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

Journal of Medicinal Chemistry
S M SamiW A Remers

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...Continue Reading

References

Jul 4, 1990·Journal of the National Cancer Institute·P SkehanM R Boyd
Jan 1, 1980·Cancer Chemotherapy and Pharmacology·M F BrañaA Jiménez
Apr 1, 1996·Journal of Computer-aided Molecular Design·S Bear, W A Remers

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Citations

Jul 10, 2013·European Journal of Medicinal Chemistry·Bo LiChun-Hao Yang
Nov 17, 2001·Bioorganic & Medicinal Chemistry·R GargC Hansch
May 12, 2015·Bioorganic & Medicinal Chemistry·Charles A JohnsonBrent M Znosko
Nov 21, 2007·The Journal of Immunology : Official Journal of the American Association of Immunologists·Wen-Hua PiaoFu-Dong Shi

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