State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, 210009, China.
Org Biomol Chem. 2012 Apr 28;10(16):3288-99. doi: 10.1039/c2ob07088j. Epub 2012 Mar 12.
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 IC(50) 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.
受简化笼状黄烷酮治疗潜力的启发，我们开发了一种通过区域选择性 Claisen/Diels-Alder 级联反应合成新型氮杂笼状藤黄类似物的化学策略。使用 DFT 方法解释了区域选择性的起源。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，氮杂笼状支架提供了合适的修饰位点，引入疏水性部分可提高细胞毒性和 IKKβ抑制活性。氮杂笼状化合物 6c 对 HepG2、A549 细胞和 IKKβ的 IC50 值分别为 2.68、2.10、8.02 μM。用 6c 进行的机制研究表明，氮杂笼状化合物在 A549 细胞中诱导细胞凋亡和细胞周期 S 期阻滞。
