Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
Bioorg Med Chem. 2012 Jul 15;20(14):4397-404. doi: 10.1016/j.bmc.2012.05.035. Epub 2012 Jun 1.
We have synthesized certain 6-substituted 9-methoxy-11H-indeno[1,2-c]quinolin-11-ones for antiproliferative evaluation. Results indicated that 6-alkylamine derivatives, 6-[2-(dimethylamino)ethylamino]-9-methoxy-11H-indeno[1,2-c]quinolin-11-one (5a) and its 6-[3-(dimethylamino)propylamino] derivative, 5b, were able to inhibit cells growth completely at a concentration of 100 μM while most of the 6-arylamine derivatives 6b-6h were inactive at the same concentration. Comparable mean GI(50) (drug molar concentration causing 50% cell growth inhibition) values for 5a (3.47 μM) and 5b (3.39 μM) indicated the cytotoxicity may not be affected by the length of alkyl substituents at C-6 position. Compound 5b, with a mean GI(50) value of 3.39 μM, was the most active and therefore was selected for further evaluation on its effects of H460 lung cancer cell cycle distribution. Results indicated that 5b induced cell cycle arrest in G2/M phase after 24h treatment, while the hypodiploid (sub-G0/G1 phase) cells increased. We found that H460 cell became shrinked after the treatment of 5b, indicating that apoptosis may be a mechanism by which 5b kills the cancer cells. DNA unwinding assay indicated that 5b may bind to DNA through intercalation. Our results have also demonstrated that PARP was cleaved while caspase-3 and caspase-8 activities were induced after the treatment of 5b at 10 μM for 24h. Thus, compound 5b intercalates DNA, induces cell cycle arrest at G2/M phase via cleavage of PARP, induces caspase-3 and caspase-8 activities, and consequently causes the cell death.
我们合成了某些 6-取代的 9-甲氧基-11H-茚并[1,2-c]喹啉-11-酮，用于评估其抗增殖活性。结果表明，6-烷基胺衍生物 6-[2-(二甲氨基)乙基氨基]-9-甲氧基-11H-茚并[1,2-c]喹啉-11-酮（5a）及其 6-[3-(二甲氨基)丙基氨基]衍生物 5b，在 100μM 浓度下能够完全抑制细胞生长，而大多数 6-芳基胺衍生物 6b-6h 在相同浓度下没有活性。5a（3.47μM）和 5b（3.39μM）的平均 GI（50）（引起 50%细胞生长抑制的药物摩尔浓度）值相当，表明细胞毒性可能不受 C-6 位烷基取代基长度的影响。化合物 5b 的平均 GI（50）值为 3.39μM，活性最高，因此被选为进一步评估其对 H460 肺癌细胞周期分布的影响。结果表明，5b 在 24h 处理后诱导细胞周期阻滞在 G2/M 期，而亚二倍体（sub-G0/G1 期）细胞增加。我们发现，H460 细胞在 5b 处理后变得皱缩，表明凋亡可能是 5b 杀死癌细胞的一种机制。DNA 解旋实验表明，5b 可能通过嵌入与 DNA 结合。我们的结果还表明，在用 5b（10μM）处理 24h 后，PARP 被切割，同时 caspase-3 和 caspase-8 的活性被诱导。因此，化合物 5b 通过嵌入 DNA，通过 PARP 的切割诱导 G2/M 期细胞周期阻滞，诱导 caspase-3 和 caspase-8 的活性，从而导致细胞死亡。
