The role of structural factors of anthraquinone compounds and their quinone-modified analogues in NADH dehydrogenase-catalysed oxygen radical formation.
Anthraquinone compounds belong to the most important class of clinical antitumour agents. However, their use is limited by their peroxidating activity, being the consequence of free radical formation initiated by three oxyreductases. This activity is considered to be the main cause of cardiotoxic effects. The affinity of anthraquinone compounds to these enzymes is an essential factor governing the rate of one-electron transfer and the generation of oxygen radicals. A series of novel derivatives and analogues of natural and synthetic anthraquinones has been examined with the aim of identifying the structural factors essential for the ability to stimulate oxygen radical formation catalysed by NADH dehydrogenase. Functional groups and moieties favouring or disfavouring the interaction of the compounds with the enzyme have been determined. The quinonoid moiety as well as at least two phenolic groups in peri positions favoured the affinity of these compounds for NADH dehydrogenase. The modification of the quinonoid structure to iminoquinonoid or carboquinonoid forms dramatically decreased interaction with the enzyme. The O'-substitution by a bulky group in the sugar moiety of daunorubicin decreased the ability of the derivatives to stimulate oxygen radical formation. It has also been shown that the presence of an ionizable amino group on the sugar moiety of daunorubicin favours interaction with the NADH dehydrogenase. However, its location is not essential for this effect.
Tarasiuk
J
J
Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdañsk, Poland.
Tkaczyk-Gobis
K
K
Stefañska
B
B
Dzieduszycka
M
M
Priebe
W
W
Martelli
S
S
Borowski
E
E
D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D009245:NADH Dehydrogenase / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism*
D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D013481:Superoxides; D009245:NADH Dehydrogenase