Marcin Wilczek

Alternative approach to the standardization of NMR spectra. Direct measurement of nuclear magnetic shielding in molecules.

Exploring the relation between shielding constants, resonance frequencies and magnetic moments of the nuclei we demonstrate that nuclear magnetic shielding can be directly observed from NMR spectra. In this approach, the absolute shielding constants of all the nuclei can be related to a single reference scale, with atomic (3)He as the primary standard. The accuracy of the data obtained using our method is confirmed comparing the (1)H and (13)C shielding constants for a series of deuterated compounds with those determined analyzing the traditional chemical shifts. Since the use of helium-3 is not in general a practical alternative, we next transfer the reference standard to the (2)H signals of external lock solvents, in this way making the method easy and ready for application with most NMR spectrometers. Finally, we illustrate our new method with the measurements of the (2/1)H primary isotope effects in several liquid deuterated solvents.

NMR frequency and magnetic dipole moment of 3He nucleus

We present new gas-phase NMR spectra which relate the resonance frequency of (3)He nucleus to the resonance frequency of the proton in tetramethylsilane (TMS). We discuss the dependence of (3)He resonance frequency on the density of the solvent gas, and we consider in detail the absolute shielding scales of both nuclei. Finally, we analyse the accuracy of the results, using the relationship between the resonance frequencies, absolute shielding constants and magnetic dipole moments of (1)H and (3)He nuclei.

Synthesis and anticonvulsant activity of novel 2,6-diketopiperazine derivatives. Part 1: perhydropyrrole[1,2-a]pyrazines.

A number of novel pyrrole[1,2-a]pyrazine derivatives were synthesized and evaluated in in vivo animal models of epilepsy. Among them, several compounds displayed promising seizure protection in the maximal electroshock seizure (MES), subcutaneous metrazol seizure (scMET), 6 Hz and pilocarpine-induced status prevention (PISP) tests, with ED(50) values comparable to the reference anticonvulsant drugs (AEDs). A critical influence of the stereochemistry and conformational preferences of the pyrrole[1,2-a]pyrazine core on in vivo pharmacological activity was observed. The mechanism of the anticonvulsant action of the agents synthesized is most probably not via inhibition of the voltage-dependent sodium (Na(+)) currents.

Expanding the substrate scope of ugi five-center, four-component reaction U-5C-4CR): ketones as coupling partners for secondary amino acids

Various symmetrical and unsymmetrical ketones were successfully coupled with secondary amino acids in the course of Ugi five-center, four-component reaction (U-5C-4CR), thus expanding the molecular diversity possible to be achieved by the reaction. The chemical yields depended on the degree of hindrance of the components employed and were satisfactory in view of possible steric interactions in the U-5C-4CR zwitterionic intermediate. The sense of diastereoinduction for reactions employing unsymmetrical ketones was examined by converting the resulting Ugi adducts into the corresponding rigid 2,6-diketopiperazine derivatives.

(S)-2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-6,12(11H,12aH)-dione—Synthesis and Crystallographic Studies

(S)-2-(4-Chlorobenzoyl)-1,2,3,4-tetrahydrobenzo[e]pyrazino[1,2-a][1,4]diazepine-6,12(11H,12aH)-dione was obtained in a three-step, one-pot synthesis, starting from optically pure (S)-2-piperazine carboxylic acid dihydrochloride. Selective acylation of the β-nitrogen atom followed by condensation with isatoic anhydride and cyclization with HATU/DIPEA to a seven-member benzodiazepine ring, led to the tricyclic benzodiazepine derivative. Crystallographic studies and initial biological screening were performed for the title compound.

Peptides and peptidoaldehydes as substrates for the Pictet–Spengler reaction

The Pictet–Spengler (PS) reaction was performed with various types of substrates: H‐Trp‐OMe and dipeptides with N‐terminal Trp as arylethylamine components and Z‐protected amino aldehydes and peptidoaldehydes as carbonyl components. We found that the C‐terminal part of Trp derivatives did not have any influence on the stereoselectivity of the reaction and the results are the same for simple esters of Trp and dipeptides.

