[Show abstract][Hide abstract] ABSTRACT: The synthesis of a novel series of seven-membered ring nucleoside analogues as candidates for biological screening and gene silencing applications is described. The key step in the synthetic approach is a stereoselective synthesis of an epoxide that is used as a common synthetic intermediate to prepare functionalized oxepane nucleoside derivatives. The conformational landscape and preferred ring-puckering of selected oxepane nucleosides was also studied by NMR, X-ray crystallography, and quantum mechanical calculations.
[Show abstract][Hide abstract] ABSTRACT: Polymorphism in
chloroquine resistance transporter (PfCRT) was shown to cause chloroquine resistance. In this report we examined the antimalarial potential of novel 3-halo chloroquine derivatives (3-chloro, 3-bromo and 3-iodo) against chloroquine-susceptible and -resistant
. All three derivatives inhibited the proliferation of
; with 3-iodo chloroquine being most effective. Moreover, 3-iodo chloroquine was highly effective at potentiating and reversing chloroquine toxicity of drug-susceptible and -resistant
No preview · Article · Oct 2015 · Antimicrobial Agents and Chemotherapy
[Show abstract][Hide abstract] ABSTRACT: Nitric oxide is an efficient catalyst for the cis-trans (E/Z) isomerization of diazenes. We compare the effect of room temperature solutions bearing low concentrations of nitric oxide, nitrogen dioxide, or oxygen on the rate of cis-trans isomerization, CTI, of the alkene bond in stilbene and on the azo double bond in azobenzene, as well as in four azo derivatives as measured by UV-vis spectroscopy. These rate enhancements can be as large as 3 orders of magnitude for azobenzene in solution. A mechanism is proposed where catalysis is promoted by the interaction of the nitric oxide with the diazene nitrogen lone pairs. Density functional theory, B3LYP/6-311++g** suggests that the binding of NO to the diazene should be weak and reversible but that its NO adduct has an E/Z isomerization barrier of 7.5 kcal/mol.
No preview · Article · Jul 2015 · Inorganic Chemistry
[Show abstract][Hide abstract] ABSTRACT: The silver salts of the conjugate bases of the nitrogen acids N-nitroacetamide (Ag[CH3C(O)NNO2] (1)), N-nitrocarbamate (Ag[R′OC(O)NNO2], R′ = CH3 (2), C2H5 (3)), N-nitrosomethylcarbamate (Ag[CH3OC(O)NNO] (4)), and N-nitro-p-tolylsulfonamide, (Ag[p-tolylSO2NNO2] (5)) react with trans-Ir(Cl)(CO)(PPh3)2 (Vaska’s complex) to give trans-Ir(η1-nitrogen acid)(CO)(PPh3)2 complexes (6–10). The related silver amides dinitramide and bistriflimide also react with trans-Ir(Cl)(CO)(PPh3)2, to give trans-Ir[η1-N(NO2)2](CO)(PPh3)2 (11) and the unusual silver adduct [trans-Ir(Cl)(CO)(PPh3)2][Ag[N(SO2CF3)2]] (12), respectively. The reaction of trimethylsilyl bistriflimide, prepared in situ from trimethylsilyl bromide and Ag[N(SO2CF3)2] in acetonitrile, and Ir(F)(CO)(PPh3)2 gives [trans-Ir(CH3CN)(CO)-(PPh3)2][N(SO2CF3)3] (13). The molecular structures of these complexes are all square planar, with the exception of 12, which is square pyramidal with the AgX ligand in the apical position. Complexes 6–9, 12, and 13 are stable to air in solution, while 10 and 11 are reactive toward oxygen.
[Show abstract][Hide abstract] 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.
No preview · Article · Mar 2015 · The Journal of Physical Chemistry B
[Show abstract][Hide abstract] 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.
Full-text · Article · Feb 2015 · European Journal of Organic Chemistry
[Show abstract][Hide abstract] ABSTRACT: The Z/E selectivity of Pd(II)-catalyzed decarboxylative Heck-type arylations of trans-cinnamaldehydes can be controlled readily by switching the reaction solvent. Depending on the type of solvent used, each of the two isomeric products can be obtained with good to excellent Z/E ratio. In THF, Z-isomers were formed preferentially, whereas DMF provided the E-isomers predominantly.
[Show abstract][Hide abstract] 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.
No preview · Article · Oct 2014 · Inorganic Chemistry
[Show abstract][Hide abstract] 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.
No preview · Article · Sep 2014 · Canadian Journal of Chemistry
[Show abstract][Hide abstract] ABSTRACT: A cell lysis mill, typically used for the breakdown of biological structures in microbiological and biochemical studies, was used as a tool for rapid, solvent-free and general synthesis of short- and long-chain substituted zwitterionic meta- and para-aminobenzoquinones, never previously prepared under solvent-free conditions. Rapid agitation and self-heating in the lysis mill enabled thermally-demanding reactions without external solvent, providing yields comparable to those obtained by conventional solution chemistry, ball milling and melt chemistry. The lysis mill is also suitable for coordination-based reactions, demonstrated by the mechanosynthesis of a mononuclear Ni(II) meta-benzoquinonemonoimine complex.
[Show abstract][Hide abstract] 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.
Preview · Article · Jan 2014 · Molecular pharmacology
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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 Plasmodium yoelii– and Plasmodium berghei ANKA–infected mice, similar to our previous observations in Plasmodium 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 whether Hz contributes to malarial anemia, P. yoelii–derived or synthetic Hz was administered to naive mice, and the development of anemia, reticulocytosis, and RBC turnover
was 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.
Full-text · Article · Aug 2013 · The Journal of Infectious Diseases
[Show abstract][Hide abstract] 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.
Combined overlay image of THG (bright crystals in blue, one scan per frame) and TP autofluorescence (oval cells in red, average of 15 sequential frame scans) of natural hemozoin crystals and red blood cells (infected with FCR-3 Plasmodium falciparum), respectively, collected at the laser excitation wavelength of 1170 nm with 100 mW average incident power and pixel dwell time of 5 μs
Full-text · Article · May 2013 · Analytical and Bioanalytical Chemistry
[Show abstract][Hide abstract] 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.
No preview · Article · Mar 2013 · Chemistry - A European Journal
[Show abstract][Hide abstract] 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.
No preview · Article · Mar 2013 · Organic & Biomolecular Chemistry
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
No preview · Article · Oct 2012 · Inorganic Chemistry