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Aromatic Nitrogen Mustard‐Based Prodrugs: Activity, Selectivity, and the Mechanism of DNA Cross‐Linking
Author(s) -
Chen Wenbing,
Han Yanyan,
Peng Xiaohua
Publication year - 2014
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201400090
Subject(s) - chemistry , nitrogen mustard , dna , adduct , alkylation , selectivity , linker , stereochemistry , prodrug , cytotoxicity , medicinal chemistry , in vitro , biochemistry , organic chemistry , medicine , surgery , chemotherapy , computer science , catalysis , operating system , cyclophosphamide
Three novel H 2 O 2 ‐activated aromatic nitrogen mustard prodrugs ( 6 – 8 ) are reported. These compounds contain a DNA alkylating agent connected to a H 2 O 2 ‐responsive trigger by different electron‐withdrawing linkers so that they are inactive towards DNA but can be triggered by H 2 O 2 to release active species. The activity and selectivity of these compounds towards DNA were investigated by measuring DNA interstrand cross‐link (ICL) formation in the presence or absence of H 2 O 2 . An electron‐withdrawing linker unit, such as a quaternary ammonia salt ( 6 ), a carboxyamide ( 7 ), and a carbonate group ( 8 ), is sufficient to deactivate the aromatic nitrogen mustard resulting in less than 1.5 % cross‐linking formation. However, H 2 O 2 can restore the activity of the effectors by converting a withdrawing group to a donating group, therefore increasing the cross‐linking efficiency (>20 %). The stability and reaction sites of the ICL products were determined, which revealed that alkylation induced by 7 and 8 not only occurred at the purine sites but also at the pyrimidine site. For the first time, we isolated and characterized the monomer adducts formed between the canonical nucleosides and the aromatic nitrogen mustard ( 15 ) which supported that nitrogen mustards reacted with dG, dA, and dC. The activation mechanism was studied by NMR spectroscopic analysis. An in vitro cytotoxicity assay demonstrated that compound 7 with a carboxyamide linker dramatically inhibited the growth of various cancer cells with a GI 50 of less than 1 μ M , whereas compound 6 with a charged linker did not show any obvious toxicity in all cell lines tested. These data indicated that a neutral carboxyamide linker is preferable for developing nitrogen mustard prodrugs. Our results showed that 7 is a potent anticancer prodrug that can serve as a model compound for further development. We believe these novel aromatic nitrogen mustards will inspire further and effective applications.