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 anti tumour agents. However, their use is limited by their peroxidating activity , being the consequence of free radical formation initiated by three oxyred uctases. This activity is considered to be the main cause of cardiotoxic ef fects. The affinity of anthraquinone compounds to these enzymes is an essen tial 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 radica l 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 phenoli c groups in peri positions favoured the affinity of these compounds for NAD H dehydrogenase. The modification of the quinonoid structure to iminoquinon oid or carboquinonoid forms dramatically decreased interaction with the enz yme. The O'-substitution by a bulky group in the sugar moiety of daunorubic in decreased the ability of the derivatives to stimulate oxygen radical for mation. It has also been shown that the presence of an ionizable amino grou p on the sugar moiety of daunorubicin favours interaction with the NADH deh ydrogenase. However, its location is not essential for this effect.