作者:Xiaojin Zhang、Xiang Li、Haopeng Sun、Zhengyu Jiang、Lei Tao、Yuan Gao、Qinglong Guo、Qidong You
DOI:10.1039/c2ob07088j
日期:——
Inspired by the therapeutic potential of the simplified caged xanthones, we have developed a chemical strategy for synthesizing novel aza-caged Garcinia analogues through a regioselective Claisen/Diels–Alder cascade reaction. The origin of regioselectivity has been explained using the DFT method. We have further evaluated the cell proliferation and IKKβ inhibitory activities of these compounds and studied their binding mode with IKKβ by molecular docking. The results suggested that the aza-caged scaffold provides a suitable modification site and the introduction of a hydrophobic moiety leads to improvement in the cytotoxicity and IKKβ inhibitory activity. The aza-caged compound 6c exhibited an IC50 value of 2.68, 2.10, 8.02 μM against the HepG2, A549 cells and IKKβ, respectively. Mechanism studies with 6c showed that the aza-caged compounds induce apoptosis and cell cycle S phase arrest in A549 cells.
受简化笼型呫吨酮治疗潜力的启发,我们开发了一种化学策略,通过区域选择性Claisen/Diels-Alder串联反应合成新颖的氮笼型藤黄模拟物。区域选择性的起源已通过DFT方法解释。我们进一步评估了这些化合物的细胞增殖和IKKβ抑制活性,并通过分子对接研究了它们与IKKβ的结合模式。结果表明,氮笼型骨架提供了合适的修饰位点,疏水基团的引入提高了细胞毒性和IKKβ抑制活性。氮笼型化合物6c对HepG2、A549细胞和IKKβ的IC50值分别为2.68、2.10、8.02 μM。6c的机理研究表明,氮笼型化合物诱导A549细胞凋亡和细胞周期S期阻滞。