Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, 3210 North Cramer Street, Milwaukee, Wisconsin 53211, USA.
J Am Chem Soc. 2011 Dec 7;133(48):19278-81. doi: 10.1021/ja2073824. Epub 2011 Nov 10.
The major concern for anticancer chemotherapeutic agents is the host toxicity. The development of anticancer prodrugs targeting the unique biochemical alterations in cancer cells is an attractive approach to achieve therapeutic activity and selectivity. We designed and synthesized a new type of nitrogen mustard prodrug that can be activated by high level of reactive oxygen species (ROS) found in cancer cells to release the active chemotherapy agent. The activation mechanism was determined by NMR analysis. The activity and selectivity of these prodrugs toward ROS was determined by measuring DNA interstrand cross-links and/or DNA alkylations. These compounds showed 60-90% inhibition toward various cancer cells, while normal lymphocytes were not affected. To the best of our knowledge, this is the first example of H(2)O(2)-activated anticancer prodrugs.
抗癌化学治疗剂的主要关注点是宿主毒性。针对癌细胞中独特的生化改变开发抗癌前药是实现治疗活性和选择性的一种有吸引力的方法。我们设计并合成了一种新型氮芥前药，它可以被癌细胞中高水平的活性氧（ROS）激活，从而释放活性化疗药物。通过 NMR 分析确定了激活机制。通过测量 DNA 链间交联和/或 DNA 烷基化来确定这些前药对 ROS 的活性和选择性。这些化合物对各种癌细胞的抑制率达到 60-90%，而正常淋巴细胞不受影响。据我们所知，这是首例 H2O2 激活的抗癌前药。
