Costache E, Nguyen C H, Guilbaud N, Léonce S, Pierré A, Atassi G, Bisagni E
UMR 176 CNRS-Institut Curie, Orsay, France.
Anticancer Drug Des. 1998 Jun;13(4):373-86.
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.
呋咱并[3,2 - e] - 和吡喃并[3,2 - e]吡啶并[4,3 - b]吲哚是由1,4,5 - 三取代的8 - 羟基 - 5H - 吡啶并[4,3 - b]吲哚合成的。中间体10 - 氯 - 6H - 呋咱并[3,2 - e]吡啶并[4,3 - b]吲哚（11）、10 - 氯 - 2,6 - 二氢 - 1H - 呋咱并[3,2 - e]吡啶并[4,3 - b]吲哚（10）和11 - 氯 - 2,3 - 二氢 - 3H,7H - 吡喃并[3,2 - e]吡啶并[4,3 - b]吲哚（15）在热条件下（180℃）被二胺取代。相比之下，11 - 氯 - 3H,7H - 吡喃并[3,2 - e]吡啶并[4,3 - b]吲哚（14）、9 - 烯丙基 - 1 - 氯 - 4,5 - 二甲基 - 5H - 吡啶并[4,3 - b]吲哚（9a）和8 - 炔丙氧基 - 4,5 - 二甲基 - 5H - 吡啶并[4,3 - b]吲哚（8）主要生成因意外的C3单元消除而产生的1 - 氨基取代的8 - 羟基 - 5H - 吡啶并[4,3 - b]吲哚衍生物。当在三种肿瘤细胞系（L1210白血病细胞、B16黑色素瘤细胞和MCF7乳腺腺癌细胞）中检测时，新的氨基取代的呋咱并[3,2 - e] - 、二氢呋咱并[3,2 - e] - 和二氢吡喃并[3,2 - e] - 吡啶并[4,3 - b]吲哚衍生物显示出细胞毒性，对2,6 - 二氢 - 1H - 呋咱并[3,2 - e]吡啶并[4,3 - b]吲哚系列尤为重要。活性最强的化合物（12b）显著抑制DNA拓扑异构酶I和II，在抑制细胞增殖和诱导L1210细胞在细胞周期的G2 + M期大量积累方面与阿霉素效力相当。然而，在针对P388白血病或B16黑色素瘤肿瘤模型进行体内测试时，12b的活性低于阿霉素。
