Design, synthesis, and cytotoxic activity of Michael acceptors and enol esters in the benzo[b]acronycine series.
A series of 2-acyl-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones (4-6) was prepared by treatment of 6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (3) with an excess of an appropriate acyl chloride in the presence of aluminum chloride. Treatment of (+/-)-cis-1-hydroxy-2-acyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones (9, 10) or (+/-)-cis-1,2-diacyloxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones (2, 11) with hydrochloric acid gave the corresponding 2-acyloxy-6-methoxy-3,3,14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-ones, exemplified by acetate 7 and butyrate 8. None of the Michael acceptors 4-6 showed significant antiproliferative activity. Enol esters 7 and 8 were markedly cytotoxic toward L1210 leukemia cells, with IC50 values within the same range of magnitude as (+/-)-cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (S23906-1), currently under phase I clinical trials. In contrast with S23906-1, enol esters 7 and 8 were not reactive toward purified DNA.
Doan Thi Mai
Huong
H
Laboratoire de Pharmacognosie de l'Université René Descartes, U.M.R./C.N.R.S. n8638, Faculté des Sciences Pharmaceutiques et Biologiques, 4, Avenue de l'Observatoire, F-75006 Paris, France.
Gaslonde
Thomas
T
Michel
Sylvie
S
Koch
Michel
M
Tillequin
François
F
Bailly
Christian
C
David-Cordonnier
Marie-Hélène
MH
Pfeiffer
Bruno
B
Léonce
Stéphane
S
Pierré
Alain
A
D000175:Acronine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D015195:Drug Design; D004952:Esters; D007939:Leukemia L1210 / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D013056:Spectrophotometry, Ultraviolet
D000970:Antineoplastic Agents; D004952:Esters; C504489:benzo(b)acronycine; D000175:Acronine