D. Scott Bohle

McGill University, Montréal, Quebec, Canada

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Publications (163)704.05 Total impact

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    ABSTRACT: We report herein spectroscopy and computational results that illustrate an efficient intramolecular deactivation pathway for meso-unsaturated boron-dipyrromethene (BODIPY) dyes in their singlet excited state. Our results show that the mechanism hinges on the structural flexibility imparted by the boron atom and on the energetic stabilization conferred by extending the conjugation into the meso substituent, which is otherwise unconjugated in the ground state. Following photoexcitation, rotation along the dihedral angle of the meso unsaturated group results in its conjugation at the expense of shifting one pyrrole moiety in dipyrrin out of the plane. Internal conversion to an energetically-hot, ground state species efficiently competes with emission. The mechanism applies to meso-vinyl, -formyl and -iminyl moieties. The presence of methyl groups at positions C1 and C7 exacerbates the energetic penalty towards conjugation of the meso groups leading to a small energy gap between relaxed excited state and ground state, and undetected emission quantum yields. Importantly, methyls at C1 and C7 prevent non-radiative deactivation in meso--aryl moieties, illus-trating that when push comes to shove, the energetic (kinetic) barrier towards reaching conjugation is too large for aryl moieties but low enough for smaller groups to effectively compete with radiative transitions. Wisely chosen meso-unsaturated BODIPY dyes may serve as richly sensitive platforms for the preparation of novel fluorogenic substrates to monitor chemical reactions or to probe the rigidity of their surrounding environment.
    The Journal of Physical Chemistry B 03/2015; DOI:10.1021/acs.jpcb.5b02080 · 3.38 Impact Factor
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    ABSTRACT: We report on the synthesis, characterization, and conformational analysis of 1,3-oxathiane nucleosides of both pyrimidine and purine nucleobases. The novel nucleoside analogues were prepared from readily available starting materials as α/β anomeric mixtures. The purine nucleosides were obtained as separable N7/N9 regioisomers. The structures were identified by extensive NMR analysis. The X-ray structure of the N7-β-OMe-purine nucleoside analogue 16 shows that the 1,3-oxathiane sugar ring adopts a perfect chair conformation with both the hydroxymethyl and the nucleobase placed in equatorial positions.
    European Journal of Organic Chemistry 02/2015; 2015(9). DOI:10.1002/ejoc.201403642 · 3.15 Impact Factor
  • D Scott Bohle, Zhijie Chua
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    ABSTRACT: The nitrogen acids RC(O)NHNO2, N-nitroamide, R = CH3 (1), C2H5 (2) and N-nitrocarbamate, R'OC(O)NHNO2, R' = CH3 (3), C2H5 (4) are a class of primary N-nitrocarboxamide compounds that oxidatively add to trans-Ir((I))(Cl)(N2)(PPh3)2 to give six-coordinate Ir((III))(η(2)-(NO2)-nitrogen acid)(H)(Cl)(PPh3)2 complexes 5-8. Unexpected fluxional behavior of the complexes in solution is observed by (1)H NMR spectroscopy. Reaction intermediates of the oxidative addition reactions were also observed and monitored using (31)P and (1)H NMR and solution IR spectroscopies. Complex 5 reacts with methyl triflate in CH3CN to generate bis(acetonitrile) complex (9) from a net loss of the nitrogen acid anion. P(CH3)2Ph reacts with 5 to give phosphine-substituted and P(CH3)2Ph addition isomers (10). Reactivity studies of 5 with CO gave metastable CO adduct isomer 11, which loses CO on prolonged standing in solution.
