Hydrogen Peroxide Inducible DNA Cross-Linking Agents: Targeted Anticancer Prodrugs

Abstract

The major concern for anticancer chemotherapeutic agents is the host toxicity. The development of anti-cancer prodrugs targeting the unique biochemical alterations in cancer cells is an attractive approach to achieve therapeutic activity and selectivity. We designed and synthesized a new type of nitrogen mustard prodrug that can be activated by high level of reactive oxygen species (ROS) found in cancer cells to release the active chemotherapy agent. The activation mechanism was determined by NMR analysis. The activity and selectivity of these prodrugs towards ROS was determined by measuring DNA interstrand crosslinks and/or DNA alkylations. These compounds showed 60–90% inhibition toward various cancer cells, while normal lymphocytes were not affected. To the best of our knowledge, this is the first example of H2O2-activated anticancer prodrugs.

Mitochondrial Induced and Self-Monitored Intrinsic Apoptosis by Antitumor Theranostic Prodrug: In Vivo Imaging and Precise Cancer Treatment

“…Boronic esters react with H 2 O 2 , which is present at elevated levels (5 μM to 1.0 mM) in cancer cells and is an ideal target for prodrug activation. 12 Few reports have utilized a ROS-activated prodrug strategy, 13 and none used theranostic agent activation. The specificity of theranostic 7 toward H 2 O 2 and prodrug activation was investigated through spectral changes under physiological conditions with ultraviolet−visible and fluorescent spectroscopy.…”

Fusogenic charge-reversal vector: a viropexis-mimicking system for gene delivery

“…Upon oxidation of the boronic acid group by intracellular ROS (e.g., H 2 O 2 ), which are known to be elevated in cancerous cells [6] and capable of oxidizing benzylboronic acid/esters [7], the quaternary ammonium releases p-hydroxylmethylenephenol (HMP) [8] and becomes a tertiary amine, which self-catalyzes further hydrolysis of the polyacrylic ester into poly(acrylic acid). The second key design is the fusogenic lipid coating.…”

Design, synthesis and biological evaluation of novel sesquiterpene mustards as potential anticancer agents

“…In another strategy, the cytotoxic agent is given in its prodrug form, which is safe to normal cells but selectively activated by certain biochemical mechanisms unique to tumor cells, such as active oxygen species (ROS) [20] and hypoxia [17], resulting in localized cytotoxicity in tumor tissues. However, most efforts have been so far not so significant and there is considerable scope for developing nitrogen mustard drugs with reduced side effects and improved selectivity.…”