Synthesis, properties and biological evaluation of substituted furo[3,2-e] and pyrano[3,2-e]pyrido[4,3-b]indoles.
Furo[3,2-e]- and pyrano[3,2-e]pyrido[4,3-b] indoles were synthesized from 1,4,5-trisubstituted 8-hydroxy-5H-pyrido[4,3-b]indoles. The intermediates, 10-chloro-6H-furo[3,2-e]pyrido[4,3-b]indole (11), 10-chloro-2,6-dihydro-1H-furo[3,2-e]pyrido-[4,3-b]indole (10) and 11-chloro-2,3-dihydro-3H,7H-pyrano[3,2-e]pyrido[4,3-b]indole (15), were substituted by diamines under thermal conditions (180 degrees C). In contrast, 11-chloro-3H,7H-pyrano[3,2-e]pyrido[4,3-b]indole (14), 9-allyl-1-chloro-4,5-dimethyl-5H-pyrido[4,3-b]indole (9a) and 8-propargyloxy-4,5-dimethyl-5H-pyrido[4,3-b]indole (8) led mainly to 1-aminosubstituted 8-hydroxy-5H-pyrido[4,3-b]indole derivatives resulting from an unexpected C3 unit elimination. When examined in three tumour cell lines (L1210 leukaemia, the B16 melanoma and the MCF7 breast adenocarcinoma) the new amino substituted furo[3,2-e]-, dihydrofuro[3,2-e]- and dihydropyrano[3,2-e]-pyrido[4,3-b]indole derivatives revealed cytotoxic properties, especially important for the 2,6-dihydro-1H-furo[3,2-e]pyrido[4,3-b]indole series. The most active compound (12b) significantly inhibits both DNA topoisomerases I and II, and is as potent as Adriamycin at inhibiting cell proliferation and inducing a massive accumulation of L1210 cells in the G2 + M phase of the cell cycle. However, 12b was less active than Adriamycin when tested in vivo against P388 leukaemia or the B16 melanoma tumour models.
Costache
E
E
UMR 176 CNRS-Institut Curie, Orsay, France.
Nguyen
C H
CH
Guilbaud
N
N
Léonce
S
S
Pierré
A
A
Atassi
G
G
Bisagni
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D007535:Isomerases / Q000037:antagonists & inhibitors; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D007211:Indoles; D007535:Isomerases