Synthesis and antiproliferative evaluation of certain indeno[1,2-c]quinoline derivatives.
Tseng CH, Chen YL, Lu PJ, Yang CN, Tzeng CC.
Although the quinoline ring is found in a wide variety of biologically active compounds and is frequently condensed with various heterocycles, synthesis and biological evaluation of the indenoquinoline skeleton attracts only very limited attention. We report herein the synthesis and antiproliferative evaluation of certain indeno[1,2-c]quinoline derivatives against the growth of six cancer cell lines including human cervical epithelioid carcinoma (HeLa), oral squamous cell carcinoma (SAS), hepatocellular carcinoma (SKHep), human stomach adenocarcinoma (AGS), prostate cancer (PC-3), and non-small cell lung cancer (A549). The results indicated that 9-methoxy-6-(piperazin-1-yl)-11H-indeno[1,2-c]quinolin-11-one (17b) is more active than its C(6)-amino derivative 17a, C(6)-morpholine and C(6)-piperidine isomers, 17c and 17d, respectively. Treatment of 17b with NH(2)OH afforded its hydroxyimino derivative 20 which is more active than the carbonyl precursor 17b. More potent agents were obtained by further derivatization of 20. Thus, antiproliferative activities decreased in an order of aminoalkoxyimino 22a-d>hydroxyimino 20>alkoxyimino 21, 22e>carbonyl 17b. Both AGS and A549 were resistant to camptothecin with GI(50) values of 23.76 and 2.80 microM, respectively, while GI(50) values for 22a-d were in the range of 5.93-7.11 microM and 0.38-0.87 microM, respectively. Among them, 22b was the most potent with GI(50) values of 0.52, 0.74, 6.76, and 0.64 microM against the growth of HeLa, SKHep, AGS, and A549 cells, respectively. Flowcytometric analysis indicated 22c can induce cell cycle arrest in S phase, and DNA polyploidy (>4n) followed by apoptosis.