Electrochemistry of potential bioreductive alkylating quinones

Driebergen, R. J.; Holthuis, J.J.M.; Blauw, J.S.; Kelder, S.J. Postma; Verboom, Willem; Reinhoudt, David N.; Linden, Willem J. van der

doi:10.1016/s0003-2670(00)83570-9

Cited by 21 publications

(6 citation statements)

References 19 publications

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“…The structure of the protonated aziridinyl quinone is considered to be an O-protonated species, the cation of which would be stabilized by delocalization. In contrast an Nprotonated species, which is not capable of delocalization, was previously proposed for the protonated aziridinyl quinone (32,36,37). The results provided below are consistent with O-protonation because the pK a is very sensitive to the quinone ring system structure (naphtho- quinone, benzoquinone, indoloquinone, benzimidazoquinone) and substituents, suggesting the presence of delocalization.…”

Section: Resultssupporting

confidence: 83%

“…A linear free energy relationship obtained as a result of this study readily distinguishes between these mechanisms. The literature often shows aziridinyl quinone protonation occurring at the aziridinyl nitrogen (33,37,41), but the dependence of pK a values on quinone substituents indicates the presence of delocalization, which must arise from O-protonation. Protonated DZQ has the relatively high pK a value of 3.8, which is supported by both direct measurement and the linear free energy relationship.…”

Section: Discussionmentioning

confidence: 99%

“…TLC (CHCl 3 /MeOH, 95:5) R f ) 0.50; IR (KBr pellet) 3447, 3240, 2926, 2362, 1655, 1618, 1508, 1284, 1148, 754 cm -1 ; 1 H NMR (CDCl 3 ) δ 9.61 (1H, bs, indole proton), 5.61 (1H, bs, amino NH), 3.79 (2H, q, J ) 6 Hz, methylene), 3.65 (2H, t, J ) 6.0 Hz methylene), 2.26, 2.24, and 2.03 (9H, 3s, methyls); MS (EI mode) m/z 266 and 268 (M + with35 Cl,37 Cl), 230 (M + -HCl), 215, 189. Anal.…”

mentioning

confidence: 99%

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

Skibo

Xing

1998

Biochemistry

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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.

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Section: Resultssupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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

Skibo

Xing

1998

Biochemistry

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“…The change of the standard Gibbs energy of reaction (3) can be computed using the thermodynamic cycle that is shown in Fig. 1 [10]. From this cycle, DG 0 is computed by the following expression:…”

Section: Methods and Theoretical Considerationsmentioning

confidence: 99%

“…Some of these molecules have recently been suggested as a new type of agent whose bioreductive activity would depend on a two-electron reduction. Therefore, it is essential to be able to predict the redox potentials and the chemical modifications needed to produce the optimum redox value [5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Prediction of one-electron electrode potentials of some quinones in dimethylsulfoxide

Namazian

Norouzi

2004

Journal of Electroanalytical Chemistry

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Electrochemistry of potentially bioreductive alkylating quinones. Part 4. Qualitative and quantitative structure‐activity relationships of aziridinylquinones

Driebergen

Moret

Janssen

et al. 1993

Recl. Trav. Chim. Pays‐Bas

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Abstract. The concept of bioreductive alkylation as a mechanism of action of aziridinylquinoid anticancer agents has been investigated. The influence of quinone substituents on quinone reduction, on protonation of the aziridines prior to and following quinone reduction and on partitioning properties of the compound was examined. Parameters obtained from a combined electrochemical, chemical-stability and lipophilicity study describing these processes were determined and correlated quantitatively in a Hansch-type QSAR study with biological data obtained from three experimental tumor models. Poor quantitative correlations between cytotoxicity in a L, ,,) clonogenic assay and the parameters were obtained. Good linear relationships, however, between antitumor activity in vivo (vs. L,,,,, leukemic mice and vs. B,, melanoma-bearing mice) and the lipophilic properties of the quinone were found. These relationships, showing a negative correlation between antitumor activity and lipophilicity, can be used to predict the activity of new, unknown compounds. No trend was evident between antitumor activity and other parameters, although some indications for potential importance of electronic and steric properties of the substituents and of their ability to form hydrogen bonds were found.

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Electrochemistry of potential bioreductive alkylating quinones

Cited by 21 publications

References 19 publications

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

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

Prediction of one-electron electrode potentials of some quinones in dimethylsulfoxide

Electrochemistry of potentially bioreductive alkylating quinones. Part 4. Qualitative and quantitative structure‐activity relationships of aziridinylquinones

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