Synthesis and cytotoxic activity of acronycine analogues in the benzo[c]pyrano[3,2-h]acridin-7-one and naphtho[1,2-b][1,7] and [1,10]-phenanthrolin-7(14H)-one series.
Condensation of 1-bromo-2-naphthalenecarboxylic acid (9) with 7-methoxy-2,2-dimethyl-2H-1-benzopyran-5-ylamine (13) followed by acid-mediated cyclization afforded 6-methoxy-3,3-dimethyl-3,14-dihydro-7H-benzo[c]pyrano[3,2-h]acridin-7-one (15), which was further methylated into 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[c]pyrano[3,2-h]acridin-7-one (benzo[c]acronycine) (3) and 6,7-dimethoxy-3,3-dimethyl-3H-benzo[c]pyrano[3,2-h]acridine (4). Osmium tetroxide oxidation of 15 gave the (+/-)-cis-diol 16, which afforded the benzopyranoacridine and benzopyranoacridone esters 17-22 upon acylation. Condensation of 9 with suitable aminoquinolines 23-25 afforded the carboxylic naphthylquinolylamines 26-28. Cyclization gave the corresponding naphtho[1,2-b][1,10]-phenanthrolin-7(14H)-ones 29 and 30, and naphtho[1,2-b][1,7]-phenanthrolin-7(14H)-one 31, which were subsequently N-methylated to the desired 14-methylnaphtho[1,2-b][1,10] and [1,7]-phenanthrolinones 6, 7, and 8. Benzo[c]pyrano[3,2-h]acridin-7-one derivatives 3, 16, and 22 displayed cytotoxic activities within the same range of magnitude as acronycine itself, whereas 7-alkoxybenzo[c]pyrano[3,2-h]acridine and 7-acyloxybenzo[c]pyrano[3,2-h]acridine derivatives 4 and 17-21 were less active when tested against L1210 murine leukemia cells in vitro. Naphthophenanthrolinones 6-8 were devoid of significant antiproliferative activity, but compounds 29-31 bearing no substituent on the nitrogen atom at position 14 were more potent.
Bongui
Jean-Bernard
JB
Laboratoire de Pharmacognosie de l'Université de Rouen-Haute Normandie, UMR 6014 CNRS, Faculté de Pharmacie, Rouen Cedex, France.
Elomri
Abdelhakim
A
Cahard
Dominique
D
Tillequin
François
F
Pfeiffer
Bruno
B
Pierré
Alain
A
Seguin
Elisabeth
E
D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology*; D000175:Acronine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry* / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D007202:Indicators and Reagents; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D010618:Phenanthrolines / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D012997:Solvents; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
D000166:Acridines; D000972:Antineoplastic Agents, Phytogenic; D001578:Benzopyrans; D007202:Indicators and Reagents; D010618:Phenanthrolines; D012997:Solvents; D000175:Acronine