Synthesis and cytotoxic activity of dimeric analogs of acronycine in the benzo[b]pyrano[3,2-h]acridin-7-one series.
Coupling of 6-hydroxy-3,3-14-trimethyl-3,14-dihydro-7H-benzo[b]pyrano[3,2-h]acridin-7-one (6) with alpha,omega-diiodoalkanes of varying length under alkaline conditions gave dimers 7-10. Halogenated ethers 11-14, cyclization products 15-17, and compounds 18-22 were also isolated in small yield from the reaction mixtures. Compounds 7-10 were more potent than acronycine and benzo[b]acronycine in inhibiting L1210 cell proliferation. The length of the alkyl ether linkage between the two benzopyranoacridone units had a dramatic influence on the cytotoxic activity. Compound 9 (n=5) was the most active, with an IC(50) value against L1210 cells within the same range of magnitude as diacetate 5, currently under clinical development.
Gaslonde
Thomas
T
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
Koch
Michel
M
Pfeiffer
Bruno
B
Léonce
Stéphane
S
Pierré
Alain
A
Tillequin
François
F
D000175:Acronine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D007202:Indicators and Reagents; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
D000972:Antineoplastic Agents, Phytogenic; D007202:Indicators and Reagents; D000175:Acronine