Nitroheterocyclic drugs cure experimental <i>Trypanosoma cruzi</i> infections more effectively in the chronic stage than in the acute stage

The insect-transmitted protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, and infects 5-8 million people in Latin America. Chagas disease is characterised by an acute phase, which is partially resolved by the immune system, but then develops as a chronic life-long infection. There is a consensus that the front-line drugs benznidazole and nifurtimox are more effective against the acute stage in both clinical and experimental settings. However, confirmative studies have been restricted by difficulties in demonstrating sterile parasitological cure. Here, we describe a systematic study of nitroheterocyclic drug efficacy using highly sensitive bioluminescence imaging of murine infections. Unexpectedly, we find both drugs are more effective at curing chronic infections, judged by treatment duration and therapeutic dose. This was not associated with factors that differentially influence plasma drug concentrations in the two disease stages. We also observed that fexinidazole and fexinidazole sulfone are more effective than benznidazole and nifurtimox as curative treatments, particularly for acute stage infections, most likely as a result of the higher and more prolonged exposure of the sulfone derivative. If these findings are translatable to human patients, they will have important implications for treatment strategies

Controlled Radical Polymerization of Vinyl Acetate Mediated by a Bis(imino)pyridine Vanadium Complex

Source type: Prin

Fast and accurate determination of absolute individual molecular weight distributions from mixtures of polymers via size exclusion chromatography- electrospray ionization mass spectrometry

We present a method to determine accurate and absolute molecular weight distributions (MWDs) as well as absolute concentrations of the individual macromolecular components in mixtures of polymers of the same monomer class yet differing in their end groups. Data gained from size exclusion chromatography coupled online to refractive index (RI) detection and electrospray ionization mass spectrometry (ESI-MS) are processed by a sophisticated computer algorithm based on the maximum entropy principle. The procedure yields, for the first time, absolute molecular weight distributions of each component corrected for chromatographic band broadening. Molecular weights of up to 10 kDa are accessible with a conventional quadrupole ion-trap mass analyzer. The method is applicable to variable polymer systems regardless of the monomer class and without the need for an external calibration or additional model assumptions. It was validated using binary and ternary mixtures of poly(methyl methacrylate) carrying labile functional groups. For the ternary mixture, maximum deviations of the reconstructed molecular weight averages and mass concentrations from the original values were 8% and 5%, respectively. © 2009 American Chemical Society

A novel one-pot procedure for the fast and efficient conversion of RAFT polymers into hydroxy-functional polymers

We report on the successful quantitative transformation of methacrylate and acrylate-type polymers prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization carrying a dithioester-end-group into hydroxy-functional polymers. The simple reaction procedure involves stirring a solution of the dithioester-capped polymer and an azo-initiator in tetrahydrofuran at elevated temperatures (T = 60 degrees C) in the presence of air. This reaction quantitatively yields hydroperoxide functionalities that can be efficiently reduced to hydroxy groups in a one-pot procedure using triphenylphosphine. Size exclusion chromatography-electrospray mass spectrometry was employed to monitor the progress of the reaction. The newbackbone-linked hydroxy group provides a versatile anchor for chemical end-group conversions and conjugation reactions with prepared RAFT polymers, which alleviates problems with the rather limited ability of the dithioester-end-group to undergo non-radical transformations

Mark-houwink parameters for the universal calibration of acrylate, methacrylate and vinyl acetate polymers determined by online size- exclusion chromatography - Mass spectrometry

Size exclusion chromatography coupled online to electrospray ionization mass spectrometry (SEC/ESI-MS) is employed to establish universal calibration (UC) relationships for a number of linear poly(alkyl acrylates) and poly(alkyl methacrylates) (pMMAs) as well as poly(vinyl acetate) synthesized via radical chain transfer polymerization. It is demonstrated that in the analyzed molecular weight range, Mark-Houwink-Kuhn-Sakurada (MHKS) coefficients can be successfully determined in relation to values of pMMA. The agreement between the UC model using mass spectrometry-derived MHKS coefficients and the measured data was generally better than 10%. The MHKS values reported herein are expected to remain valid up to 20 kDa. A comparison with the outcome of UC using literature reported MHKS coefficients determined by intrinsic viscosity-molecular weight (IV-MW) measurements is provided. Errors of more than 30% can result when these literature values are employed in the low molecular weight range (M̄n &lt; 20 kDa). Use of MHKS coefficients derived from IV-MW measurements in UC is, therefore, strongly discouraged at molecular weights below 20 kDa. © 2010 WILEY-VCH Verlag GmbH &amp; Co. KGaA, Weinheim

Mass Spectrometry in Polymer Chemistry

Combining an up-to-date insight into mass-spectrometric polymer analysis beyond MALDI with application details of the instrumentation, this is a balanced and thorough presentation of the most important and widely used mass-spectrometric methods. Written by the world's most proficient experts in the field, the book focuses on the latest developments, covering such technologies and applications as ionization protocols, tandem and liquid chromatography mass spectrometry, gas-phase ion-separation techniques and automated data processing. Chapters on sample preparation, polymer degradation and the usage of mass-spectrometric tools on an industrial scale round off the book. As a result, both entrants to the field and experienced researchers are able to choose the appropriate methods and instrumentations -- and to assess their respective strengths and limitations -- for the characterization of polymer compounds. © 2012 Wiley-VCH Verlag GmbH & Co. KGaA

Expansion of the application range of pyrolysis-gas chromatography to copolymer sequence determination: Acrylate copolymers

The sequence distribution, which describes the order of monomers in a copolymer, is notoriously hard to study. The current standard in polymer sequence determination, NMR, is limited to simple copolymers due to lack in resolution and sensitivity. Therefore, an alternative method to determine the sequence of complex copolymers in the form of a developed pyrolysis-GC-MS method was investigated. Pyrolysis-GC-MS was applied to various acrylate copolymers; in the obtained pyrograms clear trimer distributions were observed and identified. Based on these results the sequence of these systems was calculated. The determined sequence values were found to be in line with expectations, demonstrating that the method was suitable for the sequence determination of binary acrylate copolymers. The developed method was also applied on various tertiary acrylate copolymers. Tertiary copolymers form many more distinct trimers rendering assignment more challenging. Nevertheless, based on a combination of chromatographic and mass spectrometric data, all formed trimers were assigned. To the best of our knowledge, this is the first time that a tertiary acrylate is sequenced by pyrolysis-GC

Erratum: Degradation of poly(methyl methacrylate) model compounds under extreme environmental conditions (Macromolecular Chemistry and Physics (2010) 211 (1083-1097) DOI: 10.1002/macp.200900625)

Erratum is free to read on publisher websit