Hypoxia-Selective Agents Derived from Quinoxaline 1,4-Di-N-oxides

Abstract

Hypoxic cells, which are a common feature of solid tumors, but not normal tissues, are resistant to both anticancer drugs and radiation therapy. Thus the identification of drugs with selective toxicity toward hypoxic cells is an important objective in anticancer chemotherapy. The benzotriazine di-N-oxide (SR 4233, Tirapazamine) has been shown to be an efficient and selective cytotoxin for hypoxic cells. Since the bioreductive activation of Tirapazamine is thought to be due to the presence of the 1,4-di-N-oxide moiety, a series of 3-aminoquinoxaline-2-carbonitrile 1,4-di-N-oxides with a range of electron-donating and -withdrawing substitutents in the 6- and/or 7- positions has been synthesized and evaluated for toxicity to hypoxic cells. Electrochemical studies of the quinoxaline di-N-oxides and Tirapazamine showed that as the electron-withdrawing nature of the 6(7)-substituent increases, the reduction potential becomes more positive and the compound is more readily reduced. Apart from the unsubstituted 6a and the 6,7-dimethyl derivative 6c, the quinoxaline di-N-oxides have reduction potentials significantly more positive than Tirapazamine (Epc -0.90 V). The most potent cytotoxins to cells in culture were the 6,7-dichloro and 6,7-difluoro derivatives 6i and 6l, which were 30-fold more potent than Tirapazamine. The 6(7)-fluoro and 6(7)-chloro compounds, 6e and 6h, showed the greatest hypoxia selectivity. Four of the compounds, 63, 6f, 6h and 6i, killed the inner cells of multicellular tumor spheroids in vitro. In vivo Balb/c mice tolerated a dose of these four compounds twice the size of that of Tirapazamine. This study demonstrates that quinoxaline 1,4-di-N-oxides could provide useful hypoxia-selective therapeutic agents.

Energetic and structural characterization of 2‐R‐3‐methylquinoxaline‐1,4‐dioxides (R = benzoyl or tert‐butoxycarbonyl): experimental and computational studies

“…[1][2][3][4][5][6] In fact, the quinoxaline 1,4-dioxides are a group of synthetic antibacterial agents largely used as medicinal feed additives 7,8 and they are also used as bioreductive cytotoxic agents/species. [9][10][11] Several compounds derived from quinoxaline 1,4-dioxide, which were activated under hypoxic conditions, are at different stages of development to be used as drugs. These compounds are thought to be active due to the creation of cytotoxic radicals formed after N-O bond cleavage taking place in these N-dioxide compounds.…”

Synthesis of quinoxaline 1,4-di-N-oxide derivatives on solid support using room temperature and microwave-assisted solvent-free procedures

“…Some authors have used the Beirut reaction to synthesize various heterocyclic compounds by reacting benzofuroxane with enolates and enamines reporting good to excellent yields; however, when β-keto esters and diketones in basic medium (triethylamine) are used, low yields of quinoxaline 1,4-di-Noxide derivatives are obtained. 9,10 Considering the generation of the carbanion on α-methylene as a key step in the reaction mechanism that forms quinoxaline, we propose that there was greater difficulty in generating the carbanion on β-keto ester derivatives by effect resonance, which may explain the low yields in entry 4 and 5 and the lack of compounds in 3 and 10. This behavior could also explain the low yield in aromatic diketones, but this conclusion is not definite and needs further experimentation.…”

“…Subsequently, there is a nucleophilic attack of a second nitrogen on the carbonyl group with the resulting cyclization and reorganization binding ( Figure 2); however, this procedure has several limitations such as a low yield and a prolonged reaction time. [9][10][11][12] Therefore, the development of new catalysts for the synthesis of quinoxaline 1,4-di-N-oxide derivatives is highly desirable.…”

Preparation of 6-Substituted Quinoxaline JSP-1 Inhibitors by Microwave Accelerated Nucleophilic Substitution

“…Quinoxalines are an important class of nitrogen-containing heterocycles with a variety of biological activities, specifically as AMPA/Gly N receptor antagonists [1][2][3], angiotensin II receptor antagonists [4][5], anticancer agents [6][7][8][9], antiinfection agents [10][11] and immunomodulating agents [12][13].…”