Isotopic Labeling Experiments That Elucidate the Mechanism of DNA Strand Cleavage by the Hypoxia-Selective Antitumor Agent 1,2,4-Benzotriazine 1,4-Di-<i>N</i>-oxide

Shen, Xiulong; Rajapakse, Anuruddha; Gallazzi, Fabio; Junnotula, Venkatraman; Fuchs-Knotts, Tarra; Glaser, Rainer; Gates, Kent S.

doi:10.1021/tx400356y

Cited by 15 publications

(36 citation statements)

References 64 publications

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“…N-oxides also play a significant role in materials chemistry. Many heteroaromatic N-oxides are identified as potential anticancer and antimalarial drugs or reductors of bacterial deposition [5][6][7] and as antitumor agents [8]. Many heteroaromatic N-oxides are identified as potential anticancer and antimalarial drugs or reductors of bacterial deposition [5][6][7] and as antitumor agents [8].…”

Section: Introductionmentioning

confidence: 99%

Complexation of thorium with pyridine monocarboxylate-N-oxides: Thermodynamic and computational studies

Dumpala

Rawat

Boda

et al. 2018

The Journal of Chemical Thermodynamics

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a b s t r a c tThe feed wastes and waste water treatment plants are the major sources for the entry of N-oxides into the soils then to aquatic life. The complexation of actinides with potentially stable anthropogenic ligands facilitate the transportation and migration of the actinides from the source confinement. The present study describes the determination of thermodynamic parameters for the complexation of Th(IV) with the three isomeric pyridine monocarboxylates (PCNO) namely picolinic acid-N-oxide (PANO), nicotinic acid-N-oxide (NANO) and isonicotinic acid-N-oxide (IANO). The potentiometric and isothermal calorimetric titrations were carried out to determine the stability and enthalpy of the formations for all the Th(IV)-PCNO complexes. Th-PANO complexes are more stable than Th-NANO and Th-IANO complexes which can be attributed to chelate formation in the former complexes. Formation of all the Th-PCNO complexes are endothermic and are entropy driven. The geometries for all the predicted complexes are optimized the energies, bond distances and charges on individual atoms are obtained using TURBOMOLE software. The theoretical calculation corroborated the experimental determinations.

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Section: Introductionmentioning

confidence: 99%

Complexation of thorium with pyridine monocarboxylate-N-oxides: Thermodynamic and computational studies

Dumpala

Rawat

Boda

et al. 2018

The Journal of Chemical Thermodynamics

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“…3-Amino-1,2,4-benzotriazine-1,4-dioxide (ti rapaza mi ne, TPZ) and its analogs are hypoxia-selective anticancer agents ( [1], and references therein). TPZ (1) is enzymatically reduced in a single-electron way to a free radical (2), which forms DNAdamaging species under hypoxic conditions, namely, an oxidizing hydroxyl radical (OH•) ( [2], and references therein), and/or a highly reactive benzotriazinyl radical (3) that abstracts a hydrogen atom from DNA ( [3,4], and references therein) ( Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

“…The nature of DNA-damaging species is still a matter of debate. In the cell, TPZ is converted into two main relatively nontoxic metabolites, its mono-1-oxide (4), possibly via free radical (2) intermediate [2], and its nor-oxide (6), presumably via 4-oxide (5) intermediate ( Fig. 1) [5].…”

Section: Introductionmentioning

confidence: 99%

Enzymatic single-electron reduction and aerobic cytotoxicity of tirapazamine and its 1-oxide and nor-oxide metabolites

