Synthesis and Antiproliferative Evaluation of Certain Indeno[1,2-<i>c</i>]quinoline Derivatives. Part 2 Chih-Hua Tseng Cherng-Chyi Tzeng Chiao-Li Yang Pei-Jung Lu Hui-Ling Chen Hao-Yi Li You-Chung Chuang Chia-Ning Yang Yeh-Long Chen 10.1021/jm1005447.s001 https://acs.figshare.com/articles/journal_contribution/Synthesis_and_Antiproliferative_Evaluation_of_Certain_Indeno_1_2_i_c_i_quinoline_Derivatives_Part_2/2738401 Certain indeno[1,2-<i>c</i>]quinoline derivatives were synthesized and evaluated for their antiproliferation, DNA binding affinity, and topoisomerases (topo I and topo II) inhibitory activities. The preliminary results are the following: (1) substituent of the aminoalkoxyimino side chain at C<sub>11</sub> is important for antiproliferative activities in which the terminal amine preferred to be a tertiary or the cyclic five-membered pyrrolidino ring; (2) among the indeno[1,2-<i>c</i>]quinoline derivatives evaluated, (<i>E</i>)-6-hydroxy-9-methoxy-11<i>H</i>-indeno[1,2-<i>c</i>]quinolin-11-one <i>O</i>-2-(pyrrolidin-1-yl)ethyl oxime (<b>8c</b>) was found to be one of the most cytotoxic agents with a GI<sub>50</sub> value of 0.84, 0.89, and 0.79 μM against SAS, A549, and BT483, respectively, which is more active than camptothecin; (3) substituent at C<sub>6</sub> is crucial for the selective cytotoxicity in which the OH group is the most preferred while hydrogen or piperazine exhibited cytotoxicity on both cancer cells and Detroit-551; (4) a positive correlation of antiproliferative activity, DNA binding affinity, and topo I and topo II inhibitory activities has been observed for indeno[1,2-<i>c</i>]quinoline derivatives; (5) compound <b>8c</b> induced DNA fragmentation may through caspase-3 activation, phosphorylation of the histone protein H2AX at Ser139 (γ-H2AX), and PARP cleavage; (6) compound <b>8c</b> demonstrated significant tumor regression in the human breast xenograft model; (7) indeno[1,2-<i>c</i>]quinoline derivatives are a new class of molecules that have the potential to be developed as dual topo I and topo II inhibitory agents. 2010-08-26 00:00:00 GI 50 value BT PARP topo II SAS derivative OH 0.79 μ M breast xenograft model histone protein H 2AX indeno aminoalkoxyimino side chain DNA binding affinity