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.
Highlights
Hypoxia is an inevitable circumstance in most solid tumors resulting from rapid tumor growth with an inefficient microvascular system
To find new lead compounds with enhanced potency and hypoxic selectivity, we report here the design, synthesis and evaluation of a series of 3-aryl-2-quinoxalinecarbonitrile-1,4-di-N-oxide derivatives 9a–t (Figure 1) as hypoxic selective anti-tumor agents
The synthetic route of 3-aryl-2-quinoxalinecarbonitrile-1,4-di-N-oxides 9a–t is shown in Scheme 1
Summary
Hypoxia is an inevitable circumstance in most solid tumors resulting from rapid tumor growth with an inefficient microvascular system. N-oxides, aliphatic N-oxides and transition metal complexes) have been identified as hypoxic cytotoxins in recent years These compounds were selectively activated by reductive enzymes within hypoxic environment and generated toxic metabolites causing cell death [3]. TPZ was bioreductively activated through the one-electron reduction of the benzotriazine-l,4-di-N-oxide moiety by reductase to form hydroxyl and benzotriazinyl radicals that cause DNA damage. It had already been introduced into phase II and III clinical trials in combination with radiotherapy and chemotherapy for advanced head and neck cancers [4,5]. TX-402 exhibited efficient hypoxic selective anti-tumor activities against various tumor cells with a similar
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