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.