Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy.
Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy.
Int J Mol Sci. 2023 Jan 25;24(3):2356. doi: 10.3390/ijms24032356.
Despite curcumin (CUR) inhibiting cell proliferation in vitro by activating apoptotic cell death, its use in pharmacological therapy is hampered by poor solubility, low stability in biological fluids, and rapid removal from the body. Therefore, CUR-derivatives with better biological and chemical-physical characteristics are needed. The bis-ketone moiety of CUR strongly influences its stability in slightly alkaline solutions such as plasma. Here, we considered its replacement with isoxazole, beta-enamine, or oxime groups to obtain more stable derivatives. The evaluation of the chemical-physical characteristics showed that only of the isoxazole derivatives and had better potential than CUR in terms of bioavailability. The UV-visible spectrum analysis showed that derivatives and had better stability than CUR in solutions mimicking the biological fluids. When tested on a panel of cell lines, derivatives and had marked cytotoxicity (IC50 = 0.5 µM) compared with CUR only (IC50 = 17 µM) in the chronic myeloid leukemia (CML)-derived K562 cell line. The derivative was the more selective for CML cells. When administered at the average concentration found for CUR in the blood of patients, derivatives and had potent effects on cell cycle progression and apoptosis initiation, while CUR was ineffective. The apoptotic effect of derivatives and was associated with low necrosis. In addition, derivative was able to reverse drug resistance in K562 cells resistant to imatinib (IM), the reference drug used in CML therapy. The cytotoxicity of derivative on IM-sensitive and resistant cells was associated with upregulation of and expression, G2/M arrest, and triggering of apoptosis. In conclusion, derivative has chemical-physical characteristics and biological effects superior to CUR, which allow us to hypothesize its future use in the therapy of CML and CML forms resistant to IM, either alone or in combination with this drug.
尽管姜黄素 (CUR) 通过激活细胞凋亡来抑制体外细胞增殖，但由于其溶解度低、在生物流体中的稳定性差以及在体内迅速清除，其在药理学治疗中的应用受到阻碍。因此，需要具有更好的生物学和理化特性的 CUR 衍生物。CUR 的双酮部分强烈影响其在血浆等略碱性溶液中的稳定性。在这里，我们考虑用异恶唑、β-烯胺或肟取代它，以获得更稳定的衍生物。化学物理特性评估表明，只有异恶唑衍生物和具有比 CUR 更好的生物利用度潜力。紫外可见光谱分析表明，衍生物和在模拟生物流体的溶液中比 CUR 具有更好的稳定性。在一组细胞系上进行测试时，与 CUR 相比，衍生物和在慢性髓系白血病 (CML) 衍生的 K562 细胞系中具有明显的细胞毒性 (IC50 = 0.5 μM)。衍生物对 CML 细胞更具选择性。当以患者血液中 CUR 的平均浓度给药时，衍生物和对细胞周期进程和凋亡起始具有强大的作用，而 CUR 无效。衍生物和的凋亡作用与低坏死有关。此外，衍生物能够逆转对参考药物伊马替尼 (IM) 耐药的 K562 细胞的耐药性。衍生物对 IM 敏感和耐药细胞的细胞毒性与和表达上调、G2/M 期阻滞和触发凋亡有关。总之，衍生物具有优于 CUR 的理化特性和生物学效应，这使我们假设它将来可用于治疗 CML 和对 IM 耐药的 CML 形式，无论是单独使用还是与该药物联合使用。
