6- and 7-substituted 2-[2′-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3- diones: Synthesis, nucleophilic displacements, antitumor activity, and quantitative structure-activity relationships

Salah M. Sami, Robert T. Dorr, Anikó M. Sólyom, David S. Alberts, Bhashyam S. Iyengar, William A. Remers

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

New 2-[2′-(dimethylamino)ethyl]-3H-dibenz[de,h]isoquinoline-1,3-diones with substituents at the 6- and 7-positions were prepared. Nucleophilic aromatic displacement was a key reaction in the syntheses. Ten of the new compounds were more potent than the unsubstituted compound, azonafide, in a panel of tumor cells including human melanoma and ovarian cancer and murine sensitive and MDR L1210 leukemia. They also were less cardiotoxic in cell culture. Four of these compounds were not cross-resistant with the MDR leukemia, and one of them, 6-ethoxyazonafide, was nearly as potent against solid tumor cells as leukemia cells. These compounds also had good potency against human breast, colon, and lung cancer cells, including doxorubicin and mitoxantrone resistant cell lines. Advantages of the new analogues over azonafide were less in vivo, but 6-ethoxyazonafide was more effective against L1210 leukemia and subcutaneous B16 melanoma in mice. Although correlations of antitumor potency in cells and physicochemical properties of substituents were not found, there were statistically significant correlations of DNA melt transition temperature (ΔTm) with potency in solid tumor cells and sensitive and MDR resistant L1210 leukemia cells for 6-substituted azonafides and with solid tumors for 7-substituted azonafides.

Original languageEnglish (US)
Pages (from-to)1609-1618
Number of pages10
JournalJournal of Medicinal Chemistry
Volume39
Issue number8
DOIs
StatePublished - Apr 12 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Fingerprint Dive into the research topics of '6- and 7-substituted 2-[2′-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3- diones: Synthesis, nucleophilic displacements, antitumor activity, and quantitative structure-activity relationships'. Together they form a unique fingerprint.

  • Cite this