A new series of ellipticine derivatives (1-(alkylamino)-9-methoxyellipticine). Synthesis, DNA binding, and biological properties

• Published in: Journal of medicinal chemistry Vol. 31; no. 10; pp. 1951 - 1956
• Main Authors: Larue, Lionel, Rivalle, Christian, Muzard, Gabriel, Paoletti, Claude, Bisagni, Emile, Paoletti, Jacques
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01-10-1988
• Subjects: Alkaloids; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - pharmacology; Cell Line; Cell Survival - drug effects; Chemistry; DNA - metabolism; Ellipticines - analogs & derivatives; Ellipticines - metabolism; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Intercalating Agents - chemical synthesis; Intercalating Agents - pharmacology; Leukemia L1210 - pathology; Leukemia P388 - pathology; Microscopy, Fluorescence; Organic chemistry; Preparations and properties; Structure-Activity Relationship; Antineoplastic agent; Alkaloid; Biological fixation; Intercalating agent; 3T3»-Cell line; Nitrogen heterocycle; DNA; Aromatic compound; L1210-Leukemia; Tetracyclic compound; Biological activity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00118a014

A new series of ellipticine derivatives, 1-(alkylamino)-5,11-dimethyl-9-methoxy-6H-pyrido[4,3-b]carbazoles, were synthesized as potential DNA intercalating antitumor drugs. The structure of these compounds were confirmed by 1H NMR spectroscopy and mass spectrometry. These compounds are able to bind to DNA with an affinity of about 10(6) M-1, and their intercalating characteristics (lengthening and unwinding of DNA) depend upon the length of the chain in position 1. The cytotoxicities of these compounds on L1210 and NIH-3T3 cells are quite similar, and fluorescence techniques showed that the compounds are localized mainly in the cytoplasmic granules of the cells. One of these compounds appears to show a very high antitumor activity (equivalent to the more active known ellipticine analogues: 10-[[gamma-(diethylamino)propyl]amino]-6-methyl-5H- pyrido[3',4':4,5]pyrollo[2,3-g]isoquinoleine (BD40), 1-[[gamma-(diethylamino)propyl]amino]-9-methoxyellipticine (BD84) and 2-[beta-(diethylamino)ethyl]-9-hydroxyellipticinium chloride (DEAE).