Synthesis and in vitro evaluation of radioiodinated indolequinones targeting NAD(P)H: Quinone oxidoreductase 1 for internal radiation therapy
Synthesis and in vitro evaluation of radioiodinated indolequinones targeting NAD(P)H: Quinone oxidoreductase 1 for internal radiation therapy
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DOI：
10.1016/j.bmc.2014.09.006
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发表时间：
2014-11-01
影响因子：
3.5
通讯作者：
Mukai, Takahiro
中科院分区：
文献类型：
--
作者：
Sasaki, Junichi;Sano, Kohei;Mukai, Takahiro
NAD(P)H：苯醌氧化还原酶1(NQO1)是一种专有的双电子还原酶，在许多人类实体瘤中高度表达。由于NQO1可以在暴露于电离辐射后立即被诱发，我们的目标是开发一种以NQO1为靶点的放射性标记试剂，以建立一种新的内放射治疗，当与外放射治疗相结合时，放大治疗效果。我们设计了三个NQO1靶向的放射性碘化合物，包括两个醚键化合物([I-125]1和[I-125]2)和一个硫键化合物([I-125]3)，这是基于吲哚喹酮类似物通过堆积效应选择性地结合到NQO1的活性中心上。这些化合物是通过氧化碘去氰化反应成功地制备出来的，放化产率和纯度都很高。在表达NQO1的肿瘤细胞中，[I-125]1和[I-125]2很容易被代谢成p-[I-125]碘苯酚或间-[I-125]碘苯酚和[I-125]I，而[I-125]3在孵育1h后仍有85%以上的初始放射性以完整形式存在。细胞对[I-125]3的摄取显著高于[I-125]1和[I-125]2。[I-125]3的摄取具有特异性，并依赖于NQO1的表达。这些数据表明，以NQO1为靶点的新型放射性碘化合物[I-125]3可以作为一种新型的内辐射剂用于癌症的治疗。(C)2014爱思唯尔有限公司。保留所有权利。
NAD(P)H: quinone oxidoreductase 1 (NQO1) is an obligate two-electron reductase and is highly expressed in many human solid cancers. Because NQO1 can be induced immediately after exposure to ionizing radiation, we aimed to develop an NQO1-targeted radiolabeled agent to establish a novel internal radiation therapy that amplifies the therapeutic effects when combined with external radiation therapy. We designed three NQO1-targeted radioiodinated compounds including two ether linkage compounds ([I-125] 1 and [I-125] 2) and a sulfide linkage compound ([I-125] 3) based on the selective binding of indolequinone analogs to the active site of NQO1 by the stacking effect. These compounds were successfully prepared using an oxidative iododestannylation reaction with high radiochemical yields and purity. In NQO1-expressing tumor cells, [I-125] 1 and [I-125] 2 were readily metabolized to p-[I-125] iodophenol or m-[I-125] iodophenol and [I-125] I , whereas over 85% of the initial radioactivity of [I-125] 3 was observed as an intact form at 1 h after incubation. The cellular uptake of [I-125] 3 was significantly higher than those of [I-125] 1 and [I-125] 2. The uptake of [I-125] 3 was specific and was dependent on the expression of NQO1. These data suggest that the novel NQO1-targeted radioiodinated compound [I-125] 3 could be used as a novel internal radiation agent for the treatment of cancer. (C) 2014 Elsevier Ltd. All rights reserved.