Electron and Spin-Density Analysis of Tirapazamine Reduction Chemistry

Tirapazamine (TPZ, <b>1</b>, 3-amino-1,2,4-benzotriazine 1,4-<i>N</i>,<i>N</i>-dioxide), the radical anion <b>2</b> formed by one-electron reduction of <b>1</b>, and neutral radicals <b>3</b> and <b>4</b> formed by protonation of <b>2</b> at O­(N4) or O­(N1), respectively, and their N–OH homolyses <b>3</b> → <b>5</b> + ·OH and <b>4</b> → <b>6</b> + ·OH have been studied with configuration interaction theory, perturbation theory, and density functional theory. A comprehensive comparative analysis is presented of structures and electronic structures and with focus on the development of an understanding of the spin-density distributions of the radical species. The skeletons of radicals <b>3</b> and <b>4</b> are distinctly nonplanar, several stereoisomeric structures are discussed, and there exists an intrinsic preference for <b>3</b> over <b>4</b>. The <i>N</i>-oxides <b>1</b>, <b>5</b>, and <b>6</b> have closed-shell singlet ground states and low-lying, singlet biradical (<b>SP-1</b>, <b>SP-6</b>) or biradicaloid (<b>SP-5</b>) excited states. The doublet radicals <b>2</b>, <b>3</b>, and <b>4</b> are heavily spin-polarized. Most of the spin density of the doublet radicals <b>2</b>, <b>3</b>, and <b>4</b> is located in one (N,O)-region, and in particular, <b>3</b> and <b>4</b> are not C3-centered radicals. Significant amounts of spin density occur in both rings in the singlet biradical­(oid) excited states of <b>1</b>, <b>5</b>, and <b>6</b>. The dipole moment of the N2–C3­(X) bond is large, and the nature of X provides a powerful handle to modulate the N2–C3 bond polarity with opposite effects on the two NO regions. Our studies show very low proton affinities of radical anion <b>2</b> and suggest that the p<i>K</i>_a of radical [<b>2</b>+H] might be lower than 6. Implications are discussed regarding the formation of hydroxyl from <b>3</b> and/or <b>4</b>, regarding the ability of <b>5</b> and <b>6</b> to react with carbon-centered radicals in a manner that ultimately leads to oxygen transfer, and regarding the interpretation of the EPR spectra of reduced TPZ species and of their spin-trap adducts

Electron and Spin-Density Analysis of Tirapazamine Reduction Chemistry

Tirapazamine (TPZ, <b>1</b>, 3-amino-1,2,4-benzotriazine 1,4-<i>N</i>,<i>N</i>-dioxide), the radical anion <b>2</b> formed by one-electron reduction of <b>1</b>, and neutral radicals <b>3</b> and <b>4</b> formed by protonation of <b>2</b> at O­(N4) or O­(N1), respectively, and their N–OH homolyses <b>3</b> → <b>5</b> + ·OH and <b>4</b> → <b>6</b> + ·OH have been studied with configuration interaction theory, perturbation theory, and density functional theory. A comprehensive comparative analysis is presented of structures and electronic structures and with focus on the development of an understanding of the spin-density distributions of the radical species. The skeletons of radicals <b>3</b> and <b>4</b> are distinctly nonplanar, several stereoisomeric structures are discussed, and there exists an intrinsic preference for <b>3</b> over <b>4</b>. The <i>N</i>-oxides <b>1</b>, <b>5</b>, and <b>6</b> have closed-shell singlet ground states and low-lying, singlet biradical (<b>SP-1</b>, <b>SP-6</b>) or biradicaloid (<b>SP-5</b>) excited states. The doublet radicals <b>2</b>, <b>3</b>, and <b>4</b> are heavily spin-polarized. Most of the spin density of the doublet radicals <b>2</b>, <b>3</b>, and <b>4</b> is located in one (N,O)-region, and in particular, <b>3</b> and <b>4</b> are not C3-centered radicals. Significant amounts of spin density occur in both rings in the singlet biradical­(oid) excited states of <b>1</b>, <b>5</b>, and <b>6</b>. The dipole moment of the N2–C3­(X) bond is large, and the nature of X provides a powerful handle to modulate the N2–C3 bond polarity with opposite effects on the two NO regions. Our studies show very low proton affinities of radical anion <b>2</b> and suggest that the p<i>K</i>_a of radical [<b>2</b>+H] might be lower than 6. Implications are discussed regarding the formation of hydroxyl from <b>3</b> and/or <b>4</b>, regarding the ability of <b>5</b> and <b>6</b> to react with carbon-centered radicals in a manner that ultimately leads to oxygen transfer, and regarding the interpretation of the EPR spectra of reduced TPZ species and of their spin-trap adducts

