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Molecules 2012, 17(8), 9683-9696; doi:10.3390/molecules17089683
Article

Synthesis and Biological Evaluation of 3-Aryl-quinoxaline-2-carbonitrile 1,4-Di-N-oxide Derivatives as Hypoxic Selective Anti-tumor Agents

1,2, 1, 1, 3, 1 and 1,*
Received: 6 July 2012; in revised form: 1 August 2012 / Accepted: 2 August 2012 / Published: 13 August 2012
(This article belongs to the Section Medicinal Chemistry)
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Abstract: 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.
Keywords: 3-aryl-2-quinoxaline-carbonitrile 1,4-dioxide; hypoxic cytotoxic activity; SAR 3-aryl-2-quinoxaline-carbonitrile 1,4-dioxide; hypoxic cytotoxic activity; SAR
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Hu, Y.; Xia, Q.; Shangguan, S.; Liu, X.; Hu, Y.; Sheng, R. Synthesis and Biological Evaluation of 3-Aryl-quinoxaline-2-carbonitrile 1,4-Di-N-oxide Derivatives as Hypoxic Selective Anti-tumor Agents. Molecules 2012, 17, 9683-9696.

AMA Style

Hu Y, Xia Q, Shangguan S, Liu X, Hu Y, Sheng R. Synthesis and Biological Evaluation of 3-Aryl-quinoxaline-2-carbonitrile 1,4-Di-N-oxide Derivatives as Hypoxic Selective Anti-tumor Agents. Molecules. 2012; 17(8):9683-9696.

Chicago/Turabian Style

Hu, Yunzhen; Xia, Qing; Shangguan, Shihao; Liu, Xiaowen; Hu, Yongzhou; Sheng, Rong. 2012. "Synthesis and Biological Evaluation of 3-Aryl-quinoxaline-2-carbonitrile 1,4-Di-N-oxide Derivatives as Hypoxic Selective Anti-tumor Agents." Molecules 17, no. 8: 9683-9696.



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