D. Scott Bohle

Cationic and Anionic Surface Binding Sites on Nanocrystalline Zinc Oxide: Surface Influence on Photoluminescence and Photocatalysis

To probe the influence of the surface on the overall nature of zinc oxide nanocrystals (ZnO NCs) this paper examines the effects of surface modifiers: cobalt Co(II) and trimethylsilanolate, on the properties of ZnO NCs. A clear relationship between the surface, photocatalytic (PC), and photoluminescent (PL) character of ZnO is observed. With potassium trimethylsilanolate and cobalt(II) acetate we have determined that anionic binding sites occupied by silanolate contribute to 40% of the PL character of the defect emission (500-550 nm). Photodegradation of 4-nitrophenol was used as a probe to evaluate the effect of surface modification on the PC performance of ZnO NCs. At maximum silanolate modification the PC activity of ZnO was reduced by 50%. Modification of ZnO NCs with Co(II) resulted in the transfer of photoexcited electrons to the cobalt center where consequent nonradiative recombination, at energies lower than required for PC, was observed via a comparable decrease in both PL and PC activity. These results are critical for using ZnO NCs in sensory, photocatalytic, and electronic applications.

Structural and morphological characterization of hemozoin produced by Schistosoma mansoni and Rhodnius prolixus

Hemozoin (Hz) is a heme crystal produced upon the digestion of hemoglobin (Hb) by blood‐feeding organisms as a main mechanism of heme disposal. The structure of Hz consists of heme dimers bound by reciprocal iron–carboxylate interactions and stabilized by hydrogen bonds. We have recently described heme crystals in the blood fluke, Schistosoma mansoni, and in the kissing bug, Rhodnius prolixus. Here, we characterized the structures and morphologies of the heme crystals from those two organisms and compared them to synthetic β‐hematin (βH). Synchrotron radiation X‐ray powder diffraction showed that all heme crystals share the same unit cell and structure. The heme crystals isolated from S. mansoni and R. prolixus consisted of very regular units assembled in multicrystalline spherical structures exhibiting remarkably distinct surface morphologies compared to βH. In both organisms, Hz formation occurs inside lipid droplet‐like particles or in close association to phospholipid membranes. These results show, for the first time, the structural and morphological characterization of natural Hz samples obtained from these two blood‐feeding organisms. Moreover, Hz formation occurring in close association to a hydrophobic environment seems to be a common trend for these organisms and may be crucial to produce very regular shaped phases, allowing the formation of multicrystalline assemblies in the guts of S. mansoni and R. prolixus.

[28] Synthesis of pure tetramethylammonium peroxynitrite

Publisher Summary This chapter discusses the synthesis of pure tetramethylammonium peroxynitrite. The synthesis is based on a biomimetic strategy in which tetramethylammonium superoxide is reacted directly with nitric oxide. The use of ammonia as the solvent and tetramethylammonium superoxide as the superoxide source is critical in this synthesis. The synthesis of tetramethylammonium peroxynitrite, [N(CH 3 ) 4 ][ONOO], as a pure, stable, bright yellow salt. Other preparations of peroxynitrite include (1) hydrogen peroxide and nitrite ester in base, (2) the solid-state preparation by ultraviolet (UV) photolysis of potassium nitrate to give 30μmol of ONOOK per gram as a solid mixture of peroxynitrite and nitrate, and (3) the reaction of sodium azide and ozone. The reaction between tetramethylammonium hydroxide pentahydrate and potassium superoxide is a solid-phase reaction that is performed under vacuum and that requires efficient mixing and relatively long reaction times. When prepared under dry and maintained nitrogen, tetramethylammonium peroxynitrite is stored for several months with little detectable decomposition.

Synthetic Plasmodium-Like Hemozoin Activates the Immune Response: A Morphology - Function Study

