ABSTRACT
Several derivatives of 2,5-diaziridinyl-3-phenyl-1,4-benzoquinone have been synthesized and their cytotoxicities in six different human cancer cell lines (H460, H596, HT29, BE, K562 and A2780) have been determined. It was observed that certain phenol-ester derivatives were significantly more cytotoxic in all of the cell lines investigated. These esters were shown to be cleaved by esterases to form a stable meta-phenol and an unstable para-phenol. The meta-phenol was also highly cytotoxic. Several of these compounds were studied in detail using DNA cross-linking, clonogenic, apoptosis and flow cytometry assays. It is proposed that although the phenol-esters and the phenols can efficiently cross-link DNA, this mechanism alone is not sufficient to explain the toxicities of these compounds.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzoquinones/chemical synthesis , Benzoquinones/pharmacology , Esters/chemical synthesis , Esters/pharmacology , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Survival/drug effects , Chromatography, High Pressure Liquid , Clone Cells/drug effects , Cross-Linking Reagents , Electrophoresis , Esterases/chemistry , Flow Cytometry , Humans , Indicators and Reagents , Molecular Conformation , NAD(P)H Dehydrogenase (Quinone)/metabolism , Stereoisomerism , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
The cytotoxicities and DNA sequence selectivity for guanine-N7 alkylation of 22 mono- and disubstituted 2,5-diaziridinyl-1,4-benzoquinones have been investigated. Several quinones produced patterns of alkylation following reduction with a selectivity for 5'-TGC-3' sequences. This sequence selectivity appeared to be dependent only on the presence of a hydrogen in position-6 of the quinone. A computer model, based on published crystallographic data, was used to explain this selectivity. The sequence selective quinones were generally more cytotoxic that the quinones which reacted randomly.
Subject(s)
Antineoplastic Agents, Alkylating/pharmacology , Aziridines/pharmacology , Benzoquinones/pharmacology , Cross-Linking Reagents/pharmacology , DNA/metabolism , Alkylation , Antineoplastic Agents, Alkylating/chemistry , Antineoplastic Agents, Alkylating/metabolism , Aziridines/chemistry , Aziridines/metabolism , Benzoquinones/chemistry , Benzoquinones/metabolism , Cell Survival/drug effects , Computer Simulation , Cross-Linking Reagents/chemistry , Cross-Linking Reagents/metabolism , DNA/chemistry , Electrophoresis, Polyacrylamide Gel , Guanine/metabolism , Humans , Magnetic Resonance Spectroscopy , Mass Spectrometry , Models, Molecular , Nucleic Acid Conformation , Tumor Cells, CulturedABSTRACT
The cytotoxicities and DNA cross-linking abilities of 16 1,4-benzoquinones have been investigated. All of the alkylmonoaziridinyl-1,4-benzoquinones were able to interstrand crosslink DNA after reduction and were cytotoxic in vitro. Compounds lacking an aziridine group were unable to cross-link DNA and were less cytotoxic. The methyl analogues were shown to preferentially react at TGC sequences. From comparing the structural requirements for crosslinking and the cytotoxicities, a mechanism has been proposed wherein some hydroquinones can associate and react at TGC sequences in DNA. These hydroquinones can subsequently autoxidize to form a reactive quinone methide which reacts at the opposite strand to form a cross-link.
