查尔酮肟衍生物的设计、合成及免疫抑制活性评价。
Design, synthesis, and biological evaluation of chalcone oxime derivatives as potential immunosuppressive agents.
机构信息
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.
出版信息
Bioorg Med Chem Lett. 2012 May 1;22(9):3039-43. doi: 10.1016/j.bmcl.2012.03.080. Epub 2012 Mar 28.
A series of deoxybenzoin oximes were recently reported as potent immunosuppressive agents by our group. In order to continue the original research for potential immunosuppressive agents with high efficacy and low toxicity, we synthesized a series of new chalcone oximes and evaluated them for their cytotoxicities and immunosuppressive activities. Among the synthesized compounds, chalcone oximes 25 and 27 exhibited lower cytotoxicities and higher inhibitory activities on anti-CD3/anti-CD28 co-stimulated lymph node cells than other compounds. Specially, compound 27 displayed 200-fold lower cytotoxicity (CC(50)=2174.39 μM) than cyclosporin A (CC(50)=10.10 μM) and showed SI value (SI=176.69) close to cyclosporin A (SI=154.13). Besides, the preliminary mechanism of inhibition effect of compounds 25 and 27 was also detected by flow cytometry, and the compounds exerted immunosuppressive activities via inducing the apoptosis of activated lymph node cells in a dose dependent manner. Also, the deep mechanism of apoptosis was detected by Western blot analysis.
我们小组最近报道了一系列去氧苯并酮肟类化合物，它们是有效的免疫抑制剂。为了继续寻找高效低毒的潜在免疫抑制剂，我们合成了一系列新型查尔酮肟类化合物，并评价了它们的细胞毒性和免疫抑制活性。在合成的化合物中，查尔酮肟 25 和 27 的细胞毒性较低，对抗 CD3/抗 CD28 共刺激淋巴结细胞的抑制活性较高。特别地，化合物 27 的细胞毒性比环孢素 A（CC(50)=10.10 μM）低 200 倍（CC(50)=2174.39 μM），其 SI 值（SI=176.69）接近环孢素 A（SI=154.13）。此外，还通过流式细胞术检测了化合物 25 和 27 的抑制作用的初步机制，这些化合物通过诱导活化淋巴结细胞凋亡发挥免疫抑制作用，且呈剂量依赖性。此外，通过 Western blot 分析检测了凋亡的深层机制。
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