Synthesis and Biological Evaluation of 3-Aryl-quinoxaline-2-carbonitrile 1,4-Di-N-oxide Derivatives as Hypoxic Selective Anti-tumor Agents
| Autor: | Qing Xia, Xiaowen Liu, Rong Sheng, Shihao Shangguan, Yongzhou Hu, Yunzhen Hu |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
hypoxic cytotoxic activity
Stereochemistry Substituent Pharmaceutical Science 3-aryl-2-quinoxaline-carbonitrile 1 4-dioxide Antineoplastic Agents Apoptosis Article Analytical Chemistry chemistry.chemical_compound Quinoxaline Cell Line Tumor Neoplasms Quinoxalines Drug Discovery Nitriles Cytotoxic T cell Humans Physical and Theoretical Chemistry Cytotoxicity SAR Aryl Organic Chemistry Cell Hypoxia chemistry Biochemistry Chemistry (miscellaneous) Cell culture Molecular Medicine Drug Screening Assays Antitumor K562 cells |
| Zdroj: | Molecules; Volume 17; Issue 8; Pages: 9683-9696 Molecules |
| ISSN: | 1420-3049 |
| DOI: | 10.3390/molecules17089683 |
| Popis: | A series of 3-aryl-2-quinoxaline-carbonitrile 1,4-di-N-oxide derivatives were designed, synthesized and evaluated for hypoxic and normoxic cytotoxic activity against human SMMC-7721, K562, KB, A549 and PC-3 cell lines. Many of these new compounds displayed more potent hypoxic cytotoxic activity compared with TX-402 and TPZ in the tumor cells based evaluation, which confirmed our hypothesis that the replacement of the 3-amine with the substituted aryl ring of TX-402 increases the hypoxic anti-tumor activity. The preliminary SAR revealed that 3-chloro was a favorable substituent in the phenyl ring for hypoxic cytotoxicity and 7-methyl or 7-methoxy substituted derivatives exhibited better hypoxic selectivity against most of the tested cell lines. The most potent compound, 7-methyl-3-(3-chlorophenyl)-quinoxaline-2-carbonitrile 1,4-dioxide (9h) was selected for further anti-tumor evaluation and mechanistic study. It also exhibited significant cytotoxic activity against BEL-7402, HepG2, HL-60, NCI-H460, HCT-116 and CHP126 cell lines in hypoxia with IC50 values ranging from 0.31 to 3.16 μM, and preliminary mechanism study revealed that 9h induced apoptosis in a caspase-dependent pathway. |
| Databáze: | OpenAIRE |
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