State Key Laboratory of National Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
State Key Laboratory of National Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, China.
Chin J Nat Med. 2017 Dec;15(12):928-937. doi: 10.1016/S1875-5364(18)30009-8.
Considering that high levels of nitric oxide (NO) exert anti-cancer effect and the derivatives of oleanolic acid (OA) have shown potent anti-cancer activity, new O-vinyl diazeniumdiolate-based NO releasing derivatives (5a-l, 11a-l) of OA were designed, synthesized, and biologically evaluated in the present study. These derivatives could release different amounts of NO in liver cells. Among them, 5d, 5i, 5j, 11g, 11h, and 11j released more NO in SMMC-7721 cells and displayed stronger proliferative inhibition against SMMC-7721 and HepG2 cells than OA and other tested compounds. The most active compound 5j showed almost 20-fold better solubility than OA in aqueous solution, released larger amounts of NO in liver cancer cells than that in normal ones, and exhibited potent anti-hepatocellular carcinoma activity but little effect on the normal liver cells. The inhibitory activity against the cancer cells was significantly diminished upon addition of an NO scavenger, suggesting that NO may contribute, at least in part, to the activity of 5j.
考虑到高水平的一氧化氮（NO）具有抗癌作用，而齐墩果酸（OA）的衍生物也表现出很强的抗癌活性，本研究设计、合成了新的基于 O-乙烯基重氮二氧杂环丁烷的 OA 的 NO 释放衍生物（5a-l，11a-l），并在肝细胞中进行了生物评价。这些衍生物可以在肝细胞中释放不同量的 NO。其中，化合物 5d、5i、5j、11g、11h 和 11j 在 SMMC-7721 细胞中释放更多的 NO，对 SMMC-7721 和 HepG2 细胞的增殖抑制作用强于 OA 和其他测试化合物。最具活性的化合物 5j 在水溶液中的溶解度比 OA 提高了近 20 倍，在肝癌细胞中释放的 NO 量大于正常细胞，对正常肝细胞几乎没有影响，具有很强的抗肝癌活性。加入一氧化氮清除剂后，对癌细胞的抑制活性显著降低，表明一氧化氮可能至少部分参与了 5j 的活性。