Increasing evidence points to an important role for hemozoin (HZ), the malaria pigment, in the immunopathology related to this infection. However, there is no consensus as to whether HZ exerts its immunostimulatory activity in absence of other parasite or host components. Contamination of native HZ preparations and the lack of a unified protocol to produce crystals that mimic those of Plasmodium HZ (PHZ) are major technical limitants when performing functional studies with HZ. In fact, the most commonly used methods generate a heterogeneous nanocrystalline material. Thus, it is likely that such aggregates do not resemble to PHZ and differ in their inflammatory properties. To address this issue, the present study was designed to establish whether synthetic HZ (sHZ) crystals produced by different methods vary in their morphology and in their ability to activate immune responses. We report a new method of HZ synthesis (the precise aqueous acid-catalyzed method) that yields homogeneous sHZ crystals (Plasmodium-like HZ) which are very similar to PHZ in their size and physicochemical properties. Importantly, these crystals are devoid of protein and DNA contamination. Of interest, structure-function studies revealed that the size and shape of the synthetic crystals influences their ability to activate inflammatory responses (e.g. nitric oxide, chemokine and cytokine mRNA) in vitro and in vivo. In summary, our data confirm that sHZ possesses immunostimulatory properties and underline the importance of verifying by electron microscopy both the morphology and homogeneity of the synthetic crystals to ensure that they closely resemble those of the parasite. Periodic quality control experiments and unification of the method of HZ synthesis are key steps to unravel the role of HZ in malaria immunopathology.

Unexpected 5,6,7,8,9,10-Hexahydro-6,6-pentamethylenephenanthridines and 2,3,4,5-Tetrahydro-4,4-tetramethylene-1H-cyclopenta[c]quinolines from Skraup–Doebner–Von Miller Quinoline Synthesis and Their Implications for the Mechanism of That Reaction

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.

Soluble Synthetic Analogues of Malaria Pigment: Structure of Mesohematin Anhydride and its Interaction with Chloroquine in Solution†

Changing the vinyl groups of hematin anhydride to either ethyl or hydrogen groups results in increased solubility (Por=porphyrin). Determination of the weak binding constants of the antimalarial drug chloroquine to dimers of these hematin anhydride analogues suggests that solution-phase heme/drug interactions alone are unlikely to be the origin of the action of the drug.

Propionic acid side chain hydrogen bonding in the malaria pigment β-hematin

Abstract Malaria pigment, or β-hematin, the insoluble heme detoxification product resulting from the intraerythrocitic digestion of hemoglobin by young malaria trophozoites has been structurally characterized by X-ray powder diffraction and shown to contain chains of propionic acid linked dimers. Although there is considerable spectroscopic evidence for a monodentate propionate–iron interaction in this crystalline material, the spectroscopic characterization of the propionic acid dimer is limited. Herein we demonstrate the presence of the propionic acid dimer unit by H/D isotope substitution in carboxylic acid dimer. In the Raman spectrum of the deuterium substituted compound there is a circa 12 cm −1 shift, H: 1629 cm −1 vs. D: 1617 cm −1 in the symmetric ring breathing mode for the propionic acid dimer. On the other hand, the IR active asymmetric stretch has a very small shift, −1 , upon deuteration. These, and other vibrational data, are consistent with the presence of a planar carboxylic acid dimer in the structure of β-hematin.

Interaction of quinoline antimalarial drugs with ferriprotoporphyrin IX, a solid state spectroscopy study

To investigate the nature of binding of quinoline antimalarial drugs to heme and to extract experimental evidence for this binding, the interaction of ferriprotoporphyrin IX (FP) with chloroquine and quinacrine (both of which have a similar side chain) and quinoline methanol antimalarials quinine and mefloquine has been studied using IR and NIR-Raman spectroscopy in the solid state. Attenuated total reflectance infrared spectroscopic data clearly show that heme in chloroquine-FP complex is not μ-oxo dimeric indicating that the hypothesis that chloroquine binds to FP μ-oxo dimer with a stoichiometry of 1 chloroquine:2 μ-oxo dimers is not valid in the solid state. Moreover, the first vibrational spectroscopy evidence is presented for the formation of hydrogen bonding between a propionate group of heme and the tertiary amino nitrogen of chloroquine and quinacrine. Raman spectroscopy data does not provide any evidence to support the formation of a similar salt bridge in the complexes of FP with quinine and mefloquine; however, it suggests that the interaction of these drugs with FP happens through coordination of the Fe(III) center of the porphyrin to the 9-hydroxy group of the drug.

Synthesis, structure and ligand exchange reactions of Ru(TTP)(NO)(OMe)

Abstract A facile, novel preparation of the useful synthon Ru(TTP)(NO)(OMe) is reported and it has been characterized by a range of techniques, including single crystal X-ray diffraction. Subsequent methoxide substitution reactions led to the preparation in high yield and purity of a wide variety of new complexes including a mercaptide complex which is the first reported analogue of the diamagnetic nitrosyl adducts of the P-450 monooxygenases.

The novel arsenical darinaparsin is transported by cystine importing systems.

Darinaparsin (Dar; ZIO-101; S-dimethylarsino-glutathione) 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 support 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 toward cancer cells compared with ATO.