Aliphatic amine N-oxides of DNA binding agents as bioreductive drugs.
The DNA binding and cytotoxicity of four intercalating agents, namely bis-alkylamino (-N(CH2)2N(CH3)2) substituted anthraquinone, anthrapyrazole and anthracene, and mono (N(CH2)2N(CH3)2) acridinone, have been compared with their respective aliphatic amine N-oxides -N(CH2)2N+(O-)(CH3)2. The results show that, unlike the intercalators, the N-oxides do not bind to DNA. Molecular modelling illustrates that the delta + nature of the intercalator alkylamino side chains in the protonated form allows for an attractive electrostatic interaction with phosphates of the DNA backbone, whereas the delta- partial charge on the N-oxide makes such an interaction not permissible; indeed, the electrostatic interaction with the DNA phosphates will be repulsive. The N-oxides show little or no cytotoxicity against V79 cells at concentrations equimolar to the IC90 (concentration that inhibits 90% of cell proliferation) of the respective intercalators. However, the cytotoxicity of anthrapyrazole N-oxide against hypoxic V79 cells in the presence of an activating system of S9 liver fraction was enhanced significantly. The results indicate that N-oxides of DNA-affinic agents have potential as bioreductive prodrugs, since they possess low aerobic toxicity but under hypoxic conditions can be metabolised to a potent cytotoxic species presumed to be a DNA-binding tertiary amine.
Patterson
L H
LH
Department of Pharmacy, School of Applied Sciences, De Montfort University, Leicester, UK.
Craven
M R
MR
Fisher
G R
GR
Teesdale-Spittle
P
P
D000588:Amines / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology*; D002417:Cattle; D002478:Cells, Cultured; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D004273:DNA, Neoplasm / Q000187:drug effects* / Q000378:metabolism*; D007364:Intercalating Agents / Q000378:metabolism* / Q000494:pharmacology*; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010087:Oxides / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000588:Amines; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007364:Intercalating Agents; D010087:Oxides