Interactions between potential anti-tumour 2,5-bis(1-aziridinyl)-1,4-benzoquinone derivatives and glutathione: reductive activation, conjugation and DNA damage.
The interaction between glutathione and potential anti-tumour 3,6-disubstituted 2,5-bis(1-aziridinyl)-1,4-benzoquinone (BABQ) derivatives has been studied using u.v. spectrophotometry and h.p.l.c. The formation of BABQ-glutathione adducts was demonstrated in vitro for the BABQ parent compound (TW13), triaziquone (2,3,5-tris(1-aziridinyl)-1,4-benzoquinone) and for BABQ derivatives containing halogen substituents. The clinically-used BABQ derivative diaziquone (AZQ; 2,5-bis(1-aziridinyl)-3,6-bis(ethoxycarbonylamino)-1,4-benzoquinon e) did not react with glutathione. TW13 and triaziquone markedly inactivated bacteriophage M13-DNA in the presence of glutathione. This inactivation is probably produced by reductive activation of the BABQ derivative to a DNA-alkylating semiquinone radical. However, formation of bulky glutathione adducts decreases reactivity to DNA. Halogen-substituted BABQ derivatives react rapidly with glutathione to form adducts. This appeared to prevent DNA alkylation by these compounds. Comparison of these results with in vivo and in vitro activity against tumour models (L1210) suggests that in vivo halogen-substituted BABQ derivatives are efficiently inactivated by glutathione conjugation. The differences between the halogen-substituted BABQ derivatives on the one hand and TW13 and triaziquone on the other hand are probably caused by a difference in reaction mechanism with glutathione. From the viewpoint of drug design, halogen-substituted BABQ derivatives are expected to be inactive anti-tumour agents, in spite of high reactivity and activity in tumour models in vitro.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Utrecht University, The Netherlands.
K J
KJ
Lusthof
N J
NJ
de Mol
L H
LH
Janssen
B
B
Prins
W
W
Verboom
D N
DN
Reinhoudt
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001388:Aziridines / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D004249:DNA Damage; D004269:DNA, Bacterial / Q000187:drug effects*; D004347:Drug Interactions; D004926:Escherichia coli; D005978:Glutathione / Q000378:metabolism / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000378:metabolism; D051379:Mice; D011809:Quinones / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014228:Triaziquone / Q000494:pharmacology
D000970:Antineoplastic Agents; D001388:Aziridines; D004269:DNA, Bacterial; D011809:Quinones; D014228:Triaziquone; D005978:Glutathione