Novel anthraquinone derivatives with redox-active functional groups capable of producing free radicals by metabolism: are free radicals essential for cytotoxicity?
The mode of action of antitumour anthraquinone derivatives (i.e. mitoxantrone) is not clearly established yet. It includes, among others, intercalation and binding to DNA, bioreduction and aerobic redox cycling. A series of anthraquinone derivatives, with potentially bioreducible groups sited in the side chain, have been synthesized and biologically evaluated. Their redox and cytotoxic activities were screened. Derivatives which bear a 2-(dimethylamino)ethylamino substituent, known to confer high DNA affinity, demonstrated cytotoxicity but not redox activity (beside the anthraquinone reduction). Conversely, derivatives which showed redox activity were not cytotoxic toward the P388 cell line. The results suggest that bioreduction is not the main mode of action in the cytotoxicity of anthraquinones.
Department of Pharmaceutical Chemistry, The Hebrew University of Jerusalem, 91120, Jerusalem, Israel.
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D
Barasch
O
O
Zipori
I
I
Ringel
I
I
Ginsburg
A
A
Samuni
J
J
Katzhendler
D000818:Animals; D000880:Anthraquinones / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D004273:DNA, Neoplasm / Q000737:chemistry / Q000187:drug effects; D005609:Free Radicals / Q000378:metabolism*; D007364:Intercalating Agents / Q000494:pharmacology; D007941:Leukemia P388 / Q000188:drug therapy / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D010084:Oxidation-Reduction
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D005609:Free Radicals; D007364:Intercalating Agents