Purpose: The monocarbonyl analogs of curcumin (MCACs) have been widely studied for their promising antitumor activity. Pyrazole is a five-membered aromatic heterocyclic system with various bioactivities incorporated frequently in drugs. However, few of MCACs inspired pyrazole analogues were investigated. To search for more potent cytotoxic agents based on MCACs, a series of new 1,5-diaryl/heteroaryl-1,4-pentadien-3-ones inspired pyrazole moiety was synthesized and evaluated on their anti-colon cancer activities.
Methods: Fifteen new compounds were synthesized and characterized by spectral datum, and then they were tested preliminarily by MTT assay for their cytotoxic activities against a panel of four human cancer cell lines, namely, gastric (SGC-7901), liver (HepG2), lung (A549), and colon (SW620) cancer cells. Compound 7h exhibited excellent selectivity and outstanding anti-proliferation activity against SW620 cells among these 15 compounds. Further, the mechanisms were investigated by transwell migration and invasion assay, clonogenic assay, cell apoptosis analysis, cell cycle analysis, Western blot analysis.
Results: The IC₅₀ value of 7h against SW620 cells was 12 nM, being more potent than curcumin (IC₅₀ = 9.36 μM), adriamysin (IC₅₀ = 3.28 μM) and oxaliplatin (IC₅₀ = 13.33 μM). Further assays showed that 7h inhibited SW620 cell migration, invasion and colony formation obviously, which was due to its ability to induce cell cycle arrest in the G2/M and S phases and apoptosis. Western blot assay revealed that 7h decreased the protein expression of ATM gene, which may primarily contribute to its anticancer activity against SW620 cells.
Conclusion: A new MCACs 7h was synthesized and found to exhibit excellent anti-proliferation activity against SW620 cells. Further studies indicated that 7h exerted its anticancer activity against SW620 cells probably via decreasing the ATM protein expression. The present study suggested that 7h was a promising candidate as an anti-colon cancer drug for future development.

Keywords: 1, 5-diheteroarylpenta-1, 4-dien-3-one, colon cancer, cell proliferation, cell apoptosis, ATM gene


中文翻译：

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单羰基姜黄素启发的吡唑类似物作为潜在的抗结肠癌药物的合成和生物学评价。

目的：姜黄素的单羰基类似物 (MCACs) 因其具有良好的抗肿瘤活性而被广泛研究。吡唑是一种五元芳香杂环系统，具有多种生物活性，经常被纳入药物中。然而，很少有人研究了受MCACs启发的吡唑类似物。为了寻找基于 MCAC 的更有效的细胞毒剂，合成了一系列新的 1,5-二芳基/杂芳基-1,4-戊二烯-3-酮类化合物，并对其抗结肠癌活性进行了评估。
方法：合成了 15 种新化合物并通过光谱数据对其进行了表征，然后通过 MTT 法初步测试了它们对一组四种人类癌细胞系的细胞毒活性，即胃 (SGC-7901)、肝 (HepG2)、肺 ( A549) 和结肠 (SW620) 癌细胞。在这15种化合物中，化合物7h对SW620细胞表现出优异的选择性和显着的抗增殖活性。此外，通过transwell迁移和侵袭试验、克隆形成试验、细胞凋亡分析、细胞周期分析、Western印迹分析研究了这些机制。
结果：7h对SW620细胞的IC ₅₀值为12 nM，强于姜黄素（IC ₅₀= 9.36 μM)、阿霉素 (IC ₅₀ = 3.28 μM) 和奥沙利铂 (IC ₅₀ = 13.33 μM)。进一步分析表明，7h明显抑制SW620细胞迁移、侵袭和集落形成，这是由于其能够诱导细胞周期停滞在G2/M和S期和细胞凋亡。Western印迹分析显示7h降低了ATM基因的蛋白表达，这可能主要有助于其对SW620细胞的抗癌活性。
结论：合成了一种新的MCACs 7h，发现其对SW620细胞具有优异的抗增殖活性。进一步的研究表明，7h可能通过降低 ATM 蛋白表达对 SW620 细胞发挥抗癌活性。本研究表明，7h是一种很有前途的候选药物，可作为未来发展的抗结肠癌药物。

关键词： 1, 5-diheteroarylpenta-1, 4-dien-3-one, 结肠癌, 细胞增殖, 细胞凋亡, ATM基因