    Inorganic Chemistry 10/2014; 53(20). DOI:10.1021/ic5017033 · 4.79 Impact Factor
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    ABSTRACT: 1-(2-Nitrophenyl)-1-phenylamine and methyl 4-((2-nitrophenyl)amino)benzoate have been transformed into their corresponding urea derivatives through the action of chlorosulfonyl isocyanate. The initial sulfimidate product from the former reaction has sufficient stability so that it can be isolated and characterized as its disodium salt, and this, as well as three other subsequent products, have been characterized by X-ray diffraction. The corresponding intermediary urea was converted into its hydrazine derivative via a Hofmann rearrangement under oxidative conditions. Density functional theory has been used to examine the nature of the intermediates and transition states for the Hofmann rearrangement. There is little theoretical indication for a cyclic aziridinonium intermediate and the transition state between the urea and the isocyanate corresponds to a reactant-like rotation of the planar singlet nitrene before migration and formation of the new N−N bond.
    Canadian Journal of Chemistry 09/2014; 92(9). DOI:10.1139/cjc-2014-0132 · 1.01 Impact Factor
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    ABSTRACT: Darinaparsin (ZIO-101; S-dimethylarsino-glutathione; Dar) is a promising novel organic arsenical currently undergoing clinical studies in various malignancies. Dar consists of dimethylarsenic conjugated to glutathione (GSH). Dar induces more intracellular arsenic accumulation and more cell death than the FDA-approved arsenic trioxide (ATO) in vitro, but exhibits less systemic toxicity. Here, we propose a mechanism for Dar import that might explain these characteristics. Structural analysis of Dar suggests a putative breakdown product: dimethylarsino-cysteine (DMAC). We show that DMAC is very similar to Dar in terms of intracellular accumulation of arsenic, cell cycle arrest and cell death. We found that inhibition of γ-glutamyl-transpeptidase (γ-GT) protects human acute promyelocytic leukemia cells (NB4) from Dar, but not from DMAC, suggesting a role for γ-GT in the processing of Dar. Overall, our data supports a model where Dar, a GSH-S-conjugate, is processed at the cell surface by γ-GT leading to formation of DMAC, which is imported via xCT, xAG or potentially other cystine/cysteine importing systems. Further, we propose that Dar induces its own import via increased xCT expression. These mechanisms may explain the enhanced toxicity of Dar towards cancer cells compared with ATO.
    Molecular pharmacology 01/2014; 85(4). DOI:10.1124/mol.113.089433 · 4.12 Impact Factor
  • D. Scott Bohle, Zhijie Chua, Inna Perepichka
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    ABSTRACT: The in situ observation of benzotriazole ring and ring-opened isomers, which result from the Dimroth equilibrium for 1-[(nonafluorobutane)sulfonyl]benzotriazole, 1, in solution by 19F NMR and UV/Vis spectroscopy is reported. Two benzotriazoles, compound 1 and 1,1′-sulfonylbis(benzotriazole) (3), undergo Dimroth triazole ring opening and coordination to an iridium(I) metal center to give either linear diazo [IrI(η1-NNPhNSO2C4F9)(Cl)(PPh3)2] (2) or an unusual double bent diazene [IrIII(η3-NNPhNSO2Btz)(Cl)(PPh3)2] (4; Btz=benzotriazole) complex.
    ChemPlusChem 10/2013; 78(10). DOI:10.1002/cplu.201300245 · 3.24 Impact Factor
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    ABSTRACT: Low reticulocytosis, indicating reduced red blood cell (RBC) output, is an important feature of severe malarial anemia. Evidence supports a role for Plasmodium products, especially hemozoin (Hz), in suppressed erythropoiesis during malaria, but the mechanism(s) involved remains unclear. Here, we demonstrated that low reticulocytosis and suppressed erythropoietin (Epo)-induced erythropoiesis are features of malarial anemia in P. yoelii- and P. berghei ANKA-infected mice similar to our previous observations in P. chabaudi AS-infected mice. The magnitude of decreases in RBC was a reflection of parasitemia level, but low reticulocytosis was evident despite differences in parasitemia, clinical manifestation, and infection outcome. Schizont extracts and Hz from P. falciparum and P. yoelii and synthetic Hz suppressed Epo-induced proliferation of erythroid precursors in vitro, but did not inhibit RBC maturation. To determine if Hz contributes to malarial anemia, P. yoelii-derived or synthetic Hz was administered to naïve mice and the development of anemia, reticulocytosis, and RBC turnover were determined. Parasite-derived Hz induced significant decreases in RBC and increased RBC turnover with compensatory reticulocytosis, but anemia was not as severe as that in infected mice. Our findings suggest that parasite factors, including Hz, contribute to severe malarial anemia by suppressing Epo-induced proliferation of erythroid precursors.
