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

Article abstract of DOI:10.1002/recl.19931120216

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.