Molecular basis of the low activity of antitumor anthracenediones, mitoxantrone and ametantrone, in oxygen radical generation catalyzed by NADH dehydrogenase. Enzymatic and molecular modelling studies.
Synthetic antitumor anthracenedione drugs, in contrast to anthracycline antibiotics, are ineffective in free radical formation in NADH dehydrogenase system. Our results have indicated that neither the reduction potential nor the side chain conformation and the energies of border orbitals (HOMO and LUMO) determine the ability of anthracenediones to stimulate reactive oxygen species formation in NADH dehydrogenase system. It was shown that the distribution of the molecular electrostatic potential (MEP), around the quinone system was crucial for this ability. We have found for non-stimulating anthracenediones that the clouds of positive MEP cover the quinone carbon atoms while for agents effective in stimulating reactive oxygen species formation the clouds of negative MEP cover continuously the aromatic core together with the quinone system.
Tarasiuk
Jolanta
J
Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Gdansk, Poland. tarasiuk@univ.szczecin.pl
Mazerski
Jan
J
Tkaczyk-Gobis
Katarzyna
K
Borowski
Edward
E
D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002384:Catalysis / Q000187:drug effects; D004563:Electrochemistry; D007700:Kinetics; D008942:Mitoxantrone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D009245:NADH Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000880:Anthraquinones; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D008942:Mitoxantrone; D009245:NADH Dehydrogenase; C020182:ametantrone