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Fuchs, Tarra; Barnes, Charles L.; Gates, Kent S.

doi:10.1023/a:1015655507952

Cited by 5 publications

(3 citation statements)

References 8 publications

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“…Indirect evidence for the proposed generation of the C5-aryl radical, 18, can be taken from the reported formation of the C5-methyl adduct of TPZ upon exposure of TPZ to methyl radicals. 43 An alternative initiating reaction to that proposed by these authors of the methyl radical addition to the C5 position is for methyl radical addition to the oxygen of the N-O bond. There is both experimental and theoretical evidence for this reaction between TPZ and C-centered radicals.…”

Section: Discussionmentioning

confidence: 99%

“…In our case, the protonated radical for TPZ, 16 , has a calculated out of plane N1−N4−O angle of 162° (see Supporting Information, Figure S4), which could allow for a mixing of π* and σ* orbitals required for bond fragmentation. Indirect evidence for the proposed generation of the C5-aryl radical, 18 , can be taken from the reported formation of the C5-methyl adduct of TPZ upon exposure of TPZ to methyl radicals . An alternative initiating reaction to that proposed by these authors of the methyl radical addition to the C5 position is for methyl radical addition to the oxygen of the N−O bond.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of Radicals Formed Following Enzymatic Reduction of 3-Substituted Analogues of the Hypoxia-Selective Cytotoxin 3-Amino-1,2,4-Benzotriazine 1,4-Dioxide (Tirapazamine)

et al. 2010

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The mechanism by which the 1,2,4-benzotriazine 1,4-dioxide (BTO) class of bioreductive hypoxia-selective prodrugs (HSPs) form reactive radicals that kill cancer cells has been investigated by steady-state radiolysis, pulse radiolysis (PR), electron paramagnetic resonance (EPR), and density functional theory (DFT) calculations. Tirapazamine (TPZ, 3-amino BTO, 1) and a series of 3-substituted analogues, -H (2), -methyl (3), -ethyl (4), -methoxy (5), -ethoxymethoxy (6), and -phenyl (7), were reduced in aqueous solution under anaerobic steady-state radiolysis conditions, and their radicals were found to remove the substrates by short chain reactions of different lengths in the presence of formate ions. Multiple carbon-centered radical intermediates, produced upon anaerobic incubation of the compounds with cytochrome P(450) reductase enriched microsomes, were trapped by N-tert-butyl-alpha-phenylnitrone and observed using EPR. The highly oxidizing oxymethyl radical, from compound 5, was identified, and experimental spectra obtained for compounds 1, 2, 3, and 7 were well simulated after the inclusion of aryl radicals. The identification of a range of oxidizing radicals in the metabolism of the BTO compounds gives a new insight into the mechanism by which these HSPs can cause a wide variety of damage to biological targets such as DNA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Characterization of Radicals Formed Following Enzymatic Reduction of 3-Substituted Analogues of the Hypoxia-Selective Cytotoxin 3-Amino-1,2,4-Benzotriazine 1,4-Dioxide (Tirapazamine)

et al. 2010

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“…37 The selected optimized conformations were then submitted to electrostatic charge calculations. The electrostatic charges were determined so as to reproduce the B3LYP/6-311++G * * quantum molecular Mechanical Electrostatic Potential (MEP).…”

Section: Conformation Obtained and Theoretical Aspects In The Calculamentioning

confidence: 99%

Theoretical Study of Adiabatic and Vertical Electron Affinity of Radiosensitizers in Solution Part 2: Analogues of Tirapazamine

Ramalho

Cunha

Alencastro

2004

J. Theor. Comput. Chem.

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Tirapazamine is a radiosensitizer, whose biological activity is associated to its electron affinity (EA). The electron affinity can be divided in two main processes: Vertical and Adiabatic. In this work, we calculated the EAs of nitroimidazoles ( Fig. 2) using HF and DFT methods and evaluated solvent effects (water and carbon tetrachloride) on EAs. For water, we combined the Polarized Continuum Model (PCM) and free energy perturbation (Finite Difference Thermodynamic Integration, FDTI) methods. For carbon tetrachloride, we used the FDTI method. The values of adiabatic EA obtained are in agreement with experimental data (deviations of 13.25 meV). The vertical EA were calculated according to Cederbaum's Outer Valence Green Function (OVGF) method. This study, which relays on theoretical aspects of free energy calculations on charged molecules in solution, could be helpful in the rational design of new and more selective bioreductive anticancer drugs.

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