Treatment quality assessment is a crucial feature for both present and next-generation ion therapy facilities. Several approaches are being explored, based on prompt radiation emission or on PET ...signals by Formula: see text-decaying isotopes generated by beam interactions with the body. In-beam PET monitoring at synchrotron-based ion therapy facilities has already been performed, either based on inter-spill data only, to avoid the influence of the prompt radiation, or including both in-spill and inter-spill data. However, the PET images either suffer of poor statistics (inter-spill) or are more influenced by the background induced by prompt radiation (in-spill). Both those problems are expected to worsen for accelerators with improved duty cycle where the inter-spill interval is reduced to shorten the treatment time. With the aim of assessing the detector performance and developing techniques for background reduction, a test of an in-beam PET detector prototype was performed at the CNAO synchrotron-based ion therapy facility in full-beam acquisition modality. Data taken with proton beams impinging on PMMA phantoms showed the system acquisition capability and the resulting activity distribution, separately reconstructed for the in-spill and the inter-spill data. The coincidence time resolution for in-spill and inter-spill data shows a good agreement, with a slight deterioration during the spill. The data selection technique allows the identification and rejection of most of the background originated during the beam delivery. The activity range difference between two different proton beam energies (68 and 72 MeV) was measured and found to be in sub-millimeter agreement with the expected result. However, a slightly longer (2 mm) absolute profile length is obtained for in-spill data when compared to inter-spill data.
We describe the preparation of methyl 5α-methyl-α-d-glucopyranoside and of 5α-fluoro-β-d-glucopyranose per acetate and the NMR-based conformational analysis of their side chains. Both the 5α-methyl ...and 5α-fluoro substituents increase the population of the gauche,gauche side chain conformer to the extent that it becomes the predominant conformation. In the 5α-methyl series this is attributed to steric effects, whereas in the 5α-fluoro series the optimization of attractive gauche effects is the more likely reason.
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•Side chain conformation analysis of 5α-susbtituted glucopyranose derivatives.•A 5α-methyl group strongly favors the gg side chain conformation of glucopyranosides.•A 5α-fluoro substituent strongly favors the gg side chain conformation of glucopyranosides.
With a view to facilitating prediction of the exocyclic bond to the pyranoside ring in higher carbon sugars, a model is advanced that relates the relative configuration of the three stereogenic ...centers comprised of the branchpoint and of the two flanking centers (C4–C5–C6 in aldoheptoses and higher and C5–C6–C7 in sialic and ulosonic acids) to that of the simple ring-opened pentoses. Assignment of a given stereotriad as arabino, lxyo, ribo, or xylo by inspection of the Fischer projection formulas permits prediction of conformation of the exocyclic bond by comparison with the known solution (= crystal in all cases) conformations of the simple pentitols. More remote stereogenic centers in the side chain, as in the 8-position of N-acetylneuraminic acid, have little impact on the conformation of the exocyclic bond. On the basis of this model the conformation of the exocyclic bond in ring I of 6′-homologated 4,5-disubstituted 2-deoxystreptamine class aminoglycoside antibiotics was predicted and was borne out by NMR analysis of newly synthesized derivatives in D2O at pD5. The antiribosomal and antibacterial activity of these derivatives is briefly presented and discussed in terms of preorganization of the side chain for binding to the ribosomal decoding A site. It is anticipated that this predictive analysis will also find use in the prediction of the conformation of the exocyclic bonds in other 2-(1-hydroxyalkyl)-3-hydroxytetrahydropyrans and tetrahydrofurans.
The stereospecific syntheses of methyl 2-amino-2,4-dideoxy-4-C-propyl-α-d-glucopyranoside and of methyl 2-amino-2,4-dideoxy-α-D-xylo-hexopyranoside and of their 6S-deuterioisotopomers are described ...as models for ring I of the aminoglycoside antibiotics propylamycin and 4′-deoxyparomomycin, respectively. Analysis of the 1H NMR spectra of these compounds and of methyl 2-amino-2-deoxy-α-d-glucopyranoside, a model for paromomycin itself, reveals that neither deoxygenation at the 4-position, nor substitution of the C–O bond at the 4-postion by a C–C bond significantly changes the distribution of the side chain population between the three possible staggered conformations. From this it is concluded that the beneficial effect on antiribosomal and antibacterial activity of the propyl group in propylamycin does not derive from a change in side chain conformation. Rather, enhanced basicity of the ring oxygen and increased hydrophobicity and/or solvation effects are implicated.
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•Stereospecific Deuterium Labeling.•Assignment of pro-R and pro-S Hydrogens in Side Chain.•Side Chain Conformation.
