Synthesis and biological evaluation of 3-aryl-quinoxaline-2-carbonitrile 1,4-di-N-oxide derivatives as hypoxic selective anti-tumor agents.

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.

• Authors: Yunzhen Hu, Qing Xia, Shihao Shangguan, Xiaowen Liu, Yongzhou Hu, Rong Sheng
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 17 Issue 8 Pg. 9683-96 (Aug 13 2012) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 22890172 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Nitriles
• Quinoxalines
• quinoxaline-2-carbonitrile 1,4-di-N-oxide

Topics

• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Apoptosis (drug effects)
• Cell Hypoxia
• Cell Line, Tumor
• Drug Screening Assays, Antitumor
• Humans
• Neoplasms (drug therapy, metabolism)
• Nitriles (chemical synthesis, chemistry, pharmacology)
• Quinoxalines (chemical synthesis, chemistry, pharmacology)