    The Journal of Infectious Diseases 08/2013; 209(1). DOI:10.1093/infdis/jit417 · 5.85 Impact Factor
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    ABSTRACT: The pigment hemozoin is a natural by-product of the metabolism of hemoglobin by the parasites which cause malaria. Previously, hemozoin was demonstrated to have a very high nonlinear optical response enabling third harmonic generation (THG) imaging. In this study, we present a complete characterization of the nonlinear THG response of natural hemozoin in malaria-infected red blood cells, as well as in pure isostructural synthesized hematin anhydride, in order to determine optimal imaging parameters for detection. Our study demonstrates the wavelength range for optimal pulsed femtosecond laser excitation of THG from hemozoin crystals. In addition, we show the hemozoin crystal detection as a function of crystal size, incident laser power, and the emission response of the hemozoin crystals to different incident laser polarization states. Our systematic measurements of the nonlinear optical response from hemozoin establish detection limits, which are essential for the optimal design of malaria detection technologies that exploit the THG response of hemozoin.
    Analytical and Bioanalytical Chemistry 05/2013; 405(16). DOI:10.1007/s00216-013-6985-z · 3.66 Impact Factor
  • D Scott Bohle, Yuxuan Gu
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    ABSTRACT: Rapid thiolate exchange of dimethylarsonium, Me2As(+), is observed between two different thiolate species in solution. NMR is used to characterize the equilibrium constants for interthiol transfer as well the rapid intra molecular conformational dynamics which leads to the coalescence of diastereotopic methyl resonances. These rapid exchange kinetics have important consequences of arsenic's toxicity and pharmacology.
    Organic & Biomolecular Chemistry 03/2013; DOI:10.1039/c3ob40268a · 3.49 Impact Factor
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    ABSTRACT: The reaction of nitric oxide with benzyl cyanide in the presence of potassium methoxide at low temperature gave the dipotassium salt of a bis-diazeniumdiolate 2 in excellent yield. Two new stereospecific syntheses of E or Z 2-(hydroxyimino)-2-phenylacetonitrile from 2 have been found. The thermodynamics of the E/Z isomerization has been investigated spectroscopically in solution, in the solid state by differential scanning calorimetry (DSC), and theoretically in the gas phase. Evidence of catalysis by NO of E/Z oxime isomerization has been observed.
    Chemistry - A European Journal 02/2013; 19(13). DOI:10.1002/chem.201203357 · 5.93 Impact Factor
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    ABSTRACT: 2-Aryl-4-methyl-5-acetylthiazoles, which were prepared from arylthioamides and chloroacetylacetone, were treated with 6-substituted-3-formylchromones or arylaldehydes to give a series of eighteen new thiazolylchalcones in good yields. The structures of all the synthesized compounds were characterized by 1H NMR, 13C NMR, and ES-MS spectrometry. Additionally, the crystal structures of two of these chalcones were determined by X-ray diffraction analysis.
    ChemInform 02/2013; 44(6). DOI:10.1002/chin.201306093
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    ABSTRACT: The facile axial ligand exchange properties of gallium(III) protoporphyrin IX in methanol solution were utilized to explore self-association interactions by NMR techniques. Structural changes were observed, as well as competitive behavior with the ligands acetate and fluoride, which differed from that seen with the synthetic analogue gallium(III) octaethylporphyrin which lacks acid groups in its side-chains and has less solution heterogeneity as indicated by absorption and MCD spectroscopies. The propionic acid side chains of protoporphyrin IX are implicated in all such interactions of PPIX, and both dynamic metal-propionic interactions and the formation of propionate-bridged dimers are observed. Fluoride coordination provides an unusual example of slow ligand exchange, and this allows for the identification of a fluoride bridged dimer in solution. An improved synthesis of the chloride and hydroxide complexes of gallium(III) protoporphyrin IX is reported. An insoluble gallium analogue of hematin anhydride is described. In general, the interactions between solvent and the metal are found to confer very high solubility, making [Ga(PPIX)](+) a useful model for ferric heme species.
