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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,*
1 ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang University, Hangzhou 310058, China 2 Department of Pharmacy, the First Affiliated Hospital of college of Medicine, Zhejiang University, Hangzhou 310006, China 3 Institute of Pharmacology & Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
* Author to whom correspondence should be addressed.
Received: 6 July 2012 / Revised: 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 (CC BY 3.0).

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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.

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