PubMed · 13087591
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1953-08-13. ISONIAZID.. https://doi.org/10.1056/nejm195308132490709
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We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.
We demonstrate the analytical potential of 2H-{1H} NMR spectroscopy in weakly ordering, chiral lyotropic liquid crystals made of poly(gamma-benzyl-L-glutamate) (PBLG) dissolved in chloroform or dichloromethane for investigating the intramolecular dynamic processes of four deuterated diaryls (derivatives of 1-(4'-methylphenyl)naphthalene). When the rotation of the aryl groups about the sp(2)--sp(2) bond is sufficiently slow relative to the NMR timescale, the method allows the spectral discrimination of enantiomeric atropisomers or enantiotopic directions in the prochiral derivatives. The effect of the position of substituents on the phenyl group on the conformational dynamics of these compounds has been examined as well as the nature of the organic co-solvent. When coalescence phenomena are observed, simulation of the experimental 2H-{1H} lineshapes using a formalism tailored for two deuterons undergoing mutual exchange allows the rate constants and the activation parameters for the internal rotation processes to be calculated. Experimental values of DeltaH(not equal) have been compared with data evaluated by molecular modelling calculations and the activation parameters are discussed for the various compounds. It is shown that these polypeptide mesophases have no significant impact on the interconversion dynamics of these compounds. In contrast with the nematic thermotropic phases, Haller's equation cannot be used to predict the evolution of the quadrupolar splittings (Deltanu(Q) values), and hence the order parameters, versus T in the PBLG mesophases. For these particular lyotropic systems, it is shown that an exponential function of the form Deltanu(Q)[Hz]=C x exp (-E/RT[K]) provides excellent agreement between the experimental and expected Deltanu(Q) values. Analysis of the results reported in this work suggests that orientation and chiral discrimination phenomena in these lyotropic solvents could be treated separately because they would involve different interaction mechanisms.
A convenient method for distinguishing underivatized isomeric monosaccharides has been established using electrospray ionization ion trap mass spectrometry (ESI-ITMS). Mass spectra of hexoses (glucose, galactose, and mannose), N-acetylhexosamines (N-acetylglucosamine, N-acetylgalactosamine, and N-acetylmannosamine) and hexosamines (glucosamine, galactosamine, and mannosamine) dissolved in solvent containing 1 mM ammonium acetate were obtained in the positive ion mode. Glucose was distinguished from galactose and mannose in the MS(2) spectrum of the [M+NH(4)](+) ion at m/z 198. The MS(3) spectra generated from [M+NH(4)-H(2)O-NH(3)](+) at m/z 163 showed that galactose and mannose could be distinguished by the ratio of peak intensities at m/z 145 and 127, while the three N-acetylhexosamine and hexosamine stereochemical isomers could be identified by the relative abundance ratios of product ions observed in MS(3) spectra. The investigation of MS and MS(2) spectra from complexes of these monosaccharides with Na(+) and Pb(2+) failed to distinguish these monosaccharide isomers. Therefore, multiple stage mass analysis by ESI-ITMS using either [M+NH(4)](+) or [M+H](+) was useful to distinguish between the isomers of monosaccharides.