Synthesis of 1-/2-substituted-[1,2,3]triazolo[4,5- g]phthalazine-4,9-diones and evaluation of their cytotoxicity and topoisomerase II inhibition

Studies on antitumor heterocyclic quinones containing nitrogens revealed that the number and position of nitrogens on the heterocyclic ring have significance on cytotoxicity of quinones. In our continuous effort to find more cytotoxic quinone compounds, we designed triazolophthalazine analogues in o...

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Published in:Bioorganic & medicinal chemistry 2008-04, Vol.16 (8), p.4545-4550
Main Authors: Kim, Jin Sung, Rhee, Hee-Kyung, Park, Hyen Joo, Lee, Sang Kook, Lee, Chong-Ock, Park Choo, Hea-Young
Format: Article
Language:English
Subjects:
Antineoplastic agents
Azo Compounds - chemical synthesis
Azo Compounds - chemistry
Azo Compounds - pharmacology
Benzoquinones - chemistry
Biological and medical sciences
Cell Line, Tumor
Cell Survival - drug effects
Cytotoxicity
DNA Topoisomerases, Type II - metabolism
General aspects
Humans
Medical sciences
Molecular Structure
Pharmacology. Drug treatments
Phthalazines - chemical synthesis
Phthalazines - chemistry
Phthalazines - pharmacology
Rhodamines
Structure-Activity Relationship
Topoisomerase II
Topoisomerase II Inhibitors
Triazolophthalazine
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Summary:Studies on antitumor heterocyclic quinones containing nitrogens revealed that the number and position of nitrogens on the heterocyclic ring have significance on cytotoxicity of quinones. In our continuous effort to find more cytotoxic quinone compounds, we designed triazolophthalazine analogues in order to introduce more nitrogens on the heterocyclic quinones. 1-/2-Substituted-[1,2,3]triazolo[4,5- g]phthalazine-4,9-diones were synthesized by 1,3-dipolar addition of phthalazine-5,8-dione and 4-methoxybenzyl azide by modification of previously reported method. The cytotoxicity of the synthesized compounds was evaluated by a SRB (sulforhodamine B) assay against nine types of human cancer cell lines and inhibition against topoisomerase II (Topo II) of them was assessed by a decatenation assay. Most of the synthesized compounds showed considerably higher cytotoxicity than that of doxorubicin. Also, topoisomerase II inhibitory activity of the tested compounds was higher than that of etoposide and IC 50 values of the compounds were 19.4–64.5 μM.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2008.02.049