2-[2'-(Dimethylamino)ethyl]-1,2-dihydro-3H-dibenz[de,h]isoquinoline- 1,3-diones with substituents at positions 4, 8, 9, 10, and 11. Synthesis, antitumor activity, and quantitative structure-activity relationships

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

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

New 2-[2'-(dimethylamino)ethyl]-1,2-dihydro-3H- dibenz[de,h]isoquinoline-1,3-diones with substituents at the 4, 8, 9, 10, and 11 positions were synthesized. Diazonium salts prepared from aminoazonafides were key intermediates for many of the analogues. Six of the new compounds were more potent than azonafide in a panel of tumor cells including human melanoma and ovarian carcinoma and murine L1210 leukemias. Three of these compounds, the 10-OCH3, 10-OC2H5, and 10-F analogues, had better ratios of cardiotoxicity to tumor-cell toxicity than azonafide. Eight compounds were not cross-resistant with MDR L1210 leukemia, and the 10-CN analogue was more potent against solid tumor cells than leukemia cells. The 9-OH, 10-CN, and 10-F analogues had high potency against both sensitive and resistant cell lines of MFX 7 breast carcinoma and WiDr colon carcinoma and sensitivity A599 lung carcinoma. Advantages of the 10-Cl, 10-NH2, and 10-CN analogues over azonafide were apparent in P388 leukemia in mice, and the 10-CN analogue was more effective than doxorubicin in this assay. Quantitative structure- activity relationship studies revealed statistically significant correlations between DNA binding strength of 8- and 10-substituted azonafides, as measured by ΔT(m), and toxicity to tumor cells. There also were correlations between substituent size, as measured by MR, and cytotoxicity for 9- and 10- substituted azonafides and between MR and ΔT(m) for 4-and 11-substituted azonafides. Lipophilicity of substituents (Π) correlated with cytotoxicity for 9-, 10-, and 11-substituted azonafides. These results lend support to a model in which DNA binding strength influences cytotoxic potency, and lipophilicity increases DNA binding whereas large substituents decrease it.

Original languageEnglish (US)
Pages (from-to)4978-4987
Number of pages10
JournalJournal of Medicinal Chemistry
Volume39
Issue number25
DOIs
StatePublished - Dec 6 1996

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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