Impact of the basic amine on the biological activity and intracellular distribution of an aza-anthrapyrazole

BBR 3422

Kai Ming Chou, A. Paul Krapcho, Miles P. Hacker

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1337-1343
Number of pages7
JournalBiochemical Pharmacology
Volume62
Issue number10
DOIs
StatePublished - Dec 15 2001
Externally publishedYes

Fingerprint

Bioactivity
Amines
Cells
Aza Compounds
Breast Neoplasms
Cell Line
MCF-7 Cells
P-Glycoprotein
Verapamil
Cell Nucleus
Drug Resistance
Pharmaceutical Preparations
Doxorubicin
Labeling
Tumors
Cytoplasm
Clinical Trials
Pharmacology
anthrapyrazole
2-(2-aminoethyl)-5-(2-methylaminoethyl)indazolo(4,3-g,h)isoquinoline-6(2H)-one

Keywords

  • Aza-anthrapyrazole
  • DNA intercalation
  • Intracellular distribution
  • Multidrug resistance
  • P-glycoprotein
  • Photoaffinity labeling

ASJC Scopus subject areas

  • Pharmacology

Cite this

Impact of the basic amine on the biological activity and intracellular distribution of an aza-anthrapyrazole : BBR 3422. / Chou, Kai Ming; Paul Krapcho, A.; Hacker, Miles P.

In: Biochemical Pharmacology, Vol. 62, No. 10, 15.12.2001, p. 1337-1343.

Research output: Contribution to journalArticle

Chou, Kai Ming ; Paul Krapcho, A. ; Hacker, Miles P. / Impact of the basic amine on the biological activity and intracellular distribution of an aza-anthrapyrazole : BBR 3422. In: Biochemical Pharmacology. 2001 ; Vol. 62, No. 10. pp. 1337-1343.
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