Oxidatively Activated DNA‐Modifying Agents for Selective Cytotoxicity

Abstract

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.

Sensitization of melanoma cells to alkylating agent-induced DNA damage and cell death via orchestrating oxidative stress and IKKβ inhibition

“…On the other hand, recently studies showed that the cytotoxicity of alkylating reagents can be enhanced by ROS, by formation of ROS-activated prodrugs resulting in higher DNA crosslink activity. Peng's group revealed that the prodrugs of nitrogen mustard coupled with an ROS trigger unit can be triggered by H 2 O 2 to release active anticancer drugs with higher DNA crosslink activities, leading to selective toxicity toward primary leukemic lymphocytes but less toxic to normal lymphocytes [32], [33], [34], [35], [36]. In this study, we found that ROS induced by SC-514 enhanced nitrosoureas-induced DNA crosslink and cytotoxicity (Fig.…”

“…Recently studies demonstrated that the cytotoxicity of alkylating reagents can be enhanced by ROS with the effects of enhanced DNA crosslink levels and deleterious DNA damages (e.g., ICL formation or alkylation) [32], [33], [34], [35], [36]. Therefore, we further tested whether ROS would alter the DNA crosslink induced by nitrosoureas.…”

Ruthenium dihydroxybipyridine complexes are tumor activated prodrugs due to low pH and blue light induced ligand release

“…For example, cisplatin has been shown to form cross-links with nucleic acids to halt DNA replication and transcription [1, 2]. A major problem with these agents are so called “off-target” effects wherein non-cancer cells are effected by these DNA modification reactions [3, 4]. This problem generally leads to drug induced toxicity, side effects, and little margin for error between the therapeutic dose and the toxic dose.…”

Investigation of fluorinated and bifunctionalized 3-phenylchroman-4-one (isoflavanone) aromatase inhibitors

“…As a starting point, compounds 1b – e were examined for activity in MCF-7 breast cancer cells using letrozole as a positive control. 18 To examine activity, MCF-7 cells were grown under two different conditions. First, as is standard MCF-7 cells were raised in estrogen, low picomole, which has been shown to increase both estrogen and estrogen receptor content.…”