2. Academic Validation
  3. Discovery of indeno[1,2-b]quinoxaline derivatives as potential anticancer agents

Discovery of indeno[1,2-b]quinoxaline derivatives as potential anticancer agents

  • Eur J Med Chem. 2016 Jan 27:108:258-273. doi: 10.1016/j.ejmech.2015.11.031.
Chih-Hua Tseng 1,  You-Ren Chen 2,  Cherng-Chyi Tzeng 3,  Wangta Liu 4,  Chon-Kit Chou 4,  Chien-Chih Chiu 5,  Yeh-Long Chen 6
Affiliations

Affiliations

  • 1 School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Research Center for Natural Products & Drug Development, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
  • 2 Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
  • 3 Research Center for Natural Products & Drug Development, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
  • 4 Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan.
  • 5 Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Research Center for Environment Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. Electronic address: cchiu@kmu.edu.tw.
  • 6 Research Center for Natural Products & Drug Development, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung City 807, Taiwan; Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung City 807, Taiwan. Electronic address: yeloch@kmu.edu.tw.
PMID: 26686931 DOI: 10.1016/j.ejmech.2015.11.031
Abstract

We have synthesized certain indeno[1,2-b]quinoxaline derivatives for antiproliferative evaluation. Among them, 11-{[3-(dimethylamino)propoxy]imino}-N-[3-(dimethylamino) propyl]-11H-indeno[1,2-b]quinoxaline-6-carboxamide (10a) was active against the growth of MDA-MB231, PC-3, and Huh-7 with IC50 values of 0.87 (selectivity index, SI = 36.22), 0.82 (SI = 38.43), and 0.64 μM (SI = 49.23) respectively. Compound 10a was inactive against the growth of normal human fetal lung fibroblast cell line (MRC-5) with an IC50 value of 31.51 μM. Its analogs, 10b and 10c, were also active against the growth of MB231, PC-3, and Huh-7 with IC50 values of <1.0 μM in each case. Our results have also indicated compounds 10a-10c exhibited comparable inhibitory activities against Topo I and Topo II with the positive compound 2 at a concentration of 10 μM. Mechanism studies indicated that compound 10a induced cell cycle arrest at S phase via activation of Caspase-3, -7 and an increase in the protein expression of Bad and Bax but a decrease in expression of Bcl-2 and PARP, which consequently cause cell death. In addition, compound 10a attenuated the levels of phosphorylated Src, Akt-1, and Akt-2 protein levels but did not affect the total protein expression of Akt. We have also implanted human hepatocellular carcinoma cells into the yolk sac of zebrafish larvae and incubated larvae with various concentrations of 10a. Our results of the zebrafish xenograft assay confirmed the anti-tumor effect of 10ain vivo.

Keywords

Anticancer agents; Antiproliferative activity; Apoptosis; Cell cycle; Indeno[1,2-b]quinoxaline derivatives; Zebrafish xenograft assay.

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