Feriotto Giordana, Rondanin Riccardo, Marchetti Paolo, Tagliati Federico, Beninati Simone, Tabolacci Claudio, Grusi Elisa, Aguzzi Serena, Mischiati Carlo
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy.
Department of Neuroscience and Rehabilitation, University of Ferrara, 44121 Ferrara, Italy.
Life (Basel). 2023 Feb 3;13(2):431. doi: 10.3390/life13020431.
Curcumin (CUR) is a natural molecule that is unstable due to the presence of a bis-ketone. To obtain more stable derivatives in biological fluids, the bis-ketone was replaced with pyrazole or O-substituted oximes. Their stability in solution was studied by UV-visible spectrophotometry. The effects on proliferation were studied by MTT assay and/or clonogenicity assay. Induction of apoptosis was evaluated by annexin V staining and Western blot analysis. The bioavailability was obtained from the analysis of the molecular chemical-physical characteristics. The replacement of the bis-ketone with a pyrazole ring or O-substituted oximes improved the stability of all the CUR-derivative molecules. These derivatives were more stable than CUR in solution and were generally cytotoxic on a panel of cancer cell lines tested, and they promoted caspase-dependent apoptosis. Derivative was the most potent in the osteosarcoma (OS) lines. With respect to CUR, this derivative showed cytotoxicity at least three times higher in the MTT assay. In addition, in the clonogenic assay, maintained the activity in conditions of long treatment presumably by virtue of its improved stability in biological fluids. Notably, should have improved chemical-physical characteristics of bioavailability with respect to CUR, which should allow for reaching higher blood levels than those observed in the CUR trials. In conclusion, should be considered in future clinical studies on the treatment of OS, either alone or in combination with other medications currently in use.
姜黄素（CUR）是一种天然分子，由于存在双酮结构而不稳定。为了在生物流体中获得更稳定的衍生物，将双酮替换为吡唑或O-取代肟。通过紫外可见分光光度法研究了它们在溶液中的稳定性。通过MTT法和/或克隆形成试验研究了对增殖的影响。通过膜联蛋白V染色和蛋白质印迹分析评估细胞凋亡的诱导情况。生物利用度通过分子化学物理特性分析获得。用吡唑环或O-取代肟取代双酮提高了所有CUR衍生物分子的稳定性。这些衍生物在溶液中比CUR更稳定，并且对一组测试的癌细胞系通常具有细胞毒性，并且它们促进了半胱天冬酶依赖性细胞凋亡。衍生物 在骨肉瘤（OS）细胞系中最有效。相对于CUR，该衍生物在MTT试验中显示出至少高三倍的细胞毒性。此外，在克隆形成试验中， 可能由于其在生物流体中提高的稳定性而在长期治疗条件下保持活性。值得注意的是， 相对于CUR应该具有改善的生物利用度的化学物理特性，这应该允许达到比CUR试验中观察到的更高的血药浓度。总之，在未来关于OS治疗的临床研究中，应单独或与目前使用的其他药物联合考虑使用 。
