TY - JOUR
T1 - Electrochemistry of potentially bioreductive alkylating quinones
T2 - Part 4. Qualitative and quantitative structure-activity relationships of aziridinylquinones
AU - Driebergen, R.J.
AU - Moret, E.E.
AU - Janssen, L.H.M.
AU - Beijnen, J.H.
AU - Holthuis, J.J.M.
AU - Postma Kelder, S.J.
AU - Verboom, W.
AU - Reinhoudt, D.N.
AU - Lelieveld, P.
PY - 1993
Y1 - 1993
N2 - 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.
AB - 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.
M3 - Article
VL - 112
SP - 174
EP - 185
JO - Recueil des travaux chimiques des Pays-Bas
JF - Recueil des travaux chimiques des Pays-Bas
SN - 0165-0513
IS - 2
ER -