64977-04-4Relevant academic research and scientific papers
Hydrogen peroxide-responsive nitrogen mustard anti-tumor pro-drug and preparation method thereof
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Paragraph 0112; 0119-0121, (2019/10/17)
The invention discloses a hydrogen peroxide-responsive nitrogen mustard anti-tumor pro-drug and a preparation method thereof, and belongs to the field of pharmaceutical chemistry. The compound contains an alpha-ketoamide structure and a nitrogen mustard structure, can rapidly respond to H2O2, can be used as the nitrogen mustard anti-tumor pro-drug, has good response effect to H2O2, has high cell selectivity and small toxic and side effects, provides an effective, safe and highly selective anti-tumor drug, enriches the types of nitrogen mustard anti-tumor drugs, and has a good market prospect.
Aromatic nitrogen mustard-based prodrugs: Activity, selectivity, and the mechanism of DNA cross-linking
Chen, Wenbing,Han, Yanyan,Peng, Xiaohua
, p. 7410 - 7418 (2014/06/23)
Three novel H2O2-activated aromatic nitrogen mustard prodrugs (6-8) are reported. These compounds contain a DNA alkylating agent connected to a H2O2-responsive trigger by different electron-withdrawing linkers so that they are inactive towards DNA but can be triggered by H2O2 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 2O2. 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, H2O2 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 1μM, 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. H2O2-triggered alkylating agents: H2O 2-triggered DNA cross-linking agents were developed. The activity of the aromatic nitrogen mustard prodrugs is masked by introducing an electron-withdrawing linker unit that sufficiently deactivates the nitrogen mustard, whereas H2O2 triggered the conversion of the electron-withdrawing group to a donating group, releasing the active species, which effectively cross-linked DNA (see scheme).
