Synthesis and cytotoxic activity of benzo[c][1,7] and [1,8]phenanthrolines analogues of nitidine and fagaronine.
Fagaronine and nitidine are natural benzo[c] phenanthridinium alkaloids, which display antileukemic activity. Both act as topoisomerase I and topoisomerase II inhibitors. The objective of the present study was to prepare noncharged isosters of these compounds, with replacement of the aromatic A ring by a pyridine ring, present in other topoisomerase I inhibitors. Various 7,8- and 8,9-dimethoxy and metylenedioxy benzo[c][1,7] and [1,8]phenanthrolines were readily synthesized by benzyne-mediated cyclization of the corresponding substituted N-(2-halobenzyl)-5-quinolinamines or 5-isoquinolinamines. In both series, compounds bearing oxygenated substituents at positions 8 and 9 exhibited cytotoxic properties towards L1210 murine leukemia cells, which may result from their capacities to intercalate into DNA. Topoisomerase I inhibition was observed for all active compounds.
Prado
Soizic
S
Laboratoire de Pharmacognosie de l'Université René Descartes, UMR/CNRS No. 8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4 Avenue de l'Observatoire, 75006 Paris, France.
Michel
Sylvie
S
Tillequin
François
F
Koch
Michel
M
Pfeiffer
Bruno
B
Pierré
Alain
A
Léonce
Stéphane
S
Colson
Pierre
P
Baldeyrou
Brigitte
B
Lansiaux
Amélie
A
Bailly
Christian
C
D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D053119:Benzophenanthridines; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D013058:Mass Spectrometry; D051379:Mice; D010617:Phenanthridines / Q000138:chemical synthesis* / Q000494:pharmacology*; D010618:Phenanthrolines / Q000737:chemistry*; D013057:Spectrum Analysis; D059004:Topoisomerase I Inhibitors
D000470:Alkaloids; D053119:Benzophenanthridines; D010617:Phenanthridines; D010618:Phenanthrolines; D059004:Topoisomerase I Inhibitors; C002066:fagaronine; C013615:nitidine