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, PR 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, PR China.
Eur J Med Chem. 2018 Dec 5;160:1-8. doi: 10.1016/j.ejmech.2018.10.013. Epub 2018 Oct 6.
To develop multifunctional drugs, a series of celastrol/NO donor hybrids were designed, synthesized and evaluated. The detection of NO release amounts showed that the more NO of these hybrids released, the more tumor cells were inhibited. 11b, which released the highest level of NO in vitro, exhibited superior potency (IC = 0.48 ± 0.06 μM) compared to the other compounds. Further pharmacological studies showed that 11b induced dysregulations of the Hsp90 clients (Akt and Cdk4), apoptosis, and cell cycle arrested at G/G phase against A549 cells. These results suggested that inhibition of Hsp90 and release of NO was synergistic in cancer cells. Overall, the NO-releasing capacity and the inhibition of Hsp90 pathway signaling might explain the potent anti-proliferative activities of these compounds.
为了开发多功能药物，设计、合成并评价了一系列雷公藤红素/NO 供体杂化物。NO 释放量的检测表明，这些杂化物释放的 NO 越多，肿瘤细胞的抑制作用越强。在体外释放最高水平 NO 的 11b 与其他化合物相比表现出更强的效力（IC=0.48±0.06μM）。进一步的药理研究表明，11b 诱导 Hsp90 客户（Akt 和 Cdk4）失调、凋亡和细胞周期停滞在 G/G 期，从而抑制 A549 细胞。这些结果表明，Hsp90 的抑制和 NO 的释放在癌细胞中具有协同作用。总的来说，NO 的释放能力和 Hsp90 通路信号的抑制可能解释了这些化合物具有强大的抗增殖活性。
