Browsing by Author "Kuter, David"
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- ItemRestrictedExperimental and time-dependent density functional theory characterization of the UV−Visible spectra of monomeric and μ‑Oxo dimeric ferriprotoporphyrin IX(American Chemical Society, 2012) Kuter, David; Venter, Gerhard A; Naidoo, Kevin J; Egan, Timothy JSpeciation of ferriprotoporphyrin IX, Fe(III)PPIX, in aqueous solution is complex. Despite the use of its characteristic spectroscopic features for identification, the theoretical basis of the unique UV−visible absorbance spectrum of μ- [Fe(III)PPIX]2O has not been explored. To investigate this and to establish a structural and spectroscopic model for Fe(III)PPIX species, density functional theory (DFT) calculations were undertaken for H2O−Fe(III)PPIX and μ- [Fe(III)PPIX]2O. The models agreed with related Fe(III)porphyrin crystal structures and reproduced vibrational spectra well. The UV−visible absorbance spectra of H2O−Fe(III)PPIX and μ-[Fe(III)PPIX]2O were calculated using time-dependent DFT and reproduced major features of the experimental spectra of both. Transitions contributing to calculated excitations have been identified. The features of the electronic spectrum calculated for μ-[Fe(III)PPIX]2O were attributed to delocalization of electron density between the two porphyrin rings of the dimer, the weaker ligand field of the axial ligand, and antiferromagnetic coupling of the Fe(III) centers. Room temperature magnetic circular dichroism (MCD) spectra have been recorded and are shown to be useful in distinguishing between these two Fe(III)PPIX species. Bands underlying major spectroscopic features were identified through simultaneous deconvolution of UV−visible and MCD spectra. Computed UV−visible spectra were compared to deconvoluted spectra. Interpretation of the prominent bands of H2O−Fe(III)PPIX largely conforms to previous literature. Owing to the weak paramagnetism of μ-[Fe(III)PPIX]2O at room temperature and the larger number of underlying excitations, interpretation of its experimental UV−visible spectrum was necessarily tentative. Nonetheless, comparison with the calculated spectra of antiferromagnetically coupled and paramagnetic forms of the μ-oxo dimer of Fe(III)porphine suggested that the composition of the Soret band involves a mixture of π→π* and π→dπ charge transfer transitions. The Q-band and charge transfer bands appear to amalgamate into a mixed low energy envelope consisting of excitations with heavily admixed π→π* and charge transfer transitions.
- ItemOpen AccessInterference with hemozoin formation represents an important mechanism of schistosomicidal action of antimalarial quinoline methanols(Public Library of Science, 2009) Soares, Juliana B R Corrêa; Menezes, Diego; Vannier-Santos, Marcos A; Ferreira-Pereira, Antonio; Almeida, Giulliana T; Venancio, Thiago M; Verjovski-Almeida, Sergio; Zishiri, Vincent K; Kuter, David; Hunter, RogerAuthor Summary Heme is an essential molecule to most living organisms, but once in a free state it exerts toxic effects. Blood-feeding organisms evolved efficient ways to detoxify free heme derived from hemoglobin digestion. A key mechanism present in some hematophagous organisms consists of the crystallization of heme into a pigment named hemozoin. Schistosoma mansoni is one of the etiologic agents of human schistosomiasis, a parasitic disease that affects over 200 million people in tropical and subtropical areas. Hemozoin formation represents the main heme detoxification pathway in S. mansoni . Here, we report that the antimalarial quinoline methanols quinine and quinidine exert schistosomicidal effects notably due to their capacity to interfere with hemozoin formation. When quinine or quinidine were administered intraperitoneally during seven days to S. mansoni -infected mice (75 mg/kg/day), both worm and eggs burden were significantly reduced. Interestingly, hemozoin content in female worms was drastically affected after treatment with either compound. We also found that quinine caused important changes in the cellular organization of worm gastrodermis and increased expression of genes related to musculature, protein synthesis and repair mechanisms. Together, our results indicate that interference with hemozoin formation is a valid chemotherapeutic target for development of new schistosomicidal agents.
- ItemOpen AccessTowards a fragment approach to haemozoin inhibiting antimalarials : exploration of coordination and π-stacking interactions with Fe(III)PPIX by spectroscopy and synthesis(2009) Kuter, David; Egan, Timothy J; Chibale, KellyInvestigation of coordination and π-stacking interactions with ferriprotoporphyrin IX (Fe(III)PPIX) using a fragment approach was undertaken in order to propose and synthesise novel compounds which followed a hypothesised mechanism of action to inhibit β-haematin formation. Coordination of a series of pyridines, imidazoles, amines and phenolates with Fe(III)PPIX, and n-stacking interactions of these compounds with protoporphyrin IX (PPIX) and Fe(III)PPIX were measured in 40% (v/v) aq. DMSO by spectrophotometric titration.