Chemistry and DNA Alkylation Reactions of Aziridinyl Quinones:  Development of an Efficient Alkylating Agent of the Phosphate Backbone

Abstract

Described herein are detailed hydrolytic studies of a series of aziridinyl quinones, which trap nucleophiles when protonated. This study provided a compilation of the rate constants for nucleophile trapping and of the pKa values for the protonated aziridinyl quinones. A linear free energy relationship, including the antitumor agent DZQ, as well as other synthetic quinone derivatives, was obtained as a result of this study. Protonated DZQ has the relatively high pKa value of 3.8, which explains the enhanced cross-linking of DNA by DZQ and other related aziridinyl quinones at pH 4. The literature often shows aziridinyl quinone protonation occurring at the aziridinyl nitrogen, but the dependence of pKa values on quinone substituents indicates the presence of delocalization, which must arise from O-protonation. Also investigated were the DNA alkylation reactions of protonated aziridinyl quinones. At the outset of this study, we postulated that these "hard" electrophiles would alkylate the phosphate backbone of DNA. Bulk DNA is up to 35% alkylated by protonated aziridinyl quinones as judged by the incorporation of the quinone chromophore into the DNA. The presence of phosphate alkylation was verified by a 1H-31P NMR correlation experiment with DZQ-alkylated hexamer. Our modeling studies present a new picture of DZQ alkylation of DNA, where there is competition between N(7) and phosphate alkylation. The conclusions of this part of our study are that the phosphate backbone should be considered as a possible target of any DNA-alkylating agent and that an assessment of phosphate alkylation is best made with a 1H-31P NMR correlation experiment. Finally, the benzimidazole-based aziridinyl quinone 2 was observed to undergo aziridine ring opening followed by hydrolytic removal of the aminoethyl group from the quinone ring. This reaction was used to tag the phosphate backbone of DNA with aminoethyl groups. Such tags render anionic phosphates cationic and could also be employed as points of attachment for chromophores, spin labels, or other moieties to DNA.

Quinone Methide Derivatives: Important Intermediates to DNA Alkylating and DNA Cross-linking Actions

“…Skibo and co-workers recently demonstrated selective phosphate alkylation of nucleic acids with aziridinium derivatives [58]. Turnbull reported the investigation of the reactivity of a p-quinone methide with mildly nucleophilic phosphodiesters as models for nucleic acid polymers (Scheme 23) [59].…”

Characterization of Novel Synthesized Small Molecular Compounds Against Non-Small Cell Lung Cancer

“…Xing and colleagues synthesized aziridinyl quinone antitumor agents using indoles and cyclopent indoles [19–21]. The most lethal compounds are the indole-based systems with a leaving group in the 3 position.…”

Nitrogen-Containing Heterocyclic Quinones: A Class of Potential Selective Antitumor Agents

“…Some of them, 10-14, are reported in (Fig. Hydrolysis of the resulting phosphotriester results in DNA cleavage [21] (Scheme 6). These compounds are reduced by DT-diaphorase and show strong antitumor activity by virtue of their ability to cleave DNA upon reductive alkylation.…”

“…The first step of all these actions relies on the quinone bioreduction which generates electrophilic species toxic to cells. Another structural requirement for the antitumor action is the presence of alkylating centers as well as the presence of good leaving groups [21][22][23]. However, the result of these attempts is somewhat controversial.…”