Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, USA.
ChemMedChem. 2011 May 2;6(5):869-75. doi: 10.1002/cmdc.201100014. Epub 2011 Mar 4.
DNA-modifying agents are stalwarts of chemotherapeutic cancer treatments, but require significant design improvements to improve selectivity, minimize side effects, and for their widespread use to continue. Herein we present a novel design strategy in which DNA-modifying agents contain an oxidizable leaving group and a nitrogen mustard. The agents form strong electrophiles specifically when oxidized. Activation, measured by hydrolysis, illustrates that oxidants increase reactivity 1700-fold. Reaction in the presence of 2'-deoxyguanosine leads to the formation of lesions. Cytotoxicity measured in HeLa cells showed that low IC(50) values require an oxidizable hydroquinone and a nitrogen mustard fragment. Cytotoxicity measurements in 15 cancer cell lines demonstrates that oxidatively activated DNA-modifying agents are highly selective, as the analogue tested has IC(50) values less than 10 μM for only three of the 15 cell lines; in contrast, cisplatin is highly toxic to 13 of the 15 cell lines. The selective cytotoxicity of oxidatively activated DNA-damaging agents could be useful against kidney cancer cells, as the 786-O cell line model assay resulted in an IC(50) value of 5 μM.
DNA 修饰剂是化疗癌症治疗的中流砥柱，但需要进行重大的设计改进，以提高选择性、最小化副作用，并继续广泛应用。在此，我们提出了一种新的设计策略，其中 DNA 修饰剂包含可氧化的离去基团和氮芥。这些试剂在氧化时特别形成强亲电试剂。通过水解测量的活化表明，氧化剂将反应性提高了 1700 倍。在 2'-脱氧鸟嘌呤存在下的反应导致形成损伤。在 HeLa 细胞中测量的细胞毒性表明，低 IC（50）值需要可氧化的对苯二酚和氮芥片段。在 15 种癌细胞系中的细胞毒性测量表明，氧化激活的 DNA 修饰剂具有高度的选择性，因为测试的类似物对于 15 种细胞系中的仅三种具有小于 10 μM 的 IC（50）值；相比之下，顺铂对 13 种细胞系具有高度毒性。氧化激活的 DNA 损伤剂的选择性细胞毒性可能对肾癌细胞有用，因为 786-O 细胞系模型测定的 IC（50）值为 5 μM。
