Tomasz Pospieszny

Synthesis, Spectroscopic and Theoretical Studies of New Quasi-Podands from Bile Acid Derivatives Linked by 1,2,3-Triazole Rings

A novel method for the synthesis of bile acid derivatives has been developed using “click chemistry”. Intermolecular 1,3-dipolar cycloaddition of the propargyl ester of bile acids and azide groups of 1,3,5-tris(azidomethyl)benzene gave a new quasi-podands with 1,2,3-triazole rings. The structures of the products were confirmed by spectral (1H-NMR, 13C-NMR, and FT-IR) analysis, mass spectrometry and PM5 semiempirical methods. Estimation of the pharmacotherapeutic potential has been accomplished for synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS).

Synthesis, Spectroscopic and Semiempirical Studies of New Quaternary Alkylammonium Conjugates of Sterols

New quaternary alkylammonium conjugates of steroids were obtained by two step reaction of sterols (ergosterol, cholesterol, dihydrocholesterol) with bromoacetic acid bromide, followed by bimolecular nucleophilic substitution with a long chain tertiary alkylamine. The structures of products were confirmed by spectral (1H-NMR, 13C-NMR, and FT-IR) analysis, mass spectrometry and PM5 semiempirical methods. The pharmacotherapeutic potential of synthesized compounds has been estimated on the basis of Prediction of Activity Spectra for Substances (PASS).

Synthesis, spectroscopy, theoretical and biological studies of new gramine-steroids salts and conjugates

New gramine connections with bile acids (lithocholic, deoxycholic, cholic) and sterols (cholesterol, cholestanol) were synthesized. The structures of products were confirmed by spectral (NMR, FT-IR) analysis, mass spectrometry (ESI-MS) as well as PM5 semiempirical methods. Unexpectedly, the products of the reaction of gramine with cholesterol and cholestanol were symmetrical compounds consisting of two molecules of sterols connected by N(CH3)2 group. All new synthesized compounds interact in vitro with the human erythrocyte membrane and alter discoid erythrocyte shape inducing stomatocytosis or echinocytosis. Increase in the incorporation of the fluorescent dye merocyanine 540 (MC540) into the erythrocyte membrane indicates that new compounds at sublytic concentrations are capable of disturbing membrane phospholipids asymmetry and loosening the molecular packing of phospholipids in the bilayer. Gramine significantly decreases the membrane partitioning properties as well as haemolytic activity of lithocholic acid in its new salt. Moreover, both deoxycholic and cholic acids completely lost their membrane perturbing activities in the gramine salts. On the other hand, the capacity of new gramine-sterols connections to alter the erythrocyte membrane structure and its permeability is much higher in comparison with sterols alone. The dual effect of gramine on the bile acid and sterols cell membrane partitioning activity observed in our study should not be neglected in vivo.

Synthesis, Spectroscopic and Theoretical Studies of New Quaternary N,N-Dimethyl-3-phthalimidopropylammonium Conjugates of Sterols and Bile Acids

New quaternary 3-phthalimidopropylammonium conjugates of steroids were obtained by reaction of sterols (ergosterol, cholesterol, cholestanol) and bile acids (lithocholic, deoxycholic, cholic) with bromoacetic acid bromide to give sterol 3β-bromoacetates and bile acid 3α-bromoacetates, respectively. These intermediates were subjected to nuclephilic substitution with N,N-dimethyl-3-phthalimidopropylamine to give the final quaternary ammonium salts. The structures of products were confirmed by spectral (1H-NMR, 13C-NMR, and FT-IR) analysis, mass spectrometry (ESI-MS, MALDI) as well as PM5 semiempirical methods and B3LYP ab initio methods. Estimation of the pharmacotherapeutic potential has been accomplished for synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS).

Syntheses, EIMS, 1H NMR, and 13C NMR Study of 2-Mono, 1,2-Di, and 2,4-Di Substituted Derivatives of 2-Thiocytosine

Seventeen new S-ortho-(meta- and para-) bromo-(chloro- and nitro-) benzylsubstituted 2-thiocytosines as well as S and N-1 (S- and N-4) ortho-(meta- and para-) bromo-(chloro- and nitro-) benzyl disubstituted hydrohalides of 2-thiocytosines have been prepared. The 1H and 13C NMR spectra of these compounds have been assigned unambiguously using a two-dimensional 13C, 1H-one-bond correlation (HETCOR) ( 1–9 ) and a two-dimensional 13C, 1H -Long Range correlation (HMBC) ( 10–18 ) spectra. Electron-impact (EI)-induced mass spectral fragmentation of S-benzyl substituted derivatives of 2-thiocytosine has been investigated. The data obtained make the basis for distinguishing isomers.

