Antitumor activity of JS-K [O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] and related O2-Aryl diazeniumdiolates in vitro and in vivo
Antitumor activity of JS-K [O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] and related O2-Aryl diazeniumdiolates in vitro and in vivo
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DOI：
10.1021/jm060022h
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发表时间：
2006-07-13
影响因子：
7.3
通讯作者：
Keefer, Larry K.
中科院分区：
文献类型：
--
作者：
Shami, Paul J.;Saavedra, Joseph E.;Keefer, Larry K.
文献提供了代谢性一氧化氮（NO）释放介导JS-K的细胞毒性活性（针对小鼠中的人白血病和前列腺癌异种移植物）的证据，JS-K是结构R2 N-（O）=NO-Ar的化合物，其中R2 N是4-（乙氧基羰基）哌嗪-1-基，Ar是2，4-二硝基苯基。在这里，我们提出了比较数据的效力JS-K和其他41个O-2-arylated diazeniumdiolates作为HL-60人白血病细胞增殖的抑制剂，以及在NCI 51细胞系筛选其中六个。数据显示，JS-K在两种筛选中都是42种中最有效的，并表明其结构和代谢的其他特征，除了NO释放外，可能对其活性有重要贡献。对照化合物的结果暗示了JS-K的芳基化能力，并且NO释放的N-（乙氧基羰基）哌嗪副产物的令人惊讶的低IC 50值表明R2 N部分的作用。除了上述体内活性外，JS-K在大鼠肝癌模型中显示出抑癌性。
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 R2N-(O)=NO-Ar for which R2N 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 IC50 value of the N-(ethoxycarbonyl) piperazine byproduct of NO release suggests a role for the R2N moiety. In addition to the above-mentioned in vivo activities, JS-K is shown here to be carcinostatic in a rat liver cancer model.