Impact of the basic amine on the biological activity and intracellular distribution of an aza-anthrapyrazole: BBR 3422.
The anthrapyrazoles have entered clinical trials and show significant activity against breast cancer. However, these drugs are cardiotoxic and ineffective in multidrug-resistant (MDR) tumor cells. We have reported previously on the synthesis and antitumor characteristics of the 9-aza-anthrapyrazoles and their lack of cardiotoxicity; unfortunately, the leading candidates are cross-resistant in MDR-expressing cells. The results also indicated that the side arm structures of 9-aza-anthrapyrazole play a critical role in determining the drug resistance in MDR-expressing cells-only compounds that have a tertiary amine on both side arms are not cross-resistant. To further elucidate the biochemical and pharmacological impact of the side arm structures, one of the 9-aza-anthrapyrazole compounds, BBR 3422 [2-(2-aminoethyl)-5-(2-methylaminoethyl)indazolo[4,3-g,h]isoquinoline-6(2H)-one], was selected to be photolabeled with N-hydroxysuccinimidyl-4-azidosalicylic acid (NHS-ASA). In comparison to the parental compound, the photolabeled BBR 3422 was not as cytotoxic or DNA active, but it competed better than the parental compound against azidopine on P-glycoprotein labeling. In addition, confocal microscopic studies showed that BBR 3422 was clustered mainly in the cell nucleus, but its photolabeled analogue was located in the cytoplasm of the human breast cancer cell line MCF-7. Only a trace amount of both compounds was detected in the doxorubicin-derived resistant cell line MCF-7/ADR. The treatment of MCF-7/ADR cells with verapamil increased the intracellular amounts of both compounds.
Chou
K M
KM
Department of Pharmacology, University of Vermont School of Medicine, Burlington, VT 05405, USA. Kai-Ming.Chou@VTMEDNET.ORG
Paul Krapcho
A
A
Hacker
M P
MP
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001386:Azides / Q000494:pharmacology*; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple; D004587:Electrophoresis, Agar Gel; D006801:Humans; D007191:Indazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007546:Isoquinolines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D019920:Photoaffinity Labels / Q000494:pharmacology; D013347:Subcellular Fractions; D014316:Tritium; D014407:Tumor Cells, Cultured
C439813:2-(2-aminoethyl)-5-(2-methylaminoethyl)indazolo(4,3-g,h)isoquinoline-6(2H)-one; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001386:Azides; D004095:Dihydropyridines; D007191:Indazoles; D007546:Isoquinolines; D019920:Photoaffinity Labels; D014316:Tritium; C041130:azidopine; D004247:DNA