Search

$$(E)$$ -6-Hydroxy-9-methoxy-6-(piperazin-1-yl)-11 $$H$$ -indeno[1,2- $$c$$ ]quinolin-11-one $$O$$ -2-(pyrrolidin-1-yl)ethyl oxime ( 2c) was identified as a potential dual topo I/II inhibitor in our previous paper. In continuation for the search of more potent compounds, we describe herein the preparation of certain indeno[1,2- $$c$$ ]quinoline derivatives and evaluation of their antiproliferation, DNA binding affinity, and topoisomerases (topo I and topo II) inhibitory activities. Among them, $$(E)$$ -9-[3-(dimethylamino)propoxy]-11 $$H$$ -indeno[1,2- $$c$$ ]quinolin-11-one $$O$$ -3-(dimethylamino)propyl oxime ( 11b) and its analog 11c exhibited approximately equal activity to the lead compound 2c against the growth of HeLa and A549 cancer cells. Both compounds 11b and 11c were more active than 2c in the inhibition of topo I and topo II. However, none of them exhibited significant DNA binding affinity while 2c was a very strong DNA binding agent. Compound 11b exhibited a high oral bioavailability of 39.8 % while the oral bioavailability of 2c and 11c was only 10.9 and 8.6 %, respectively. The in vivo anti-tumor evaluation of 11b in nude mice bearing subcutaneous breast cancer tumors revealed that treatment with low (10 mg/kg) or high (30 mg/kg) doses of 11b dramatically diminished tumor growth. Therefore, compound 11b is identified as a potential non-DNA intercalating dual topo I/II inhibitor. [ABSTRACT FROM AUTHOR]

A number of 2,4,5-triaryl-1 H-imidazole derivatives were synthesized and evaluated for their antiproliferative activities against the growth of five cell lines including three non-small cell lung cancers (H460, H1299, and A549), one breast cancer (MCF-7), and one normal diploid embryonic lung cell line (MRC-5). Preliminary results indicated that both 2-(5-bromofuran-2-yl)-4,5-bis{4-[3-(dimethylamino) propoxy] phenyl}-1 H-imidazole ( 10f) and 4,5-bis{4-[3-(dimethylamino)propoxy]phenyl}-2-(5-nitrofuran-2-yl)-1 H -imidazole ( 10g) were selectively active against the growth of H1229 with an IC of less than 0.1 μM, thus were more active than topotecan (IC > 10.0 μ M). However, both 10f and 10g exhibited only marginal cytotoxicity against H460, A549, MCF-7, and MRC-5 requiring an IC of at least 4.16 μM. Our results also indicated that 10f induced H1299 cell cycle arrest at G0/G1 through the inactivation of p38 MAPK, JNK, ERK, as well as the expression of SIRT1 and survivin. These results suggested that 10f might have therapeutic potential against H1299 (non-small cell lung cancer cell). [ABSTRACT FROM AUTHOR]