Synthesis and Evaluation of Radiolabeled Phosphoramide Mustard with Selectivity for Hypoxic Cancer Cells,ACS Medicinal Chemistry Letters

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Synthesis and Evaluation of Radiolabeled Phosphoramide Mustard with Selectivity for Hypoxic Cancer Cells
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2017-11-09 00:00:00 , DOI: 10.1021/acsmedchemlett.7b00355
Wenting Zhang _{1,

2} , Wei Fan _{1,

2} , Zhengyuan Zhou ₃ , Jered Garrison _{1,

2,

4,

5}

Affiliation

Tumor hypoxia has been widely explored over the years as a diagnostic and therapeutic marker. Herein, we synthesized an alkyne functionalized version of evofosfamide, a hypoxia-selective prodrug. The purpose of this effort was to investigate if this novel 2-nitroimidazole phosphoramide nitrogen mustard (2-NIPAM) retained hypoxia selectivity and could be utilized in radiopharmaceutical development to significantly increase retention of conjugated agents in hypoxic cells. 2-NIPAM demonstrated good hypoxia selectivity with a 62- and 225-fold increase in cytotoxicity toward PC-3 and DU145 human prostate cancer cell lines, respectively, under hypoxic conditions. Radiolabeling of 2-NIPAM with ¹²⁵I was accomplished through a Cu(I)-mediated azide–alkyne cycloaddition reaction. The ¹²⁵I-conjugate demonstrated 13.6 and 17.8% lower efflux rates for DU145 and PC-3 cells, correspondingly, under hypoxic conditions, suggesting that the increased retention is likely due to the known intracellular trapping mechanism. In conclusion, these studies demonstrate the potential of 2-NIPAM in serving as a trapping agent for radiopharmaceutical development.

中文翻译：

放射性标记磷酰胺芥菜对缺氧癌细胞的选择性合成与评价

多年来，肿瘤缺氧已被广泛地用作诊断和治疗标志物。在本文中，我们合成了一种炔烃功能化版本的evofosfamide，它是一种缺氧选择性前药。这项工作的目的是研究这种新型的2-硝基咪唑磷酰胺氮芥（2-NIPAM）是否保留了低氧选择性，并可以用于放射性药物开发中以显着增加结合剂在低氧细胞中的保留。2-NIPAM在低氧条件下对PC-3和DU145人前列腺癌细胞系显示出良好的低氧选择性，对PC-3和DU145人前列腺癌细胞系的细胞毒性分别增加62倍和225倍。用¹²⁵ I放射性标记2-NIPAM是通过Cu（I）介导的叠氮化物-炔烃环加成反应完成的。在¹²⁵I-结合物在缺氧条件下相应地证明DU145和PC-3细胞的外排率降低了13.6和17.8％，这表明保留的增加可能是由于已知的细胞内捕获机制所致。总之，这些研究证明了2-NIPAM在用作放射性药物开发的捕集剂方面的潜力。

更新日期：2017-11-09

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