On the Reaction Mechanism of Tirapazamine Reduction Chemistry: Unimolecular N–OH Homolysis, Stepwise Dehydration, or Triazene Ring-Opening

The initial steps of the activation of tirapazamine (TPZ, <b>1</b>, 3-amino-1,2,4-benzotriazine 1,4-<i>N</i>,<i>N</i>-dioxide) under hypoxic conditions consist of the one-electron reduction of <b>1</b> to radical anion <b>2</b> and the protonation of <b>2</b> at O­(N4) or O­(N1) to form neutral radicals <b>3</b> and <b>4</b>, respectively. There are some questions, however, as to whether radicals <b>3</b> and/or <b>4</b> will then undergo N–OH homolyses <b>3</b> → <b>5</b> + ·OH and <b>4</b> → <b>6</b> + ·OH or, alternatively, whether <b>3</b> and/or <b>4</b> may react by dehydration and form aminyl radicals via <b>3</b> → <b>11</b> + H₂O and <b>4</b> → <b>12</b> + H₂O or phenyl radicals via <b>3</b> → <b>17</b> + H₂O. These outcomes might depend on the chemistry <i>after the homolysis</i> of <b>3</b> and/or <b>4</b>, that is, dehydration may be the result of a two-step sequence that involves N–OH homolysis and formation of ·OH aggregates of <b>5</b> and <b>6</b> followed by H-abstraction within the ·OH aggregates to form hydrates of aminyls <b>11</b> and <b>12</b> or of phenyl <b>17</b>. We studied these processes with configuration interaction theory, perturbation theory, and density functional theory. All stationary structures of OH aggregates of <b>5</b> and <b>6</b>, of H₂O aggregates of <b>11</b>, <b>12</b>, and <b>17</b>, and of the transition state structures for H-abstraction were located and characterized by vibrational analysis and with methods of electron and spin-density analysis. The doublet radical <b>17</b> is a normal spin-polarized radical, whereas the doublet radicals <b>11</b> and <b>12</b> feature quartet instabilities. The computed reaction energies and activation barriers allow for dehydration in principle, but the productivity of all of these channels should be low for kinetic and dynamic reasons. With a view to plausible scenarios for the generation of latent aryl radical species <i>without</i> dehydration, we scanned the potential energy surfaces of <b>2</b>–<b>4</b> as a function of the (O)­N1–Y (Y = C5a, N2) and (O)­N4–Z (Z = C4a, C3) bond lengths. The elongation of any one of these bonds by 0.5 Å requires less than 25 kcal/mol, and this finding strongly suggests the possibility of bimolecular reactions of the spin-trap molecules with <b>2</b>–<b>4</b> concomitant with triazene ring-opening

Reconstruction of mitogenomes by NGS and phylogenetic implications for leaf beetles

<p>Mitochondrial genome (mitogenome) sequences are frequently used to infer phylogenetic relationships of insects at different taxonomic levels. Next-generation sequencing (NGS) techniques are revolutionizing many fields of biology, and allow for acquisition of insect mitogenomes for large number of species simultaneously. In this study, 20 full or partial mitogenomes were sequenced from pooled genomic DNA samples by NGS for leaf beetles (Chrysomelidae). Combined with published mitogenome sequences, a higher level phylogeny of Chrysomelidae was reconstructed under maximum likelihood and Bayesian inference with different models and various data treatments. The results revealed support for a basal position of Bruchinae within Chrysomelidae. In addition, two major subfamily groupings were recovered: one including seven subfamilies, namely Donaciinae, Criocerinae, Spilopyrinae, Cassidinae, Cryptocephalinae, Chlamisinae and Eumolpinae, another containing a non-monophyletic Chrysomelinae and a monophyletic Galerucinae.</p

Bind3P: Optimization of a Water Model Based on Host–Guest Binding Data

We report a water model, Bind3P (Version 0.1), which was obtained by using sensitivity analysis to readjust the Lennard-Jones parameters of the TIP3P model against experimental binding free energies for six host–guest systems, along with pure liquid properties. Tests of Bind3P against >100 experimental binding free energies and enthalpies for host–guest systems distinct from the training set show a consistent drop in the mean signed error, relative to matched calculations with TIP3P. Importantly, Bind3P also yields some improvement in the hydration free energies of small organic molecules and preserves the accuracy of bulk water properties, such as density and the heat of vaporization. The same approach can be applied to more sophisticated water models that can better represent pure water properties. These results lend further support to the concept of integrating host–guest binding data into force field parametrization

