Synthesis and biological evaluation of modified acridines: the effect of N- and O- substituent in the nitrogenated ring on antitumor activity.
A series of new acridines has been prepared by cyclodehydration of N-(2,3-dihydro-1,4-benzodioxin-6-yl)anthranilic acid in acidic media following classical procedures. All these compounds have in common a dioxygenated ring fused to the acridine. The tetracyclic system possesses a linear or angular structure formed by intramolecular cyclisation. The last ring and the substituent of the system modify, in an interesting way, the antitumor activity of acridines. Several of the studied compounds displayed significant cytotoxic activity (inhibition of L1210 and HT-29 cell proliferation). The most cytotoxic compound 13a, shows more activity than m-AMSA in inhibiting L1210 and HT-29 cell proliferation and this compound has been selected as a development candidate for further evaluation. The activity results also indicate that the new 11-O-substituted compounds are of considerable interest with high levels of cytotoxic activity. The angular or non-linear dioxinoacridine 10 was equiactive with the linear structure 7. Pentacyclic analogues (14 and 15) were more cytotoxic than the tetracyclic compounds (up to twofold).
Sánchez
Isabel
I
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, Universitat de Barcelona, Spain.
Reches
Rosa
R
Caignard
Daniel Henry
DH
Renard
Pierre
P
Pujol
Maria Dolors
MD
D000166:Acridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry*; D013329:Structure-Activity Relationship
D000166:Acridines; D000970:Antineoplastic Agents; D009584:Nitrogen; D010100:Oxygen