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

Abstract

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.

Dual roles of extracellular signal-regulated kinase (ERK) in quinoline compound BPIQ-induced apoptosis and anti-migration of human non-small cell lung cancer cells

“…BPIQ was synthesized described as previously published [10, 12]. BPIQ was freshly dissolved in DMSO (<0.01% final concentration) before assays.…”

“…2,9-Bis[2-(pyrrolidin-1-yl)ethoxy]-6-{4-[2-(pyrrolidin-1-yl)ethoxy] phenyl}-11 H -indeno[1,2- c ]quinoline-11-one (BPIQ), a synthetic quinoline, exerts anti-growth and apoptosis-inducing potential against cancer cell lines including hepatocellular carcinoma cells [10, 12], non-small cell lung cancer (NSCLC) [19] and retinoblastoma cells [20]. Recently, our work further showed the BPIQ-induced apoptosis of cancer cells was mitochondrial-dependent [19].…”

Topoisomerase 1B poisons: Over a half‐century of drug leads, clinical candidates, and serendipitous discoveries

“…This compound induces γ‐H2AX formation in cells and causes apoptosis via PARP/caspase‐3. 20 mg/kg of 78 daily slowed the growth of breast cancer xenografts in mice . The indoloquinolinediones and azaindoloquinolinediones (which are structurally similar to 78 ) also have Top1/Top2 inibitory activities (although Top1 inhibition is more potent) suggesting that this scaffold might be promising for dual topoisomerase inhibition.…”

Identification of dehydroxy isoquine and isotebuquine as promising anticancer agents targeting K+ channel

“…Quinoline | 639 ROMERO Et al. alkaloids derived from plants, animals, and micro-organisms have showed remarkable antitumor activity against different cancer cells (Jain, Chandra, Jain, Pathak, & Vaidya, 2016). Also, several examples of synthetic quinolines have been reported by multiple research groups worldwide as promising anticancer agents (Beauchard et al, 2009;Czoch, Pognan, Kaczmarek, & Boraty, 1994;Ferlin, Gatto, Chiarelotto, & Palumbo, 2001;Gamal, Khan, Maksoud, El-Din, & Oh, 2014;Heiniger, Gakhar, Prasain, Hua, & Nguyen, 2010;Kim et al, 2001;Martirosyan, Rahim-Bata, Freeman, Clarke, & Howard, 2004;Perzyna et al, 2002;Tseng, Chen, Lu, Yang, & Tzeng, 2008;Tseng et al, 2009Tseng et al, , 2010Utsugi et al, 1997). In particular, compounds based on 4-aminoquinolines have received largely attention by its significant anticancer activity (Chen, Chen, Wang, Han, & Tzeng, 2005;Chen, Chung, Chen, Chen, & Jeng, 2002;Chen et al, 2006Chen et al, , 2011Kakadiya et al, 2010;Lee et al, 2004;Lu et al, 2010;Mejía et al, 2009;Sanchez et al, 2011;Su et al, 1995;Via, Gia, Gasparotto, & Ferlin, 2008).…”