Characterization of anthracenediones and their photoaffinity analogs.
In an attempt to overcome the cardiotoxicity and cross-resistance problems caused by the anticancer drugs anthracyclines and anthracenediones during chemotherapy, we have developed a series of aza-anthracenedione compounds by modifying the chromophore and the side arms of anthracyclines and anthracenediones. One of these aza-anthracenediones, 6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione (BBR 2778), which is currently under phase II clinical trials, showed remarkable antitumor activity and appeared to lack a cardiotoxic effect in preclinical studies. However, it was still cross-resistant against multidrug resistance (MDR) cells expressing P-glycoprotein (P-gp). In contrast, another aza-anthracenedione, 6,9-bis[[2-(dimethylamino)ethyl]amino]benzo[g]isoquinoline-5,10-dione, which has side arm structures different from those of BBR 2778, was highly active against MDR cells. In this study, BBR 2778, BBR 2378, and an anthracenedione compound, 1,4-bis[(2-aminoethyl)amino]-5,8-dimethyl-9,10-anthracenedione, were used to assess the relationship between the chemical structures of these drugs and their interactions with DNA and P-gp. In addition, the biological and pharmacological influences of photoaffinity labeling were also studied for BBR 2778 and DEH. As the results indicate, the photolabeled analogs of BBR 2778 and DEH were less DNA-reactive and less cytotoxic. The more lipophilic compound, BBR 2378, and the photolabeled analogs of BBR 2778 and DEH inhibited P-gp labeling by azidopine better than did the more hydrophilic parental compounds. These studies suggested that the DNA binding affinity of BBR 2778 and DEH could be important in determining their cytotoxicity, and that the chemical structure of the side arms and the lipophilicity of these drugs are critical in determining their cross-resistance.
Chou
Kai-Ming
KM
Department of Pharmacology, School of Medicine, University of Vermont, Burlington, VT 05405, USA. kai-ming.chou@vtmednet.org
Krapcho
A Paul
AP
Horn
David
D
Hacker
Miles
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D000880:Anthraquinones / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002478:Cells, Cultured; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D019920:Photoaffinity Labels / Q000494:pharmacology*; D051381:Rats
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000880:Anthraquinones; D000970:Antineoplastic Agents; C096156:BBR 2378; D007546:Isoquinolines; D019920:Photoaffinity Labels; D004247:DNA; C086548:pixantrone