There is accumulating evidence that compounds containing N-acylhydrazone or 4-chromenone moieties can be active against multiple cancer cell types, yet the combined effect of these chemical groups is unclear. This study aimed to develop more effective anti-cancer compounds by combining 4-chromenone and N-acylhydrazone. Thirteen derivatives were designed, synthesized, and characterized, and their structures were identified using nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. Most of the derivatives exhibited moderate to high efficacy in inhibiting the clonogenicity of HCT116 colon cancer cells. In particular, derivative 12, (E)-N'-((6-methoxy-4-oxo-4H-chromen-3-yl)methylene)isonicotinohydrazide, strongly inhibited clonogenicity (GI50 = 34.8 μM) of HCT116 cells and aurora kinase A (aurA) activity in vitro (IC50 = 1.4 μM). In silico docking experiment predicted that derivative 12 interacts with aurA based on computational docking and calculations of binding free energy. When derivative 12 was exposed to HCT116 cells, the phosphorylation of aurA at Thr288 was dose-dependently decreased within 60 min. Further analysis showed that derivative 12 destroyed the mitotic spindle in HCT116 cells. These results suggest that derivatives of 4-chromenone combined with N-acylhydrazone are feasible in the development of selective aurA inhibitor and could be considered potential chemotherapeutic agents.

中文翻译：

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4-色酮衍生物与N-酰基hydr联用的极光激酶A抑制剂的设计，合成与评价

越来越多的证据表明，含有N-酰基hydr或4-色酮部分的化合物可能对多种癌细胞具有活性，但这些化学基团的联合作用尚不清楚。这项研究旨在通过将4-色酮和N-酰基hydr结合起来开发更有效的抗癌化合物。设计，合成和表征了十三种衍生物，并使用核磁共振谱和高分辨率质谱法鉴定了它们的结构。大多数衍生物在抑制HCT116结肠癌细胞的克隆形成性方面表现出中等至高的功效。尤其是衍生物12（E）-N'-（（（6-甲氧基-4-氧代-4H-铬基-3-基）亚甲基）异二十二酰肼，强烈抑制了克隆形成性（GI50 = 34。8μM的HCT116细胞和极光激酶A（aurA）的体外活性（IC50 = 1.4μM）。在计算机对接实验中，基于计算对接和结合自由能的计算，预测衍生物12与aurA相互作用。当衍生物12暴露于HCT116细胞时，Thr288处aurA的磷酸化在60分钟内呈剂量依赖性降低。进一步的分析表明，衍生物12破坏了HCT116细胞中的有丝分裂纺锤体。这些结果表明4-色酮与N-酰基hydr的衍生物在选择性aurA抑制剂的开发中是可行的，并且可以被认为是潜在的化学治疗剂。当衍生物12暴露于HCT116细胞时，Thr288处aurA的磷酸化在60分钟内呈剂量依赖性降低。进一步的分析表明，衍生物12破坏了HCT116细胞中的有丝分裂纺锤体。这些结果表明4-色酮与N-酰基hydr的衍生物在选择性aurA抑制剂的开发中是可行的，并且可以被认为是潜在的化学治疗剂。当衍生物12暴露于HCT116细胞时，Thr288处的aurA磷酸化在60分钟内呈剂量依赖性降低。进一步的分析表明，衍生物12破坏了HCT116细胞中的有丝分裂纺锤体。这些结果表明4-色酮与N-酰基hydr的衍生物在选择性aurA抑制剂的开发中是可行的，并且可以被认为是潜在的化学治疗剂。