Correlation of DNA reactivity and cytotoxicity of a new class of anticancer agents: aza-anthracenediones.
Doxorubicin and mitoxantrone are carboxyclic anti-cancer drugs that interact with DNA through intercalation. Our laboratory has synthesized a new series of anti-tumor agents, the aza-anthracenediones, which are structurally related to mitoxantrone but contain a heterocyclic, rather than a carbocyclic, chromophore. Both the in vivo and in vitro anti-tumor activities of these compounds were exquisitely sensitive to the positioning of the nitrogen atom within the heterocyclic backbone. Compounds having a 2-aza were 30- to 100-fold more potent than the 1-aza or the di-aza compounds against L1210 cells in vitro. When tested in vivo, the 2-aza-anthracenediones had marked anti-tumor activity, in some cases curative, whereas the 1-aza-anthracenediones had but minimal antitumor activity. To define the importance of the aza positioning on DNA reactivity, spectral shift and gel mobility assays were used. The spectral shift assay suggested that the 2-aza compounds reacted with DNA solely through intercalation whereas the 1-aza-anthracenediones, and mitoxantrone all reacted with DNA through intercalative and non-intercalative processes. The affinity of DNA binding was five to seven times greater for the 2-aza compounds compared to the 1-aza or the di-aza derivatives. The retardation of supercoiled pBR322 DNA mobility in agarose gel electrophoresis further suggested an intercalative type of DNA interaction. Differences in DNA interaction appear related to but can not completely account for differences in cytotoxicity of the aza anthracenediones.
Hazlehurst
L A
LA
Department of Pharmacology, University of Vermont College of Medicine, Burlington 05405, USA.
Krapcho
A P
AP
Hacker
M P
MP
D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D004273:DNA, Neoplasm / Q000378:metabolism; D006571:Heterocyclic Compounds; D007364:Intercalating Agents; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D051379:Mice; D008942:Mitoxantrone / Q000378:metabolism / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000880:Anthraquinones; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D006571:Heterocyclic Compounds; D007364:Intercalating Agents; D008942:Mitoxantrone