DNA binding, cardiac superoxide production and cytotoxicity of daunomycin analogs.
Pyridoanthraquinones are potent antibacterial agents especially against gram-positive organisms. We tested two major biologic actions of these compounds: DNA intercalation and superoxide (O2-) production in sarcosomes. Using the bathochromic and hypochromic shifts induced by intercalation, followed by Scatchard analysis, we calculated dissociation constants and the number of binding sites per base pair for several analogues. We compared O2- production using cytochrome c reduction. Unsubstituted compounds do not bind to DNA or change its melting temperature (Tm). Placing a morpholino or piperidyl group at C-5 enhances the binding to DNA. The tetracyclic compounds were equipotent at producing O2- and were 20-fold more active than daunomycin. These compounds were unusual in their solid tumor cytotoxicity.
Nachtman
J P
JP
Roginski
E T
ET
Banning
J W
JW
Wormser
H C
HC
Abramson
H N
HN
Corbett
T H
TH
D000107:Acetylation; D000818:Animals; D002470:Cell Survival / Q000187:drug effects*; D003574:Cytochrome c Group / Q000302:isolation & purification; D004247:DNA / Q000378:metabolism*; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D007364:Intercalating Agents; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000096:biosynthesis*
D003574:Cytochrome c Group; D007364:Intercalating Agents; D013481:Superoxides; D004247:DNA; D003630:Daunorubicin