻唑-2-基）-2,5-二苯甲基四唑鎓溴化物（MTT）分析表明DDHCB可以选择性抑制BRCA突变细胞的增殖，并具有合成杀伤力。DDHCB还可以诱导DNA双链断裂，并具有增加γ-H2AX病灶定量的能力。此外，DDHCB可以增加HARP-1937细胞中PARP-1-DNA的捕获并抑制PAR的形成。进一步的研究表明DDHCB诱导了细胞凋亡和G2 / M周期停滞。最后，我们发现DDHCB以低毒性抑制了HCC-1937异种移植物的生长。体内机制显示DDHCB处理的肿瘤中γ-H2AX的水平升高，表明DDHCB在体内具有PARP-1抑制能力。我们的研究结果表明，DDHCB在乳腺癌治疗方面的未来发展是有希望的。