Electrochemistry of potential bioreductive alkylating quinones : Part 2. Electrochemical properties of 2,5-bis(1-aziridinyl)-3,6-bis(ethoxycarbonylamino)-1,4-benzoquinone and some model compounds

The reduction mechanism of 2,5-bis(1-aziridinyl)-3,6-bis(ethoxycarbonylamino)-1,4-benzoquinone (Diaziquone, AZQ) and several model compounds of the mono- and bis(1-aziridinyl)quinone type at the dropping mercury electrode in aqueous solutions was studied. In addition, the influence of methyl substitution of the aziridinyl moiety at the 2-position on the protonation of the aziridine nitrogen was investigated. Substituent effects on quinone reduction and aziridine protonation prior to and following quinone reduction were studied qualitatively

Electrochemistry of potentially bioreductive alkylating quinones : Part 1. Electrochemical properties of relatively simple quinones, as model compounds of mitomycin- and aziridinylquinone-type antitumour agents

The influence of methyl-, hydroxy and amino substituents on the electrochemical behaviour of simple 1,4-naphtho-and 1,4-benzoquinones, model compounds of many quinoid antitumour agents, in aqueous media was studied. Significant changes in electrochemical behaviour were observed, potentially the result of a change in the electron density of the quinone moiety, pre- or post-protonation of substituents, hydrogen bond formation, tautomerization reactions and steric interactions between the quinone moiety and substituents. The information obtained was of benefit in the elucidation of the reduction mechanisms of quinoid antitumour agents such as aziridnylquinones and mitomycins

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

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 L1210 clonogenic assay and the parameters were obtained. Good linear relationships, however, between antitumor activity in vivo (vs. L1210 leukemic mice and vs. B16 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

Electrochemistry of potentially bioreductive alkylating quinones. Part 3. Quantitative structure-electrochemistry relationships of aziridinylquinones

The concept of bioreductive alkylation as a mechanism of action of aziridinylquinoid anticancer agents has been investigated by the use of electrochemical techniques. Properly substituted aziridinylquinones are activated by an electrochemical step (reduction of the quinone function), followed by protonation of the aziridinyl moiety to the alkylating species. The influence of substitution on quinone reduction, on protonation and on subsequent opening of the aziridines (prior to and after quinone reduction) has been examined. A series of mono- and poly(1-aziridinyl)-quinones has been synthesized and analyzed by direct current (d.c.) polarography. The half-wave potential (E1/2 value of the quinone reduction and the pKred and pKred2 (reflecting the ease of protonation at the mercury electrode of one and two aziridinyl rings, respectively) were used in a Hammett type QSAR analysis. A linear relationship between E1/2 and the electronic substituent constant ¿p was obtained for simple quinones. Deviations from linearity were observed, due to steric and/or resonance interactions which influence quinone reduction, with amino- and halogen-substituted quinones. Unknown ¿p values could be calculated. Relationship between pKred2 and some physical-chemical parameters show that electronic and steric properties of quinone substituents affect pKred2. In addition, the formation of a hydrogen bond between the quinone substituent and the adjacent aziridinyl ring (which may thwart aziridine protonation) and the presence of a methyl substituent at position 2 of the aziridine (which facilitates protonation) are of importance. Results of this study have lead to a better knowledge of the individual substituents with respect to their electronic and steric influences on quinone reduction and aziridine protonation, which may be of importance if these processes play a decisive role in cytostatic activity as well as toxicity