Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
Bioorg Med Chem. 2009 Nov 1;17(21):7465-76. doi: 10.1016/j.bmc.2009.09.021. Epub 2009 Sep 16.
A number of 6-arylindeno[1,2-c]quinoline derivatives were synthesized and evaluated for their antiproliferative activities against the growth of five cancer cell lines including human hepatocelluar carcinoma (Hep G2, Hep 3B and Hep2.2.1), non-small cell lung cancer (A549 and H1299), and normal diploid embryonic lung cell line (MRC-5). The preliminary results indicated that 9-(3-(dimethylamino)propoxy)-6-(4-(3-(dimethylamino)propoxy)phenyl)-2-fluoro-11H-indeno[1,2-c]quinolin-11-one (14c) was the most potent with GI(50) values of 0.61, 0.67, 0.59, and 0.72 microM against the growth of Hep G2, Hep 3B, Hep 2.2.1, and H1299 cells, respectively. Results have also shown that 2,9-bis(3-(dimethylamino)propoxy)-6-(4-(3-(dimethylamino)propoxy)phenyl)-11H-indeno[1,2-c]quinolin-11-one (17), which exhibited GI(50) of 0.60 and 0.68 microM against the growth of Hep G2 and A549, respectively, was more active than the positive topotecan and irinotecan. Compound 17 was less toxic than topotecan against the growth of normal cell (MRC-5) and therefore, was selected for further evaluation. Results indicated that compound 17 induce cell cycle arrest in G2/M phase, DNA fragmentation, and disrupt the microtubule network in A549 cells. The apoptotic induction may through the cleavage of PARP.
合成了一系列 6-芳基茚并[1,2-c]喹啉衍生物，并评估了它们对五种癌细胞系（包括人肝癌细胞系（Hep G2、Hep 3B 和 Hep2.2.1）、非小细胞肺癌细胞系（A549 和 H1299）和正常二倍体胚胎肺细胞系（MRC-5））生长的抗增殖活性。初步结果表明，9-(3-(二甲氨基)丙氧基)-6-(4-(3-(二甲氨基)丙氧基)苯基)-2-氟-11H-茚并[1,2-c]喹啉-11-酮（14c）对 Hep G2、Hep 3B、Hep 2.2.1 和 H1299 细胞的生长具有最强的抑制作用，GI50 值分别为 0.61、0.67、0.59 和 0.72 μM。结果还表明，2,9-双(3-(二甲氨基)丙氧基)-6-(4-(3-(二甲氨基)丙氧基)苯基)-11H-茚并[1,2-c]喹啉-11-酮（17）对 Hep G2 和 A549 的生长具有 GI50 值分别为 0.60 和 0.68 μM，比阳性对照拓扑替康和伊立替康更具活性。化合物 17 对正常细胞（MRC-5）的生长毒性低于拓扑替康，因此被选为进一步评估。结果表明，化合物 17 可诱导 A549 细胞周期停滞在 G2/M 期，导致 DNA 片段化，并破坏微管网络。凋亡诱导可能通过 PARP 的裂解。
