Shami Paul J, Saavedra Joseph E, Bonifant Challice L, Chu Jingxi, Udupi Vidya, Malaviya Swati, Carr Brian I, Kar Siddhartha, Wang Meifeng, Jia Lee, Ji Xinhua, Keefer Larry K
Department of Internal Medicine, Division of Medical Oncology, University of Utah, Salt Lake City, 84112, USA.
J Med Chem. 2006 Jul 13;49(14):4356-66. doi: 10.1021/jm060022h.
The literature provides evidence that metabolic nitric oxide (NO) release mediates the cytotoxic activities (against human leukemia and prostate cancer xenografts in mice) of JS-K, a compound of structure R(2)N-N(O)=NO-Ar for which R(2)N is 4-(ethoxycarbonyl)piperazin-1-yl and Ar is 2,4-dinitrophenyl. Here we present comparative data on the potencies of JS-K and 41 other O(2)-arylated diazeniumdiolates as inhibitors of HL-60 human leukemia cell proliferation, as well as in the NCI 51-cell-line screen for six of them. The data show JS-K to be the most potent of the 42 in both screens and suggest that other features of its structure and metabolism besides NO release may contribute importantly to its activity. Results with control compounds implicate JS-K's arylating ability, and the surprisingly low IC(50) value of the N-(ethoxycarbonyl)piperazine byproduct of NO release suggests a role for the R(2)N moiety. In addition to the above-mentioned in vivo activities, JS-K is shown here to be carcinostatic in a rat liver cancer model.
文献表明，代谢性一氧化氮（NO）释放介导了JS-K（一种结构为R(2)N-N(O)=NO-Ar的化合物，其中R(2)N为4-(乙氧羰基)哌嗪-1-基，Ar为2,4-二硝基苯基）对小鼠体内人白血病和前列腺癌异种移植瘤的细胞毒性活性。在此，我们给出了JS-K与其他41种O(2)-芳基化二氮烯二醇盐作为HL-60人白血病细胞增殖抑制剂的效力比较数据，以及其中6种在NCI 51细胞系筛选中的数据。数据显示，在这两种筛选中，JS-K都是42种化合物中效力最强的，这表明除了NO释放外，其结构和代谢的其他特征可能对其活性有重要贡献。对照化合物的结果表明了JS-K的芳基化能力，并且NO释放的副产物N-(乙氧羰基)哌嗪令人惊讶的低IC(50)值表明R(2)N部分发挥了作用。除上述体内活性外，本文还表明JS-K在大鼠肝癌模型中具有抗癌作用。
