Development and use of a high-throughput bacterial DNA gyrase assay to identify mammalian topoisomerase II inhibitors with whole-cell anticancer activity
| Autor: | Sandra Nelson, Tracy L. Twinem, David T. Stanton, Carl E. Catrenich, Kelly M. Makin, Siddhartha Roychoudhury |
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| Rok vydání: | 2003 |
| Předmět: |
0301 basic medicine
High-throughput screening Cell Antineoplastic Agents 01 natural sciences Biochemistry DNA gyrase Analytical Chemistry 03 medical and health sciences Anti-Infective Agents Bacterial Proteins Ciprofloxacin Cell Line Tumor medicine Animals Humans Topoisomerase II Inhibitors biology Molecular Structure Cell growth Topoisomerase Melanoma medicine.disease Molecular biology 0104 chemical sciences 010404 medicinal & biomolecular chemistry 030104 developmental biology medicine.anatomical_structure DNA Topoisomerases Type II Cell culture DNA Gyrase Drug Design biology.protein Molecular Medicine Biological Assay Topoisomerase-II Inhibitor Biotechnology |
| Zdroj: | Journal of biomolecular screening. 8(2) |
| ISSN: | 1087-0571 |
| Popis: | A high-throughput screen (HTS) was developed and used to identify inhibitors of bacterial DNA gyrase. Among the validated hits were 53 compounds that also inhibited mammalian topoisomerase II with IC(50) values of12.5 micro g/mL for 51 of them. Using computational methods, these compounds were subjected to cluster analysis to categorize them according to their chemical and structural properties. Nine compounds from different clusters were tested for their whole-cell inhibitory activity against 3 cancer cell lines-NCI-H460 (lung), MCF7 (breast), and SF-268 (CNS)-at a concentration of 100 micro M. Five compounds inhibited cell growth by50% for all 3 cell lines tested. These compounds were tested further against a panel of 53 to 57 cell lines representing leukemia, melanoma, colon, CNS, ovarian, renal, prostate, breast, and non-small cell lung cancers. In this assay, PGE-7143417 was found to be the most potent compound, which inhibited the growth of all the cell lines by 50% at a concentration range of 0.31 to 2.58 micro M, with an average of 1.21 micro M. An additional 17 compounds were also tested separately against a panel of 10 cell lines representing melanoma, colon, lung, mammary, ovarian, prostate, and renal cancers. In this assay, 4 compounds-PGE-3782569, PGE-7411516, PGE-2908955, and PGE-3521917-were found to have activity with concentrations for 50% cell growth inhibition in the 0.59 to 3.33, 22.5 to 59.1, 7.1 to100, and 24.7 to100 micro M range. |
| Databáze: | OpenAIRE |
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