Novel Angular Benzophenazines: Dual Topoisomerase I and Topoisomerase II Inhibitors as Potential Anticancer Agents
| Autor: | Irina S. Chuckowree, Adrian Folkes, Rory Dodd, Stephen Paul Wren, and Alistair J. Stewart, Warren Miller, Luke Burgess, Sukhjit Sohal, David J. Hardick, Prakash Mistry, Timothy C. Hancox, Nigel Vicker, Chris Liddle, Shouming Wang, William A. Denny, Wendy Dangerfield, Peter Charlton, John Milton |
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| Rok vydání: | 2002 |
| Předmět: |
Tertiary amine
medicine.drug_class Transplantation Heterologous Biological Availability Mice Nude Antineoplastic Agents Carboxamide Mice Structure-Activity Relationship Drug Discovery Tumor Cells Cultured medicine Animals Humans Topoisomerase II Inhibitors Enzyme Inhibitors Cytotoxicity Mice Inbred BALB C biology Chemistry Topoisomerase Stereoisomerism Biological activity Drug Resistance Multiple respiratory tract diseases Multiple drug resistance Biochemistry Drug Resistance Neoplasm Cell culture biology.protein Phenazines Molecular Medicine Female Drug Screening Assays Antitumor Topoisomerase I Inhibitors Topoisomerase-II Inhibitor Neoplasm Transplantation |
| Zdroj: | Journal of Medicinal Chemistry. 45:721-739 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23 parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576 ((R)-4j' '). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation. |
| Databáze: | OpenAIRE |
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