Abstract

A series of furoxan derivatives of chromone were prepared. The antiproliferative activities were tested against five cancer cell lines HepG2, MCF-7, HCT-116, B16, and K562, and two normal human cell lines L-02 and PBMCs. Among them, compound 15a exhibited the most potent antiproliferative activity. It was also found 15a produced more than 8 µM of NO at the peak time of 45 min by Griess assay. Generally, antiproliferative activity is positively related to NO release to some extent. Further in-depth studies on apoptosis-related mechanisms showed that 15a caused S-phase cell cycle arrest in a concentration-dependent manner and induced apoptosis significantly through mitochondria-related pathways. Human apoptosis protein array assay also demonstrated 15a increased the expression levels of pro-apoptotic Bax, Bad, HtrA2 and Trail R2/DR5. The expression of catalase and cell cycle blocker claspin were similarly up-regulated. In balance, 15a induced K562 cells death through both endogenous and exogenous pathways.

摘要

制备了一系列色酮的呋喃喃衍生物。测试了针对五种癌细胞系HepG2，MCF-7，HCT-116，B16和K562以及两种正常人细胞系L-02和PBMC的抗增殖活性。在它们之中，化合物15a表现出最有效的抗增殖活性。通过Griess分析还发现15a在45分钟的峰值时间产生了超过8 µM的NO。通常，抗增殖活性在一定程度上与NO的释放呈正相关。对细胞凋亡相关机制的进一步深入研究表明，15a以浓度依赖的方式引起S期细胞周期停滞，并通过线粒体相关途径显着诱导细胞凋亡。人类凋亡蛋白阵列测定也证明了15a增加了促凋亡Bax，Bad，HtrA2和Trail R2 / DR5的表达水平。过氧化氢酶和细胞周期阻滞剂claspin的表达同样被上调。平衡而言，15a通过内源性途径和外源性途径诱导K562细胞死亡。