Toward Hypoxia-Selective DNA-Alkylating Agents Built by Grafting Nitrogen Mustards onto the Bioreductively Activated, Hypoxia-Selective DNA-Oxidizing Agent 3-Amino-1,2,4-benzotriazine 1,4-Dioxide (Tirapazamine)

Abstract

Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide) is a heterocyclic di-N-oxide that undergoes enzymatic deoxygenation selectively in the oxygen-poor (hypoxic) cells found in solid tumors to generate a mono-N-oxide metabolite. This work explored the idea that the electronic changes resulting from the metabolic deoxygenation of tirapazamine analogues might be exploited to activate a DNA-alkylating species selectively in hypoxic tissue. Toward this end, tirapazamine analogues bearing nitrogen mustard units were prepared. In the case of the tirapazamine analogue 18a bearing a nitrogen mustard unit at the 6-position, it was found that removal of the 4-oxide from the parent di-N-oxide to generate the mono-N-oxide analogue 17a did indeed cause a substantial increase in reactivity of the mustard unit, as measured by hydrolysis rates and DNA-alkylation yields. Hammett sigma values were measured to quantitatively assess the magnitude of the electronic changes induced by metabolic deoxygenation of the 3-amino-1,2,4-benzotriazine 1,4-dioxide heterocycle. The results provide evidence that the 1,2,4-benzotiazine 1,4-dioxide unit can serve as an oxygen-sensing prodrug platform for the selective unmasking of bioactive agents in hypoxic cells.

Tirapazamine has no Effect on Hepatotoxicity of Cisplatin and 5‐fluorouracil but Interacts with Doxorubicin Leading to Side Changes in Redox Equilibrium

“…As mentioned above, tirapazamine displays a several dozen, even a hundred higher cytotoxicity towards many cancers in anaerobic as compared to aerobic conditions [1,2]. Interestingly, under normoxia, it has a moderate antitumour activity [36,37].…”

“…However, tirapazamine led to an increase in the Absolute incidence of histological abnormalities among control and drug-exposed animals (six animals per group). Scoring system is presented in brackets according to the Dixon system 1 level of lipid peroxidation products, a rise in hepatic NADPH level by several times and elevation HMG-CoA reductase immunoreactivity in rats receiving doxorubicin versus the group of DOX.…”

Novel delivery approaches for cancer therapeutics

“…A hypoxia-selective anti-tumor agent, demonstrated preparation of mono-N-oxide analogue by removal of 4-oxide from tirapazamine (parent di-N-dioxide). It bears a nitrogen mustard unit, which exhibits significant alkylating properties [158]. Peng and group developed H 2 O 2 activated aromatic nitrogen mustard based prodrugs where the DNA alkylating agent is connected to a H 2 O 2 responsive trigger by an electron withdrawing group.…”

Simple, High‐Yield Syntheses of DNA Duplexes Containing Interstrand DNA‐DNA Cross‐Links Between an N4‐Aminocytidine Residue and an Abasic Site

“…Interstrand DNA-DNA cross-links are often studied as critical, medicinally-relevant DNA lesions generated by anticancer chemotherapeutic agents such as cis -platin, carboplatin, bendamustine, or chlorambucil (Cheson and Leoni, 2011; Johnson et al, 2014; Povirk and Shuker, 1994; Rajski and Williams, 1998; Schärer, 2005; Zhu et al, 2013). In addition, there is evidence that some as-yet-unidentified endogenous DNA cross-link(s) may drive human aging (Bergstrahl and Sekelsky, 2007; Niedernhofer et al, 2005).…”