1,3,5-Triazepane-2,6-diones as structurally diverse and conformationally constrained dipeptide mimetics: identification of malaria liver stage inhibitors from a small pilot library

The development of the 1,3,5-triazepane-2,6-dione system as a novel, conformationally restricted, and readily accessible class of dipeptidomimetics is reported. The synthesis of the densely functionalized 1,3,5-triazepane-2,6-dione skeleton was achieved in only four steps from a variety of simple linear dipeptide precursors. To extend the practical value of 1,3,5-triazepane-2,6-diones, a general polymer-assisted solution-phase synthesis approach amenable to library production in a multiparallel format was developed. The conformational preferences of the 1,3,5-triazepane-2,6-dione skeleton were investigated in detail by NMR spectroscopy and X-ray diffraction. The ring exhibits a characteristic folded conformation which was compared to that of related dipeptide-derived scaffolds including the more planar 2,5-diketopiperazine (DKP). Molecular and structural diversity was increased further through post-cyclization appending operations at urea nitrogens. Preliminary biological screens of a small collection of 1,3,5-triazepane-2,6-diones revealed inhibitors of the underexplored malaria liver stage and suggest strong potential for this dipeptide-derived scaffold to interfere with and to modulate biological pathways.     

Stereoselective alkylation of N-Boc-protected-5-substituted delta-lactams: synthesis of alpha, delta-disubstituted delta-amino acids

N-Boc-protected-5-substituted delta-lactams were readily prepared from the corresponding beta 3-amino acids. Alkylation reactions of their Na enolates with various electrophiles proceeded in high yields with high facial selectivity. The structure of the alkylation products was confirmed by single-crystal X-ray analysis. This method provides a fast access to optically active alpha, delta-disubstituted delta-amino acids.     

Flexibility of solid-phase microextraction for passive sampling of atmospheric pesticides

For low volatile pesticides, the applications of solid-phase microextraction (SPME) as an air sampler were reported with sampling time chosen in the linear stage of the sorption kinetics because of long equilibrium time. In these pre-equilibrium conditions, sampling rates (SRs) expressed as the volume of air sampled by the SPME sampler per unit of time, were used to estimate analytes concentrations in air. In the present study, to achieve good extraction performance and accurate calibration, the sorption kinetics of several pesticides with SPME were investigated in detail, with a focus on parameters influencing SRs. Linear air velocity was found to be the main parameter affecting SRs. For exposed fibers, with air velocities below 20–25 cm s⁻¹, SRs increased with increasing air velocity. When linear air velocity was equal to or greater than 25–30 cm s⁻¹, it had little effect on SRs. To improve the flexibility of SPME, different configurations of SPME were compared, i.e. different lengths of fibers exposed, retracted fibers, exposed fibers with grids. SRs were linearly proportional to exposed lengths of fibers. Using grids, lower SRs and wider calibration time range were achieved. SRs for retracted fibers were the lowest among the different experimented configurations. The accuracy of calibration was improved and more flexibility of SPME was provided.     

Spin-State-Selective TPPI: A New Method for Suppression of Heteronuclear Coupling Constants in Multidimensional NMR Experiments

A novel multidimensional NMR pulse sequence tool, spin-state-selective time-proportional phase incrementation (S(3) TPPI), is introduced. It amounts to application of different TPPIs on the two components of doublets so that their frequencies can be manipulated independently. The chief application is for suppression of large heteronuclear one-bond coupling constants in indirect dimensions of multidimensional experiments without interchanging the two transverse magnetization components of doublets as conventional decoupling does, which is advantageous when they relax at different rates such as by partial compensation of dipolar and CSA relaxation contributions. For experimental confirmation we use a sample of (15)N-labeled neural cell adhesion molecule modules 1 and 2, a protein with a molecular weight of about 20 kDa. The new tool is general and can be combined with many multidimensional NMR experiments for proteins.     

Comparison of UV and visible Raman spectroscopy of bulk metal molybdate and metal vanadate catalysts

The visible (532 and 442 nm) and UV (325 nm) Raman spectra of bulk mixed metal oxides (metal molybdates and metal vanadates) were compared on the same spectrometer, for the first time, to allow examination of how varying the excitation energy from visible to UV affects the resulting Raman spectra. The quality of the Raman spectra was found to be a strong function of the absorption properties of the bulk mixed oxide. For bulk mixed metal oxides that absorb weakly in the visible and UV regions, both the visible and UV Raman spectra were of high quality and exhibit identical vibrational bands, but with slightly different relative intensities. For bulk mixed metal oxides that absorb strongly in the UV and visible regions and/or strongly in the UV and weakly in the visible regions, the visible Raman spectra are much richer in structural information and of higher resolution than the corresponding UV Raman spectra. This is a consequence of the strong UV absorption that significantly reduces the sampling volume and number of scatterers giving rise to the Raman signal. The shallower escape depth of UV Raman, however, was not sufficient to detect vibrations from the surface metal oxide species that are present on the outermost surface layer of these crystalline mixed metal oxide phases as previously suggested. It was also demonstrated that there is no sample damage by the more energetic UV excitation when very low laser powers and fast detectors are employed, thus avoiding the need of complicated fluidized bed sample arrangements sometimes used for UV Raman investigations. The current comparative Raman investigation carefully documents, for the first time, the advantages and disadvantages of applying different excitation energies in collecting Raman spectra of bulk mixed metal oxide materials.     

Chirality and Spectroscopic Changes Induced by the Recognition of Ethyl 5-Amino-2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl Carbamate Analogs by Tubulin

The two chiral isomers of ethyl 5-amino-2-methyl-l,2-di-hydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate, NSC 613863 (R-isomer)-(+) and NSC 613862 (S-isomer)-(-) (CI980) and the three achiral analogs NSC 330770 (2-de-methylated analog A), NSC 337238 and C179 are potent microtubule inhibitors. These ligands interact with tubulin overlapping the colchicine binding site. This study addresses the effects of recognition by tubulin on the conformational properties of the ligands. The near-UV CD (circular dichroism) band of the R-isomer was suppressed, while that of the S-isomer displayed a more intense negative band when these compounds were bound to tubulin. Interestingly, the three other initially achiral compounds became optically active upon binding to tubulin; particularly, analog A exhibited a negative CD band on the order of magnitude of chiral compounds. The CD changes are reversible, highly specific and actually permit measuring the binding of the ligands by tubulin. These CD changes are compatible with the deformation of the bound ligands. Fluorescence emission is strongly enhanced and blue shifted upon binding to tubulin. Water among a solvent series had a specific solvent effect, except on the 1,2-dehydro analogs NSC 337238 and C179, suggesting hydrogen bonding to Nl. The emission of tubulin-bound R-isomer, S-isomer and analog A could be mimicked by solvent viscosity, supporting the notion that the intramolecular rotation between the pyridopyrazine and phenyl rings is frozen upon binding.