PUBLICATION
Discovery of indeno[1,2-b]quinoxaline derivatives as potential anticancer agents
- Authors
- Tseng, C.H., Chen, Y.R., Tzeng, C.C., Liu, W., Chou, C.K., Chiu, C.C., Chen, Y.L.
- ID
- ZDB-PUB-151222-11
- Date
- 2016
- Source
- European Journal of Medicinal Chemistry 108: 258-273 (Journal)
- Registered Authors
- Keywords
- Anticancer agents, Antiproliferative activity, Apoptosis, Cell cycle, Indeno[1,2-b]quinoxaline derivatives, Zebrafish xenograft assay
- MeSH Terms
-
- Animals
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology*
- Apoptosis/drug effects
- Cell Line
- Cell Proliferation/drug effects
- Dose-Response Relationship, Drug
- Drug Discovery*
- Drug Screening Assays, Antitumor
- Humans
- Indenes/chemical synthesis
- Indenes/chemistry
- Indenes/pharmacology*
- Molecular Structure
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/pathology
- Quinoxalines/chemical synthesis
- Quinoxalines/chemistry
- Quinoxalines/pharmacology*
- Structure-Activity Relationship
- Zebrafish
- PubMed
- 26686931 Full text @ Eur. J. Med. Chem.
Citation
Tseng, C.H., Chen, Y.R., Tzeng, C.C., Liu, W., Chou, C.K., Chiu, C.C., Chen, Y.L. (2016) Discovery of indeno[1,2-b]quinoxaline derivatives as potential anticancer agents. European Journal of Medicinal Chemistry. 108:258-273.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping