A series of NO-donating mono- or diester derivatives of brefeldin A were designed, synthesized and biologically evaluated. Some derivatives exhibited potent antiproliferative activity with low IC₅₀ values. The most potent NO-donating hybrid 13b exhibited stronger cytotoxicity against human prostate cancer PC-3 cells, human colon carcinoma HT-29 cells and human liver cancer HepG-2 cells than BFA with IC₅₀ values of 25 nM, 160 nM and 180 nM, respectively. More importantly, compound 13b showed good selectivity between human normal and tumor liver cells with selectivity index of 33. Additionally, 13b released higher levels of NO in HepG-2 cells than L-02 cells. Further mechanism concerning cellular apoptosis showed that 13b induced apoptosis and S phase cell cycle arrest in HepG-2 cells. Incubation with 13b increased the number of HepG-2 cells with collapsed mitochondrial membrane at low concentrations in dose-dependent manner. In addition, by using the Human Apoptosis Protein Array kit, several apoptosis-related proteins, including HO-1, HO-2 and survivin, were found to be markedly downregulated by 13b in HepG-2 cells. Furthermore, in western blot assay, 13b increased the expression of Bax, Cyt c and caspase 3, and reduced the relative levels of Bcl-2, Bcl-xl and pro-caspase 3 in HepG-2 cells.

设计，合成和生物学评估了布雷菲德菌素A的一系列NO供体单酯或二酯衍生物。一些衍生物表现出有效的抗增殖活性，IC ₅₀值低。与BFA相比，最有力的NO捐赠杂种13b对人前列腺癌PC-3细胞，人结肠癌HT-29细胞和人肝癌HepG-2细胞具有更强的细胞毒性，IC ₅₀值分别为25 nM，160 nM和180 nM ， 分别。更重要的是，化合物13b在人正常肝细胞和肿瘤肝细胞之间显示出良好的选择性，选择性指数为33。此外，13b在HepG-2细胞中释放的NO水平要高于L-02细胞。有关细胞凋亡的进一步机制表明13b诱导了HepG-2细胞的凋亡和S期细胞周期停滞。与13b一起温育以剂量依赖的方式增加了低浓度时线粒体膜塌陷的HepG-2细胞的数量。此外，通过使用人类凋亡蛋白阵列试剂盒，发现了一些凋亡相关蛋白，包括HO-1，HO-2和survivin，在HepG-2细胞中被13b明显下调。此外，在蛋白质印迹试验中，13b增加了HepG-2细胞中Bax，Cyt c和caspase 3的表达，并降低了Bcl-2，Bcl-xl和前胱天蛋白酶3的相对水平。