    Inorganic Chemistry 10/2012; 51(20):10747-61. DOI:10.1021/ic301106g · 4.79 Impact Factor
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    ABSTRACT: Sustained erythropoiesis and concurrent bone marrow hyperplasia are proposed to be responsible for low bone mass density (BMD) in chronic hemolytic pathologies. As impaired erythropoiesis is also frequent in these conditions, we hypothesized that free heme may alter marrow and bone physiology in these disorders. Bone status and bone marrow erythropoiesis were studied in mice with hemolytic anemia (HA) induced by phenylhydrazine (PHZ) or Plasmodium infection and in bled mice. All treatments resulted in lower hemoglobin concentrations, enhanced erythropoiesis in the spleen and reticulocytosis. The anemia was severe in mice with acute hemolysis, which also had elevated levels of free heme and ROS. No major changes in cellularity and erythroid cell numbers occurred in the bone marrow of bled mice, which generated higher numbers of erythroid blast forming units (BFU-E) in response to erythropoietin. In contrast, low numbers of bone marrow erythroid precursors and BFU-E and low concentrations of bone remodelling markers were measured in mice with HA, which also had blunted osteoclastogenesis, in opposition to its enhancement in bled mice. The alterations in bone metabolism were accompanied by reduced trabecular bone volume, enhanced trabecular spacing and lower trabecular numbers in mice with HA. Taken together our data suggests that hemolysis exerts distinct effects to bleeding in the marrow and bone and may contribute to osteoporosis through a mechanism independent of the erythropoietic stress.
    PLoS ONE 09/2012; 7(9):e46101. DOI:10.1371/journal.pone.0046101 · 3.53 Impact Factor
    This article is viewable in ResearchGate's enriched format
  • D Scott Bohle, Erin L Dodd, Peter W Stephens
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    ABSTRACT: Malaria pigment, the heme detoxification product of malaria's invasion, digestion, and growth inside mammalian red blood cells, is an insoluble phase of iron(III)protoporphyrin-IX. Even though its structure was determined in 2000 by powder X-ray diffraction, significant questions remain about its formation and possible interaction with quinoline antimalarial drugs. A recent structural study, also with X-ray powder diffraction, has reconfirmed that the material isolated from the parasite is isostructural with its synthetic equivalent. It was recently suggested that other isomers may also be formed and may be present in synthetic samples. In particular, a series of stereoisomers are possible for the arrangement of vinyl groups on the periphery of the dimerized porphyrin rings. In principle, any given dimer can have vinyl groups at the α or β sites, and at γ or δ sites. In this paper, several models are evaluated, both biphasic and homogeneous methyl/vinyl disorder, against several sets of diffraction data, both published and new. We conclude that methyl/vinyl disorder is intrinsic to the system, and that the evidence at hand does not support the existence of any other crystalline isomers in carefully prepared samples of either natural or synthetic samples. Finally, the porphyrinporphyrin interactions are evaluated using Scheidt's indicies for porphyrin π-stacking, and we find modest to weak π-interactions in these condensed phases.
