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Synthesis of 6-chloroisoquinoline-5,8-diones and pyrido[3,4-b]phenazine-5,12-diones and evaluation of their cytotoxicity and DNA topoisomerase II inhibitory activity

Title
Synthesis of 6-chloroisoquinoline-5,8-diones and pyrido[3,4-b]phenazine-5,12-diones and evaluation of their cytotoxicity and DNA topoisomerase II inhibitory activity
Authors
Kim J.S.Rhee H.-K.Park H.J.Lee I.-K.Lee S.K.Suh M.-E.Lee H.J.Ryu C.-K.Choo H.-Y.P.
Ewha Authors
유충규박혜영이상국이화정
SCOPUS Author ID
유충규scopus; 박혜영scopus; 이화정scopus
Issue Date
2007
Journal Title
Bioorganic and Medicinal Chemistry
ISSN
0968-0896JCR Link
Citation
vol. 15, no. 1, pp. 451 - 457
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
The substituted chloroisoquinolinediones and pyrido[3,4-b]phenazinediones were synthesized, and the cytotoxic activity and topoisomerase II inhibitory activity of the prepared compounds were evaluated. Chloroisoquinolinediones have been prepared by the reported method employing 6,7-dichloroisoquinoline-5,8-dione. The cyclization to pyrido[3,4-b]phenazinediones was achieved by adding the aqueous sodium azide solution to the dimethylformamide solution of corresponding chloroisoquinoline-5,8-dione. The cytotoxicity of the synthesized compounds was evaluated by a SRB (Sulforhodamine B) assay against various cancer cell lines such as A549 (human lung cancer cell line), SNU-638 (human stomach cancer cell), Col2 (human colon cancer cell line), HT1080 (human fibrosarcoma cell line), and HL-60 (human leukemia cell line). Almost all the synthesized pyrido[3,4-b]phenazinediones showed greater cytotoxic potential than ellipticine (IC50 = 1.82-5.97 μM). In general, the cytotoxicity of the pyrido[3,4-b]phenazinediones was higher than that of the corresponding chloroisoquinolinediones. The caco-2 cell permeability of selected compounds was 0.62 × 10-6-35.3 × 10-6 cm/s. The difference in cytotoxic activity among tested compounds was correlated with the difference in permeability to some degree. To further investigate the cytotoxic mechanism, the topoisomerase II inhibitory activity of the synthesized compounds was estimated by a plasmid cleavage assay. Most of compounds showed the topoisomerase II inhibitory activity (28-100%) at 200 μM. IC50 values for the most active compound 6a were 0.082 μM. However, the compounds were inactive for DNA relaxation by topoisomerase I at 200 μM. © 2006 Elsevier Ltd. All rights reserved.
DOI
10.1016/j.bmc.2006.09.040
Appears in Collections:
약학대학 > 약학과 > Journal papers
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