Marcin K. Chmielewski

The 4-oxopentyl group as a labile phosphate/thiophosphate protecting group for synthetic oligodeoxyribonucleotides

Abstract An efficient and economical method for the solid-phase synthesis of oligodeoxyribonucleotides and their phosphorothioate analogues is described. The method entails the use of the 4-oxopentyl group for phosphate/thiophosphate protection. Post-synthesis removal of the protecting group is easily and rapidly achieved under mild conditions at ambient temperature using either pressurized gaseous amines or concentrated ammonium hydroxide.

Investigations on Synperiplanar and Antiperiplanar Isomers of Losartan: Theoretical and Experimental NMR Studies

Losartan inhibits the renin-angiotensin-aldosterone system by blocking the angiotensin II receptor. It is commonly used in cardiovascular diseases, such as hypertension. Several publications applied the ab initio and density functional theory methods to investigate the molecule of losartan. Only in one of them were the nuclear magnetic resonance spectra calculations carried out, and their results were correlated with the experimental values. The authors focused their attention on calculations of the anion form of losartan, taking into consideration both its synperiplanar and antiperiplanar configurations. Coefficients of determination and mean absolute deviation parameters were calculated for the experimental and calculated chemical shifts for every used basis set. They showed a noticeably stronger correlation for the anti-isomers than for the syn-isomers. Moreover, the solvation model increased the value of this parameter. The results of calculations confirmed that an anti-conformation of the analyte seems to be the preferred one, and such an orientation might be most potent within the receptor cavity, which is in agreement with the results of previous studies.

2-Pyridinyl-N-(2,4-difluorobenzyl)aminoethyl Group As Thermocontrolled Implement for Protection of Carboxylic Acids

A thermolabile protecting group strategy for carboxylic acids is expanded. Thermosensitive esters are readily prepared using a known procedure, and their stability under neutral condition is investigated. Effective thermolytic deprotection initiated only by temperature for different carboxylic acids is demonstrated, and the compatibility of a thermolytic protecting group with acidic and basic protecting groups in an orthogonal protection strategy is also presented. This study showed interesting correlations between the pKa of acids and the deprotection rate of their well-protected moieties.

UNIT 2.7 Deoxyribonucleoside Phosphoramidites

The detailed preparation of deoxyribonucleoside phosphoramidites bearing a 4‐[N‐methyl‐N‐(2,2,2‐trifluoroacetyl)amino]butyl group for P(III) protection is presented. The use of this group circumvents nucleobase alkylation during oligonucleotide deprotection. Two syntheses of phosphoramidites starting from either a phosphordichloridite precursor or a bis‐(N,N‐diisopropylamino)chlorophosphine intermediate are described for the phosphinylation of suitably protected deoxyribonucleosides.

Experimental and computational studies on a protonated 2-pyridinyl moiety and its switchable effect for the design of thermolytic devices

1D and 2D NMR investigations as well as computational studies, including static quantum-mechanics calculations, density function theory formalism, and classical molecular dynamics, were applied to determine the protonation sites in the thermolabile protecting group (TPG) containing a 2-pyridynyl moiety within its structure. This protecting group has three possible sites for protonation: an azomethine (pyridinic) atom (N1), 2-aminoethanol residue (N2), and 4-amino substituent (N4). Our investigations showed that the protonation mainly occurs on the N1 atom. Such protonation seems to be a major inhibitory factor in the thermal removal of 2-pyridynyl TPG by the “chemical switch” approach and decreases the aromaticity of the pyridine ring. We also discussed possible participation of N2 nitrogen in irreversible intramolecular cyclization under acidic conditions.

On the Interactions of Fused Pyrazole Derivative with Selected Amino Acids: DFT Calculations

Due to the increasing prevalence of neoplasms, there is a permanent need for new selective cytostatic compounds. Anticancer drugs can act in different ways, affecting protein expression and synthesis, including disruption of signaling pathways within cells. Continuing our previous research aiming at elucidating the mechanism of pyrazole’s anticancer activity, we carried out in silico studies on the interactions of fused pyrazole derivative with alanine, lysine, glutamic acid, and methionine. The objective of the study is to improve our understanding of the possible interactions of pyrazole derivatives with the above-mentioned amino acids. For this purpose, we apply the DFT formalism (optimization using the B3LYP, CAM-B3LYP, PBE0, and M06L functionals) and interaction energy calculations (counterpoise corrected method based on the basis set superposition error, BSSE) together with QTAIM approach and estimation of the 1H NMR chemical shifts of analyzed pyrazole derivative using different basis sets and DFT functionals in CPCM solvation model (and water used as a solvent).

3-(N-tert-butylcarboxamido)-1-propyl and 4-oxopentyl groups for phosphate/thiophosphate protection in oligodeoxyribonucleotide synthesis.

This unit provides procedures for the preparation of deoxyribonucleoside phosphoramidites and appropriate phosphordiamidite precursors with P(III) protecting groups different than the standard 2-cyanoethyl group. Specifically, these phosphoramidites are functionalized with the 3-(N-tert-butylcarboxamido)-1-propyl or 4-oxopentyl groups. The usefulness of these novel deoxyribonucleoside phosphoramidites in the solid-phase synthesis of a 20-mer DNA oligonucleotide and its phosphorothioated analog is demonstrated. It is also shown that removal of the 3-(N-tert-butylcarboxamido)-1-propyl phosphate/thiophosphate-protecting group from these oligonucleotides is rapidly effected under thermolytic conditions at neutral pH, whereas the 4-oxopentyl group is preferably removed by treatment with pressurized ammonia gas or concentrated ammonium hydroxide at ambient temperature. These detailed methods constitute an economical and alkylation-free approach to large-scale preparations of therapeutic oligonucleotides.