State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, School of Traditional Chinese Pharmacy, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, China.
Eur J Med Chem. 2020 Aug 15;200:112386. doi: 10.1016/j.ejmech.2020.112386. Epub 2020 May 6.
A series of phenylsulfonyfuroxan-based NO-releasing scopoletin derivatives were designed and synthesized in the study. All target compounds showed significantly improved antiproliferative activity against four cancer cell lines (MDA-MB-231, MCF-7, HepG2 and A459) and lower cytotoxicity toward normal liver LO2 cells. Derivative 47 concentration-dependently inhibited the colony formation of MDA-MB-231 cells. NO-releasing assessment indicated that the intracellular NO level was almost positively correlated with the antiproliferative ability. Compound 47, which released the highest amounts of NO, showed the best potency (IC = 1.23 μM) against MDA-MB-231 cells. Mechanism research revealed for the first time that 47 blocked the proliferation of MDA-MB-231 cells by activating mitochondrial apoptosis pathway and arresting cell cycle at G2/M phase. Taken together, as a novel scopoletin derivative, 47 exhibited excellent inhibitory effects against malignant cancer cells and lower toxicity on normal cells. Thus, an in-depth evaluation of 47 to explore its complete therapeutic potential for cancer treatment is warranted.
本研究设计并合成了一系列基于苯磺酰基呋喃酮的一氧化氮释放型山莨菪素衍生物。所有目标化合物对四种癌细胞系（MDA-MB-231、MCF-7、HepG2 和 A459）的增殖均显示出显著改善的抑制活性，且对正常肝 LO2 细胞的细胞毒性较低。化合物 47 浓度依赖性地抑制 MDA-MB-231 细胞的集落形成。NO 释放评估表明，细胞内 NO 水平与增殖抑制能力几乎呈正相关。释放最多 NO 的化合物 47 对 MDA-MB-231 细胞表现出最佳的效力（IC=1.23 μM）。机制研究首次揭示，47 通过激活线粒体凋亡途径和将细胞周期阻滞在 G2/M 期来阻止 MDA-MB-231 细胞的增殖。综上所述，作为一种新型山莨菪素衍生物，47 对恶性癌细胞具有优异的抑制作用，对正常细胞的毒性较低。因此，有必要对 47 进行深入评估，以探索其用于癌症治疗的全部治疗潜力。
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