Synthesis and biological evaluation of 2,7-Dihydro-3H-dibenzo[de,h]cinnoline-3,7-dione derivatives, a novel group of anticancer agents active on a multidrug resistant cell line.
A series of anthrapyridazone derivatives with one or two basic side chains at various positions in the tetracyclic chromophore have been synthesized. The key intermediates in the synthesis are 2,7-dihydro-3H-dibenzo[de,h]cinnoline-3,7-diones 1, 12 and 15 monosubstituted at position 2 (4d, 16a-e), or 6 (2a-f) or disubstituted at positions 2 and 6 (4a-c) or 2 and 8 (17a-e) with appropriate alkylaminoalkylamines. All analogues showed in vitro cytotoxic activity against murine leukemia (L1210) and human leukemia (K562) cell lines. The compounds were also active against human leukemia multidrug resistant (K562/DX) cell line with resistance index (RI) in the range 1-3 depending on the compound's structure. Two of the most active in vitro compounds 4a and 11 were tested in vivo against murine P388 leukemia and displayed antileukemic activity comparable with that of Mitoxantrone. DNA-binding assays were performed and DNA affinity data were correlated with the structures of the compounds. The cytoplasmatic membrane affinity values (log k'(IAM)) have also been determined and the correlation with the resistance indexes discussed. The anthrapyridazones constitute a novel group of antitumor compounds that can overcome multidrug resistance.
Stefańska
Barbara
B
Department of Pharmaceutical Technology, Gdańsk University of Technology 80-952, Gdańsk, Poland.
Arciemiuk
Małgorzata
M
Bontemps-Gracz
Maria M
MM
Dzieduszycka
Maria
M
Kupiec
Agnieszka
A
Martelli
Sante
S
Borowski
Edward
E
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D007202:Indicators and Reagents; D007941:Leukemia P388 / Q000188:drug therapy; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008942:Mitoxantrone / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C477022:2,7-dihydro-3H-dibenzo(de,h)cinnoline-3,7-dione; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D006576:Heterocyclic Compounds, 4 or More Rings; D007202:Indicators and Reagents; D004317:Doxorubicin; D008942:Mitoxantrone