    Chemistry & Biodiversity 09/2012; 9(9):1891-902. DOI:10.1002/cbdv.201200033 · 1.81 Impact Factor
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    ABSTRACT: Nitric oxide adds to methyl acetoacetate in the presence of KOH in methanol at room temperature to form potassium acetylsydnonate N-oxide (K1) with an (E)-diazeniumdiolation and potassium acetate diazenium diolate (K(2)2) from a (Z)-diazeniumdiolation. A study of the reaction with LiOH, NaOH, and NMe(4)OH and with ethyl acetate substrate reveals that the temperature of the reaction greatly influences the nitric oxide reactivity. At 23 °C, nitric oxide adds to give both E and Z products, whereas at -5 °C the gas reacts almost exclusively to give Z addition. The (Z)-diazeniumdiolation products, namely, the alkali metal and NMe(4)(+) salts of methyl and ethylbutenoate-2-diazeniumdiolate-3-hydroxylate (3(2-) and 4(2-)), are isolated in good yields. The alkali metal salts are not amenable for recrystallization because of their ready decomposition in aqueous solutions. However, [NMe(4)](2)[MeC(O)C(N(2)O(2))CO(2)Me] is readily recrystallized from a methanol/acetonitrile solvent mixture. The crystals are unambiguously characterized by X-ray crystallography. NMR spectra for all of the 3(2-) and 4(2-) salts reveal the presence of two isomers in aq solutions. But the structure of the NMe(4)(+) salt contains only one of the isomers. Our attempts to cyclize the isolated and purified butenoatediazeniumdiolates from the (Z)-diazeniumdiolation to the E-containing sydnonate products were unsuccessful. TGA/DSC data for all of the products demonstrate the thermal instability of the salts at high temperatures. The salts decompose exothermally possibly with the release of N(2)O among other gases.
    The Journal of Organic Chemistry 08/2012; 77(17):7313-8. DOI:10.1021/jo301025k · 4.64 Impact Factor
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    ABSTRACT: By careful choice of reaction conditions 1-methylnaphtho[1,8-de]-1,2,3-triazine and 1,3-dimethylnaphtho[1,8-de]-1,2,3-triazinium triflate are readily prepared by the alkylation of 1H-naphtho[1,8-de]-1,2,3-triazine. The electronic spectra for these bathochromically shifted dyes are reported for a range of solvents as are their vibrational spectra and theoretical structures from density functional theory, B3LYP/6-311++G**. The 15N substitution into the middle nitrogen atom allows for the identification of strong azine bands in the IR and Raman spectra as well as in the 15N NMR spectrum. X-ray crystallography is used to characterize the solid-state structures of two of these new triazine derivatives and these structures are used to benchmark the theoretical and spectroscopic discussions. The corresponding 1,3-dimethyltriazinium radical is prepared and characterized by cyclic voltammetry, spectroelectrochemistry, and EPR spectroscopy. Unlike the related transient 1,2,4-triazene radicals, the 1,3-dimethyl-1,2,3-naphthotriazyl radical is markedly more stable.
    ChemPlusChem 05/2012; 77(5). DOI:10.1002/cplu.201200021 · 3.24 Impact Factor
  • D. Scott Bohle, Erin L. Dodd
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    ABSTRACT: Gallium(III) protoporphyrin IX forms a dimeric propionate-bridged dimer, 2, that is a soluble diamagnetic analogue of hematin anhydride. The single-crystal structure of 2 corresponds to a nondisordered inversion-symmetric dimer similar to malaria pigment but, unlike it, has a six-coordinate metal and an intraporphyrin rather than an interporphyrin hydrogen bond. NMR NOE correlations demonstrate the presence of the propionate linkage in solutions with pyridine. Taken together, this is the first single-crystal X-ray diffraction study of a propionate-linked dimer as found in malaria pigment and the first evidence for its presence in solution.
