Electron-deficient DNA-intercalating agents as antitumor drugs: aza analogues of the experimental clinical agent N-[2-(dimethylamino)ethyl]acridine-4-carboxamide
| Autor: | William Alexander Denny, Qingping Chen, Bruce Charles Baguley, Leslie W. Deady |
|---|---|
| Rok vydání: | 1994 |
| Předmět: |
Stereochemistry
medicine.drug_class Nitro compound Carboxamide Antineoplastic Agents chemistry.chemical_compound Mice Structure-Activity Relationship In vivo Drug Discovery medicine Animals Naphthyridines Cytotoxicity chemistry.chemical_classification Molecular Structure Chemistry Leukemia P388 Biological activity DNA Intercalating Agents Acridine Nitro Molecular Medicine Acridines Neoplasm Transplantation |
| Zdroj: | Journal of medicinal chemistry. 37(5) |
| ISSN: | 0022-2623 |
| Popis: | A series of azaacridine (benzonaphthyridine) analogues of the drug N-[2-(dimethylamino)ethyl]-acridine-4-carboxamide (DACA) (currently in clinical trial) were synthesized. These compounds showed DNA binding affinities similar to that of DACA, as determined by the fluorometric ethidium displacement assay, but were generally less potent cytotoxins against P388 leukemia in vitro. The only compounds showing higher cytotoxicity than DACA were analogues with nitro substituents at the (acridine) 1-position; by analogy with the 1-nitroacridine nitracrine, these compounds probably undergo reductive metabolism. The only azaacridine to show significant in vivo antileukemic activity was benzo[b][1,5]naphthyridine-6-carboxamide. A possible reason for the unexpectedly low activity of these compounds (given the wide acceptability of substituents in DACA) may be their much lower lipophilicities, which are likely to result in lower rates of cell uptake. |
| Databáze: | OpenAIRE |
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