The combined treatment with histone deacetylase (HDAC) inhibitors with peroxisome proliferator-activated receptor γ (PPARγ) agonists has displayed significant anticancer efficacy. Based on these results, a series of cloxiquine derivatives were prepared as potent HDAC inhibitors for the treatment of melanoma. Among these compounds, CS4 exhibited excellent inhibitory effects on HDAC1 (IC50 = 38 nM) and HDAC6 (IC50 = 12 nM), and had good antiproliferative effects against A375 and SK-MEL-5 melanoma cells (IC50 values, 1.20 and 0.93 μM, respectively). Mechanism research indicated that CS4 inhibited SK-MEL-5 cell growth by promoting α-tubulin and histone 3 (H3) acetylation. At the metabolic level, treatment with BG11 activated PPARγ and blocked glycolysis in SK-MEL-5 cells, which mediated partial antimelanoma effects of CS4. In addition, CS4 also induced cell cycle arrest at G2, suppressed migration and facilitated apoptosis of SK-MEL-5 cells. More importantly, compound CS4 demonstrated significant in vivo anticancer effect compared with SAHA, and exhibited neglectable toxicity. Consequently, CS4 is the potent HDAC inhibitor, which may be developed as the candidate antimelanoma drug.

中文翻译：

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通过激活 PPARγ 发现氯昔喹衍生物作为有效的 HDAC 抑制剂治疗黑色素瘤


组蛋白脱乙酰酶 （HDAC） 抑制剂与过氧化物酶体增殖物激活受体γ （PPARγ） 激动剂的联合治疗显示出显着的抗癌功效。基于这些结果，制备了一系列氯昔喹衍生物作为治疗黑色素瘤的有效 HDAC 抑制剂。在这些化合物中，CS4 对 HDAC1 （IC50 = 38 nM） 和 HDAC6 （IC50 = 12 nM） 表现出优异的抑制作用，对 A375 和 SK-MEL-5 黑色素瘤细胞具有良好的抗增殖作用 （IC50 值分别为 1.20 和 0.93 μM）。机制研究表明，CS4 通过促进 α-微管蛋白和组蛋白 3 （H3） 乙酰化来抑制 SK-MEL-5 细胞生长。在代谢水平，BG11 处理激活 PPARγ 并阻断 SK-MEL-5 细胞中的糖酵解，这介导了 CS4 的部分抗黑色素瘤作用。此外，CS4 还诱导 G2 细胞周期停滞，抑制迁移并促进 SK-MEL-5 细胞凋亡。更重要的是，与 SAHA 相比，化合物 CS4 表现出显著的体内抗癌作用，并且表现出可忽略不计的毒性。因此，CS4 是有效的 HDAC 抑制剂，可作为候选抗黑色素瘤药物开发。