Center of Drug Discovery, China Pharmaceutical University, Nanjing, PR China.
Org Biomol Chem. 2012 May 21;10(19):3882-91. doi: 10.1039/c2ob25252j. Epub 2012 Apr 4.
A series of O(2)-glycosylated diazeniumdiolate-based derivatives of oleanolic acid (4-19) were synthesized and their anti-human hepatocellular carcinoma (HCC) activities were evaluated. Compound 6 selectively inhibited HCC, but not non-tumor liver cell proliferation. This inhibition was attributed to high levels of nitric oxide (NO) released in HCC cells. Importantly, 6 exhibited low acute toxicity (LD(50) = 173.3 mg kg(-1)) and potent inhibition of HCC tumor growth in mice (3 mg kg(-1) iv). Furthermore, 6 induced HCC cell apoptosis, which was accompanied by lower mitochondrial membrane potentials and Bcl2 expression, but with higher cytochrome C release, Bax, caspase 3 and 9 expression activities in HCC cells. Collectively, 6 may be a promising candidate drug for the intervention of HCC.
一系列以齐墩果酸为母体的 O(2)-糖基化重氮二酮类化合物（4-19）被合成，并评估了它们对人肝癌（HCC）的活性。化合物 6 选择性地抑制 HCC，但不抑制非肿瘤性肝细胞增殖。这种抑制作用归因于 HCC 细胞中释放的高水平一氧化氮（NO）。重要的是，6 表现出低的急性毒性（LD(50) = 173.3 mg kg(-1))，并能有效抑制小鼠 HCC 肿瘤生长（3 mg kg(-1)iv）。此外，6 诱导 HCC 细胞凋亡，伴随着更低的线粒体膜电位和 Bcl2 表达，但伴随着更高的细胞色素 C 释放、Bax、caspase 3 和 9 的表达活性。总的来说，6 可能是一种有前途的 HCC 干预候选药物。