Šarlauskas¹,

Nemeikaitė-Čėnienė²,

Maroziene³

et al. 2018

chemija

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Aerobic cytotoxicity of 3-amino-1,2,4-benzotriazine-1,4-dioxide (tirapazamine, TPZ), a bioreductively activated hypoxia-specific anticancer agent, is responsible for TPZ side effects in chemotherapy. In order to clarify its mechanisms, we examined the aerobic cytotoxicity of TPZ and its main metabolites, 3-amino-1,2,4-benzotriazine-1-oxide and 3-amino-1,2,4-benzotriazine in murine hepatoma MH22a cells, and their reduction by NADPH:cytochrome P-450 reductase (P-450R) and ferredoxin:NADP+ reductase (FNR). Analogous studies of several quinones and nitroaromatic compounds with similar values of single-electron reduction midpoint potentials (E17) were carried out. In single-electron reduction by P-450R and FNR, the reactivity of TPZ and its monoxide was similar to that of quinones and nitroaromatics, and increased with an increase in their E17. The cytotoxicity of TPZ and its metabolites possessed a prooxidant character, because it was partly prevented by an antioxidant N,N’-diphenyl-p-phenylene diamine and desferrioxamine, and potentiated by 1,3-bis(2-chloroethyl)-1-nitrosourea. Importantly, the cytotoxicity of TPZ and, possibly, its 1-N-oxide, was much higher than that of quinones and nitroaromatics with similar values of E17 and redox cycling activities. A possible additional factor in the aerobic cytotoxicity of TPZ is its reductive activation in oxygen-poor cell nuclei, leading to the formation of DNA-damaging species similar to those forming under hypoxia.

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“…Pyridine and quinoline N-oxides find application in regioselective and enantioselective catalysis (Hwang et al, 2014). Many heteroaromatic N-oxides have been identified as potential anticancer (Shen et al, 2014) and antimalarial drugs (Ibrahim et al, 2010), reducers of bacterial deposition (Vanoyan et al, 2010), and antitumour (Chowdhury et al, 2012) and anti-HIV agents (Balzarini et al, 2005). They have also been used in the radiotherapy of cancer (Zię ba-Mizgała et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Investigation of the effect of the N-oxidation process on the interaction of selected pyridine compounds with biomacromolecules: structural, spectral, theoretical and docking studies

et al. 2019

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Two new N‐oxide compounds, namely glycinium 2‐carboxy‐1‐(λ1‐oxidaneyl)‐1λ4‐pyridine‐6‐carboxylate–glycine–water (1/1/1), C2H6NO2+·C7H4NO5−·C2H5NO2·H2O or [(2,6‐HpydcO)(HGLY)(GLY)(H2O)], 1, and methyl 6‐carboxy‐1‐(λ1‐oxidaneyl)‐1λ4‐pyridine‐2‐carboxylate, C8H7NO5 or 2,6‐HMepydcO, 2, were prepared and identified by elemental analysis, FT–IR, Raman spectroscopy and single‐crystal X‐ray diffraction. The X‐ray analysis of 1 revealed an ionic compound containing a 2,6‐HpydcO− anion, a glycinium cation, a neutral glycine molecule and a water molecule. Compound 2 is a neutral compound with two independent units in its crystal structure. In addition to the hydrogen bonds, the crystal network is stabilized by π–π stacking interactions of the types pyridine–carboxylate and carboxylate–carboxylate. The thermodynamic stability and charge‐distribution patterns for isolated molecules of 2,6‐H2pydcO and 2,6‐HMepydcO, and their two similar derivatives, pyridine‐2,6‐dicarboxylic acid (2,6‐H2pydc) and dimethyl 1‐(λ1‐oxidaneyl)‐1λ4‐pyridine‐2,6‐dicarboxylate (2,6‐Me2pydcO), were studied by density functional theory (DFT) and natural bond orbital (NBO) analysis, respectively. The ability of these compounds and their analogues to interact with nine selected biomacromolecules (BRAF kinase, CatB, DNA gyrase, HDAC7, rHA, RNR, TrxR, TS and Top II) was investigated using docking calculations.

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Isotopic Labeling Experiments That Elucidate the Mechanism of DNA Strand Cleavage by the Hypoxia-Selective Antitumor Agent 1,2,4-Benzotriazine 1,4-Di-N-oxide

Cited by 15 publications

References 64 publications

Complexation of thorium with pyridine monocarboxylate-N-oxides: Thermodynamic and computational studies

Complexation of thorium with pyridine monocarboxylate-N-oxides: Thermodynamic and computational studies

Enzymatic single-electron reduction and aerobic cytotoxicity of tirapazamine and its 1-oxide and nor-oxide metabolites

Investigation of the effect of the N-oxidation process on the interaction of selected pyridine compounds with biomacromolecules: structural, spectral, theoretical and docking studies

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