HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Impact of the basic amine on the biological activity and intracellular distribution of an aza-anthrapyrazole: BBR 3422.

Abstract
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.
AuthorsK M Chou, A Paul Krapcho, M P Hacker
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 62 Issue 10 Pg. 1337-43 (Nov 15 2001) ISSN: 0006-2952 [Print] England
PMID11709193 (Publication Type: Journal Article)
Chemical References
  • 2-(2-aminoethyl)-5-(2-methylaminoethyl)indazolo(4,3-g,h)isoquinoline-6(2H)-one
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Azides
  • Dihydropyridines
  • Indazoles
  • Isoquinolines
  • Photoaffinity Labels
  • Tritium
  • azidopine
  • DNA
Topics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
  • Antineoplastic Agents (chemistry, metabolism, pharmacology)
  • Azides (pharmacology)
  • Binding, Competitive
  • Cell Division (drug effects)
  • DNA (drug effects, metabolism)
  • Dihydropyridines (pharmacology)
  • Drug Interactions
  • Drug Resistance, Multiple
  • Electrophoresis, Agar Gel
  • Humans
  • Indazoles (chemistry, metabolism, pharmacology)
  • Isoquinolines (chemistry, metabolism, pharmacology)
  • Photoaffinity Labels (pharmacology)
  • Subcellular Fractions
  • Tritium
  • Tumor Cells, Cultured

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: