Synthesis and antiproliferative evaluation of certain indeno[1,2-c]quinoline derivatives. Part 2.
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 microM 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 (gamma-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.
Tseng
Chih-Hua
CH
Department of Medicinal and Applied Chemistry, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
Tzeng
Cherng-Chyi
CC
Yang
Chiao-Li
CL
Lu
Pei-Jung
PJ
Chen
Hui-Ling
HL
Li
Hao-Yi
HY
Chuang
You-Chung
YC
Yang
Chia-Ning
CN
Chen
Yeh-Long
YL
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry; D053938:DNA Fragmentation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007192:Indenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D010091:Oximes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011804:Quinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013237:Stereoisomerism; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D014183:Transplantation, Heterologous
C552106:6-hydroxy-9-methoxy-11H-indeno(1,2-c)quinolin-11-one O-2-(pyrrolidin-1-yl)ethyl oxime; D000970:Antineoplastic Agents; D006912:Hydroxyquinolines; D007192:Indenes; D010091:Oximes; D011804:Quinolines; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004247:DNA