Magnetic polymer microcapsules loaded with Nile Red fluorescent dye

Fabrication of multifunctional smart vehicles for drug delivery is a fascinating challenge of multidisciplinary research at the crossroads of materials science, physics and biology. We demonstrate a prototypical microcapsule system that is capable of encapsulating hydrophobic molecules and at the same time reveals magnetic properties. The microcapsules are prepared using a templated synthesis approach where the molecules to be encapsulated (Nile Red) are present in the organic droplets that are suspended in the polymerization solution which also contains magnetic nanoparticles. The polymer (polypyrrole) grows on the surface of organic droplets encapsulating the fluorescent dye in the core of the formed microcapsule which incorporates the nanoparticles into its wall. For characterization of the resulting structures a range of complementary physicochemical methodology is used including optical and electron microscopy, magnetometry, 1H NMR and spectroscopy in the visible and X-ray spectral ranges. Moreover, the microcapsules have been examined in biological environment in in vitro and in vivo studies.

Anti-inflammatory Potential of Flavonoids from the Aerial Parts of Corispermum marschallii

The isolation of phenolics from aerial parts of Corispermum marschallii yielded a total of 13 compounds including nine previously undescribed patuletin and spinacetin glycosides. These were identified as patuletin 3- O-β-d-galactopyranosyl-7- O-β-d-glucopyranoside (1), spinacetin 3- O-β-d-galactopyranosyl-7- O-β-d-glucopyranoside (2), patuletin 3- O-(6″- O-β-d-glucopyranosyl)-β-d-galactopyranoside (3), patuletin 3- O-(6″- O-α-l-arabinopyranosyl)-β-d-galactopyranoside (4), patuletin 3- O-(2″- O-(5‴- O-α-l-arabinopyranosyl)-β-d-apiofuranosyl)-β-d-galactopyranoside (5), patuletin 3- O-(2″- O-β-d-apiofuranosyl)-β-d-galactopyranoside (6), spinacetin 3- O-β-d-galactopyranoside (7), patuletin 3- O-β-d-galactopyranosyl-7- O-(6‴- O-feruloyl)-β-d-glucopyranoside (8), and spinacetin 3- O-β-d-galactopyranosyl-7- O-(6‴- O-feruloyl)-β-d-glucopyranoside (9). Structure elucidation was based on UV-visible, multistage MS, and 1D and 2D NMR spectroscopy and chemical derivatization, which allowed the identification on the glycosides with two different hexose moieties occurring at different positions of the aglycones. Most of the compounds tested inhibited the production of pro-inflammatory factors such as ROS, IL-8, and TNF-α in stimulated neutrophils.

Novel (S )-1,3,4,12a-tetrahydropyrazino[2,1- c ][1,4]benzodiazepine-6,12(2 H ,11 H )-dione derivatives: Selective inhibition of MV-4-11 biphenotypic B myelomonocytic leukemia cells’ growth is accompanied by reactive oxygen species overproduction and apoptosis

A series of optically pure (R)- and (S)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4]benzodiazepine-6,12(2H,11H)-dione derivatives was designed and synthesized as novel anthramycin analogues in a three-step, one-pot procedure, and tested for their antiproliferative activity on nine following cell lines: MV-4-11, UMUC-3, MDA-MB-231, MCF7, LoVo, HT-29, A-549, A2780 and BALB/3T3. The key structural features responsible for exhibition of cytotoxic effect were determined: the (S)-configuration of chiral center and the presence of hydrophobic 4-biphenyl substituent in the side chain. Introduction of bromine atom into the 8 position (8g) or substitution of dilactam ring with benzyl group (8m) further improved the activity and selectivity of investigated compounds. Among others, compound 8g exhibited selective cytotoxic effect against MV-4-11 (IC50 = 8.7 μM) and HT-29 (IC50 = 17.8 μM) cell lines, while 8m showed noticeable anticancer activity against MV-4-11 (IC50 = 10.8 μM) and LoVo (IC50 = 11.0 μM) cell lines. The cell cycle arrest in G1/S checkpoint and apoptosis associated with overproduction of reactive oxygen species was also observed for 8e and 8m.