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Oxidatively Activated DNA‐Modifying Agents for Selective Cytotoxicity
Author(s) -
Li Guorui,
Bell Tiffany,
Merino Edward J.
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100014
Subject(s) - cytotoxicity , chemistry , cisplatin , dna , hela , nitrogen mustard , electrophile , cell culture , biochemistry , dna damage , cancer cell , stereochemistry , combinatorial chemistry , cell , biology , cancer , in vitro , chemotherapy , catalysis , genetics , cyclophosphamide
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 μ M 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 μ M .