Spectroscopic evidence for anthracenedione antineoplastic agent self-association and complex formation with flavin nucleotides.
Dihydroxyanthraquinone (DHAQ) and ametantrone (anthraquinone) are two new anthracenedione antineoplastic agents which were found by proton NMR spectroscopy to self-associate in aqueous media. Self-association was consistent with a bimolecular model, with average association constant values of 3400 and 2900 M-1 determined for DHAQ and ametantrone, respectively. Both anthracenediones interacted with the flavin nucleotides FMN and FAD to produce concentration-dependent upfield shifts of the flavin isoalloxazine ring proton signals, as observed by proton NMR spectroscopy. Average association constant values obtained for FMN-DHAQ, FAD-DHAQ, FMN-ametantrone, and FAD-ametantrone complexation were 5100, 2600, 4300, and 1600 m-1, respectively. Optical difference spectroscopy confirmed FMN-DHAQ complexation, which resulted in a hyperchromic, bathochromic shift of the DHAQ spectrum following addition of FMN. These results were consistent with the formation of a pi-pi bimolecular ring-stacking complex. Information obtained on anthracenedione self-association and complexation with flavins may be of consequence in the interpretation of anthracenedione-DNA binding data and flavoprotein-mediated anthracenedione metabolic activation.
D000880:Anthraquinones / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism; D005486:Flavin Mononucleotide / Q000378:metabolism*; D005182:Flavin-Adenine Dinucleotide / Q000378:metabolism*; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy; D008942:Mitoxantrone / Q000031:analogs & derivatives; D013053:Spectrophotometry; D013696:Temperature
D000880:Anthraquinones; D000970:Antineoplastic Agents; D046911:Macromolecular Substances; D005182:Flavin-Adenine Dinucleotide; D005486:Flavin Mononucleotide; D008942:Mitoxantrone; C020182:ametantrone