    Inorganic Chemistry 03/2012; 51(8):4411–4413. DOI:10.1021/ic2027303 · 4.79 Impact Factor
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    ABSTRACT: Ga(III)protoporphyrin-IX (Ga-PP) has been proposed as a model for the key interporphyrin interactions in malaria pigment. Unlike the paramagnetic parent iron heme derivatives, Ga-PP is readily soluble in methanol (MeOH). We report optical, mass spectroscopic, and theoretical results for Ga-PP as well as its reactions with myoglobin. UV-visible absorption and MCD spectroscopy show that Ga-PP exhibits a typical spectrum for a main group metal: a Q-band at 539 nm and a B band at 406 nm when dissolved in MeOH. We also report optical data for Zn(II)protoporphyrin IX (Zn-PP) dissolved in MeOH, which exhibits a Q-band at 545 nm and a B band at 415 nm. ESI mass spectral data for Ga-PP dissolved in MeOH show the presence of predominantly monomers, with smaller fractions of dimers [(Ga-PP)(2)] and trimers. UV-visible and MCD absorption spectroscopy and ESI mass spectral data demonstrate the successful insertion of monomeric Ga-PP into apo-Mb. Ga-PP-Mb exhibits a B band at 417 nm and Q bands at 545 and 584 nm, which are all red-shifted from the free Ga-PP values. The calculated electronic structures and frontier molecular orbitals of Ga-PP, (Ga-PP)(2) and Zn-PP fit the previously reported trends in band energies and oscillator strengths as a function of molecular orbital energies. These new data can be applied to explain the experimentally observed optical spectroscopy. The observed Q-band energies are accounted for by calculated (HOMO-LUMO) gap of the frontier MOs, while the split in the two top occupied MOs accounts for the magnitude of the Q-band oscillator strength as well as the experimentally observed Q to B band energy separation. Although Ga-PP shares more spectroscopic properties with Zn-PP than it does with Fe(III)PPIX, the trivalent oxidation state allows this molecule to be used as a model for ferric hemes in heme proteins.
    Inorganic Chemistry 02/2012; 51(6):3743-53. DOI:10.1021/ic202731g · 4.79 Impact Factor
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    ABSTRACT: The real mechanism of the Skraup-Doebner-Von Miller quinoline synthesis remains controversial and not well understood despite several mechanistic studies reported on the matter. A series of unexpected and unusual 5,6,7,8,9,10-hexahydro-6,6-pentamethylenephenanthridines and 2,3,4,5-tetrahydro-4,4-tetramethylene-1H-cyclopenta[c]quinolines have been obtained through the Skraup-Doebner-Von Miller quinoline synthesis. On the basis of these unexpected results and in agreement with some of the previously reported quinoline syntheses, an alternative mechanistic pathway is proposed for this variant of the reaction. It involves the formation of a Schiff base through a reaction between the ketone and the aniline derivative in the first step, followed by a cycloalkenylation at the ortho-position to the amine functional group of the aniline derivative, and an annulation in the final step to close the quinoline ring, leading to a dihydroquinoline derivative. To the best of our knowledge, this is the first report of such a mechanistic pathway being proposed for any variant of the Skraup-Doebner-Von Miller quinoline synthesis.
    The Journal of Organic Chemistry 02/2012; 77(6):2784-90. DOI:10.1021/jo202681r · 4.64 Impact Factor
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    ABSTRACT: 2‐Aryl‐4‐methyl‐5‐acetylthiazoles, which were prepared from arylthioamides and chloroacetylacetone, were treated with 6‐substituted‐3‐formylchromones or arylaldehydes to give a series of eighteen new thiazolylchalcones in good yields. The structures of all the synthesized compounds were characterized by 1H NMR, 13C NMR, and ES‐MS spectrometry. Additionally, the crystal structures of two of these chalcones were determined by X‐ray diffraction analysis.
    Journal of Heterocyclic Chemistry 01/2012; 49:768-773. DOI:10.1002/jhet.853 · 0.87 Impact Factor

Publication Stats

3k Citations
704.05 Total Impact Points

Institutions

  • 2004–2015
    • McGill University
      • • Department of Chemistry
      • • Institute of Parasitology
      Montréal, Quebec, Canada
  • 2013
    • University of Yaoundé II
      Jaúnde, Centre Region, Cameroon
  • 1992–2012
    • University of Wyoming
      • Department of Chemistry
      Laramie, WY, United States
  • 2011
    • Polish Academy of Sciences
      • Instytut Fizyki
      Warsaw, Masovian Voivodeship, Poland
  • 2009
    • McGill University Health Centre
      Montréal, Quebec, Canada
  • 2001–2005
    • Leidos Biomedical Research
      Maryland, United States