Thio Analogs of Pyrimidine Bases: Synthesis, Spectroscopic Study, and In Silico Biological Activity Evaluation of New 2-o-(m- and p-)Chlorobenzylthio-6-Methyl-5-Piperidino-(Morpholino-)Methyluracils

Six new 2-o-(m- and p-)chlorobenzylthio-6-methyl-5-piperidino-(or morpholino-) methyluracils have been prepared. The structures of these compounds were confirmed by spectroscopic (FT-IR, UV-Vis, 1H NMR, 13C NMR, and HMBC) and elemental analyses. Estimation of pharmacotherapeutic potential has been made for synthesized compounds on the basis of prediction of activity spectra for substances (PASS).

Thio Analogs of Pyrimidine Bases: Synthesis And Spectroscopic Study of New Potentially Biologically Active Disulfides of N,O-(N,N- or O,O-)-Di- and N,N,O-Tri-(o-, m-, and p-)bromobenzyl-2-thiouracils

Nine new disulfides of N,O-(N,N- or O,O-)-di- and N,N,O-tri-(o-, m- and p-)bromobenzyl-2-thiouracils have been prepared. The structures of these compounds were confirmed by spectroscopic (FT-IR, UV-Vis, 1H NMR) and elemental analyses. Estimation of pharmacotherapeutic potential has been made for synthesized compounds on the basis of Prediction of Activity Spectra for Substances (PASS).

Haemolytic activity of formyl- and acetyl-derivatives of bile acids and their gramine salts

&NA; Bile acids (lithocholic: LCA, deoxycholic: DCA and cholic: CA) and their formyl‐ and acetyl‐derivatives can be used as starting material in chemical synthesis of compounds with different biological activity strongly depended on their chemical structures. Our previous studies showed that biological activity of bile acids salts with gramine toward human erythrocytes was significantly different from the activity of bile acids alone. Moreover, gramine effectively modified the membrane perturbing activity of other steroids. As a continuation of our work, the haemolytic activity of formyl‐ and acetyl‐substituet bile acids as well as their gramine salts was studied in vitro. The structures of new compounds were confirmed by spectral (NMR, FT‐IR) analysis, mass spectrometry (ESI‐MS) as well as PM5 semiempirical methods. The results shown that the haemolytic activity of formyl‐ and acetyl‐LCA and DCA was significantly higher in comparison with their native forms at the whole concentration range. At high concentration, formyl derivative of CA was as effective as LCA and DCA derivatives whereas at lower concentration its haemolytic activity was at the level of original acid. The acetyl‐CA was not active as membrane perturbing agents. Furthermore, gramine significantly decreased the membrane‐perturbing activity of hydrophobic bile acids derivatives. The results obtained with the cellular system are in line with physicochemical calculation. Graphical abstract Figure. No caption available. HighlightsFormyl‐ and acetyl‐modifications of bile acids increased their cytotoxicity.Gramine reduces membrane‐perturbing activity of bile acids derivatives.Formyl‐ and acetyl‐substituents modify the lipophilicity of bile acids.

Quaternary Alkylammonium Conjugates of Steroids: Synthesis, Molecular Structure, and Biological Studies

The methods of synthesis as well as physical, spectroscopic (1H-NMR, 13C-NMR, and FT-IR, ESI-MS), and biological properties of quaternary and dimeric quaternary alkylammonium conjugates of steroids are presented. The results were contrasted with theoretical calculations (PM5 methods) and potential pharmacological properties (PASS). Alkylammonium sterols exhibit a broad spectrum of antimicrobial activity comparable to squalamine.

Differentiation of the Isomeric o-(m- and p-) Nitro-(Chloro- and Bromo-)Benzyl-2,4-(and 2,1-) Disubstituted 2-Thiocytosinium Halides by Electron Impact Ionisation and Fast Atom Bombardment Mass Spectrometry:

Electron ionisation (EI) and fast atom bombardment (FAB) mass spectral fragmentations of nine 2,4-(and 2,1-) disubstituted o-(m- and p-)nitro-(chloro- and bromo-)-2-thiocytosinium halides are investigated. Fragmentation pathways, whose elucidation is assisted by accurate mass measurements and metastable transitions [EI-mass spectrometry (MS)], as well as FAB/collision-induced dissociation (CID) mass spectra measurements are discussed. The correlations between the abundances of the (C11H10N4SO2)+ 1–3; (C11H10N3SCl)+ 4–6 and (C11H10N3SBr)+ 7–9 ions and the selected fragment ions (EI-MS), as well as (C18H16N5SO4)+ 1–3; (C18H16N3SCl2)+ 4–6 and (C18H16N3SBr2) + 7–9 ions and the selected ions (C7H6NO2)+ 1–3; (C7H6Cl)+ 4–6; (C7H6Br)+ 7–9 (FAB-MS) are discussed. The data obtained can be used for distinguishing isomers.