The oxidative deamination of N-nitroso N-acetylneuraminic acid (NeuAc) derivatives is a useful reaction for the formation of 5-desamino-5-hydroxy NeuAc derivatives and their stereoisomers. We ...demonstrated previously that replacement of the classical nucleophile in these reactions, acetic acid, by phenols resulted in a novel double displacement process with substitution of the acetoxy group at the 4-position taking place in addition to that of the 5-acetamido group, for which we postulated a mechanism centered on the formation of a highly reactive vinyl diazonium ion. We now extend these studies to encompass the use of hydroxylamine-based systems and weakly basic amines as nucleophile. We find that the nature of the product depends significantly on the pKa of the nucleophile, with the more acidic species typically affording only substitution at the 5-position, while the less acidic species give mixtures of elimination products and disubstitution products. The use of aniline as nucleophile is of particular note as it affords a novel aziridine spanning positions 4- and 5- of the neuraminic acid skeleton.
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•Oxidative Deamination.•Double substitution.•Aziridine formation.
Abstract Goal Proton treatment monitoring with Positron-Emission-Tomography (PET) is based on comparing measured and Monte Carlo (MC) predicted β+ activity distributions. Here we present PET β+ ...activity data and MC predictions both during and after proton irradiation of homogeneous PMMA targets, where protons were extracted from a cyclotron. Methods and materials PMMA phantoms were irradiated with 62 MeV protons extracted from the CATANA cyclotron. PET activity data were acquired with a 10 × 10 cm2 planar PET system and compared with predictions from the FLUKA MC generator. We investigated which isotopes are produced and decay during irradiation, and compared them to the situation after irradiation. For various irradiation conditions we compared one-dimensional activity distributions of MC and data, focussing on Δw50%, i.e., the distance between the 50% rise and 50% fall-off position. Results The PET system is able to acquire data during and after cyclotron irradiation. For PMMA phantoms the difference between the FLUKA MC prediction and our data in Δw50% is less than 1 mm. The ratio of PET activity events during and after irradiation is about 1 in both data and FLUKA, when equal time-frames are considered. Some differences are observed in profile shape. Conclusion We found a good agreement in Δw50% and in the ratio between beam-on and beam-off activity between the PET data and the FLUKA MC predictions in all irradiation conditions.
Infectious diseases due to multidrug-resistant pathogens, particularly carbapenem-resistant Enterobacteriaceae (CREs), present a major and growing threat to human health and society, providing an ...urgent need for the development of improved potent antibiotics for their treatment. We describe the design and development of a new class of aminoglycoside antibiotics culminating in the discovery of propylamycin. Propylamycin is a 4′-deoxy-4′-alkyl paromomycin whose alkyl substituent conveys excellent activity against a broad spectrum of ESKAPE pathogens and other Gram-negative infections, including CREs, in the presence of numerous common resistance determinants, be they aminoglycoside modifying enzymes or rRNA methyl transferases. Importantly, propylamycin is demonstrated not to be susceptible to the action of the ArmA resistance determinant whose presence severely compromises the action of plazomicin and all other 4,6-disubstituted 2-deoxystreptamine aminoglycosides. The lack of susceptibility to ArmA, which is frequently encoded on the same plasmid as carbapenemase genes, ensures that propylamycin will not suffer from problems of cross-resistance when used in combination with carbapenems. Cell-free translation assays, quantitative ribosome footprinting, and X-ray crystallography support a model in which propylamycin functions by interference with bacterial protein synthesis. Cell-free translation assays with humanized bacterial ribosomes were used to optimize the selectivity of propylamycin, resulting in reduced ototoxicity in guinea pigs. In mouse thigh and septicemia models of Escherichia coli, propylamycin shows excellent efficacy, which is better than paromomycin. Overall, a simple novel deoxy alkyl modification of a readily available aminoglycoside antibiotic increases the inherent antibacterial activity, effectively combats multiple mechanisms of aminoglycoside resistance, and minimizes one of the major side effects of aminoglycoside therapy.
An intramolecular hydrogen bond between the protonated equatorial 7’‐methylamino group of apramycin and the vicinal axial 6’‐hydroxy group acidifies the 6’‐hydroxy group leading to a strong hydrogen ...bond to A1408 in the ribosomal drug binding pocket in the decoding A site of the small ribosomal subunit. In 6’‐epiapramycin, the trans‐nature of the 6’‐hydroxy group and the 7’‐methylamino group results in a much weaker intramolecular hydrogen bond, and a consequently weaker cooperative hydrogen bonding network with A1408, resulting overall in reduced inhibition of protein synthesis and antibacterial activity.
The cis‐configuration of the equatorial 7’‐methylamino and axial 6’‐alcohols is demonstrated to be a critical element in an essential co‐operative hydrogen bonding network with A1408 in the interaction of the aminoglycoside antibiotic apramycin with the decoding A site of the bacterial ribosome.
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