Bind3P: Optimization of a Water Model Based on Host–Guest Binding Data

We report a water model, Bind3P (Version 0.1), which was obtained by using sensitivity analysis to readjust the Lennard-Jones parameters of the TIP3P model against experimental binding free energies for six host–guest systems, along with pure liquid properties. Tests of Bind3P against >100 experimental binding free energies and enthalpies for host–guest systems distinct from the training set show a consistent drop in the mean signed error, relative to matched calculations with TIP3P. Importantly, Bind3P also yields some improvement in the hydration free energies of small organic molecules and preserves the accuracy of bulk water properties, such as density and the heat of vaporization. The same approach can be applied to more sophisticated water models that can better represent pure water properties. These results lend further support to the concept of integrating host–guest binding data into force field parametrization

Binding Enthalpy Calculations for a Neutral Host–Guest Pair Yield Widely Divergent Salt Effects across Water Models

Dissolved salts are a part of the physiological milieu and can significantly influence the kinetics and thermodynamics of various biomolecular processes, such as binding and catalysis; thus, it is important for molecular simulations to reliably describe their effects. The present study uses a simple, nonionized host–guest model system to study the sensitivity of computed binding enthalpies to the choice of water and salt models. Molecular dynamics simulations of a cucurbit[7]­uril host with a neutral guest molecule show striking differences in the salt dependency of the binding enthalpy across four water models, TIP3P, SPC/E, TIP4P-Ew, and OPC, with additional sensitivity to the choice of parameters for sodium and chloride. In particular, although all of the models predict that binding will be less exothermic with increasing NaCl concentration, the strength of this effect varies by 7 kcal/mol across models. The differences appear to result primarily from differences in the number of sodium ions displaced from the host upon binding the guest rather than from differences in the enthalpy associated with this displacement, and it is the electrostatic energy that contributes most to the changes in enthalpy with increasing salt concentration. That a high sensitivity of salt affecting the choice of water model, as observed for the present host–guest system despite it being nonionized, raises issues regarding the selection and adjustment of water models for use with biological macromolecules, especially as these typically possess multiple ionized groups that can interact relatively strongly with ions in solution

Improving the Efficiency and Activity of Electrocatalysts for the Reduction of CO₂ through Supramolecular Assembly with Amino Acid-Modified Ligands

The use of hydrogen-bonding interactions to direct the noncovalent assembly of a Re-based bimetallic supramolecular electrocatalyst containing either tyrosine or phenylalanine residues is reported. Computational modeling and spectroelectrochemical characterization indicate that under catalytic conditions the phenol residues of tyrosine can act both as pendant proton sources and participate in the structural assembly of the bimetallic active species. As a result, an increased rate of catalysis is observed experimentally for the reductive disproportionation of CO₂ to CO and CO₃^2– by a tyrosine-modified complex in comparison to a control complex containing phenylalanine residues. These findings demonstrate that noncovalent assembly is a powerful method for generating new bimetallic electrocatalyst systems where the choice of substituent can be used to both control structural assembly and introduce cocatalytic moieties

Patterning Poly(dimethylsiloxane) Microspheres via Combination of Oxygen Plasma Exposure and Solvent Treatment

Here a simple low-cost yet robust route has been developed to prepare poly­(dimethylsiloxane) (PDMS) microspheres with various surface wrinkle patterns. First, the aqueous-phase-synthesized PDMS microspheres are exposed to oxygen plasma (OP), yielding the oxidized SiO_<i>x</i> layer and the corresponding stiff shell/compliant core system. The subsequent solvent swelling and solvent evaporation induce the spontaneous formation of a series of curvature and overstress-sensitive spherical wrinkles such as dimples, short rodlike depressions, and herringbone and labyrinth patterns. The effects of the experimental parameters, including the radius and Young’s modulus of the microspheres, the OP exposure duration, and the nature of the solvents, on these tunable spherical wrinkles have been systematically studied. The experimental results reveal that a power-law dependence of the wrinkling wavelength on the microsphere radius exists. Furthermore, the induced wrinkling patterns are inherently characteristic of a memory effect and good reversibility. Meanwhile, the corresponding phase diagram of the wrinkle morphologies on the spherical surfaces vs the normalized radius of curvature and the excess swelling degree has been demonstrated. It is envisioned that the introduced strategy in principle could be applied to other curved surfaces for expeditious generation of well-defined wrinkle morphologies, which not only enables the fabrication of solids with multifunctional surface properties, but also provides important implications for the morphogenesis in soft materials and tissues

Additional file 1 of Characteristics of human papillomavirus prevalence and infection patterns among women aged 25–64 according to age groups and cytology results in Ordos City, China

Additional file 1.  eTable 1. Prevalence of different HPV genotypes infection by age group. eTable 2. Prevalence of different HPV genotypes infection by cytology results