Amino-Substituted 2-[2′-(Dimethylamino)ethyl]-1,2-dihydro-3H-dibenz [de,h] isoquinoline-1,3-diones. Synthesis, Antitumor Activity, and Quantitative Structure-Activity Relationship

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

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48 Scopus citations

Abstract

Sets of 2-[2′-(dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline-1,3-diones with amino and actylamino groups at each of the eight positions on the anthracene nucleus were synthesized from appropriately substituted anthracenes. Their evaluation in in vitro antitumor and cardiotoxicity assays revealed a very strong dependence of potency on the position of substitution. Certain compounds, including the 4-, 5-, 7-, and 9-amino derivatives, showed significantly higher potency than the unsubstituted parent compound, azonafide. Among them, 7-aminoazonafide had low cardiotoxicity relative to cytotoxicity. In general, the acetylamino analogues were less potent than the amino derivatives against tumor cells and neonatal rat heart myocytes; however, 5-(acetylamino)azonafide was highly cardiotoxic. 9-Aminoazonafide was more efficacious than azonafide or amonafide against P388 leukemia in mice. Statistically significant correlations were made between the ability of amino analogues to increase the transition melt temperature (ΔTm) of DNA and their potency against solid tumors, leukemia cells, or cardiac myocytes.

Original languageEnglish (US)
Pages (from-to)983-993
Number of pages11
JournalJournal of Medicinal Chemistry
Volume38
Issue number6
DOIs
StatePublished - Mar 1 1995

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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