Synthesis and Antiproliferative Evaluation of Certain Indeno[1,2-c]quinoline Derivatives. Part 2

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：August 26, 2010
• 年：2010
• 卷：53
• 期：16
• 页码：6164-6179
• 全文大小：1328K
• 年卷期：v.53,no.16(August 26, 2010)
• ISSN：1520-4804

文摘

Certain indeno[1,2-c]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 C₁₁ 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-c]quinoline derivatives evaluated, (E)-6-hydroxy-9-methoxy-11H-indeno[1,2-c]quinolin-11-one O-2-(pyrrolidin-1-yl)ethyl oxime (8c) was found to be one of the most cytotoxic agents with a GI₅₀ 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 C₆ 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-c]quinoline derivatives; (5) compound 8c induced DNA fragmentation may through caspase-3 activation, phosphorylation of the histone protein H2AX at Ser139 (γ-H2AX), and PARP cleavage; (6) compound 8c demonstrated significant tumor regression in the human breast xenograft model; (7) indeno[1,2-c]quinoline derivatives are a new class of molecules that have the potential to be developed as dual topo I and topo II inhibitory agents.