Publications by authors named "Zbigniew Czarnocki"

42 Publications

"Clicking" fragment leads to novel dual-binding cholinesterase inhibitors.

Bioorg Med Chem 2021 Jul 7;42:116269. Epub 2021 Jun 7.

National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland; National Centre for Nuclear Research, 05-400 Otwock-Świerk, Poland.

Cholinesterase inhibitors are potent therapeutics in the treatment of Alzheimer's disease. Among them, dual binding ligands have recently gained a lot of attention. We discovered novel dual-binding cholinesterase inhibitors, using "clickable" fragments, which bind to either catalytic active site (CAS) or peripheral anionic site (PAS) of the enzyme. Copper(I)-catalyzed azide-alkyne cycloaddition allowed to effectively synthesize a series of final heterodimers, and modeling and kinetic studies confirmed their ability to bind to both CAS and PAS. A potent acetylcholinesterase inhibitor with IC = 18 nM (compound 23g) was discovered. A target-guided approach to link fragments by the enzyme itself was tested using butyrylcholinesterase.
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http://dx.doi.org/10.1016/j.bmc.2021.116269DOI Listing
July 2021

Novel podophyllotoxin and benzothiazole derivative induces transitional morphological and functional changes in HaCaT cells.

Toxicol In Vitro 2021 Jun 13;73:105144. Epub 2021 Mar 13.

Department for Histology and Embryology, Medical University of Warsaw, Chalubinskiego 5, 02-004, Poland. Electronic address:

Podophyllotoxin (PPT) is an antimitotic drug used topically in the treatment of anogenital warts. Due to its toxicity it cannot be administered systemically as an anticancer agent. However, modified PPT derivatives such as etoposide and teniposide are used clinically as systemic agents. Thus, we invented novel PPT derivative KL3 that was synthesized by photocyclization. Earlier we have shown that KL3 has an anticancer effect in various cell lines. Here we compared the toxicity of KL3 vs PPT on non-cancerous normal human keratinocytes (HaCaT) and peripheral blood mononuclear cells (PBMC) showing that KL3 is less toxic than PPT to non-cancerous cells. At concentrations that neither induced cell death, nor affected cell cycle, KL3 in HaCaT cells evoked transient ultrastructural features of ER stress, swelling of mitochondria and elongation of cytoplasmic processes. Those changes partially reversed with prolonged incubation while features of autophagy were induced. PPT in equivalent concentrations induced HaCaT cell death by cell cycle arrest, intrinsic apoptosis and finally disintegration of cell membranes followed by secondary necrosis. In conclusion, we show that the KL3 derivative of PPT in contrast to PPT allows repair of normal keratinocytes and triggers mechanisms that restore non-tumor cell homeostasis.
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http://dx.doi.org/10.1016/j.tiv.2021.105144DOI Listing
June 2021

Fentanyl Family at the Mu-Opioid Receptor: Uniform Assessment of Binding and Computational Analysis.

Molecules 2019 Feb 19;24(4). Epub 2019 Feb 19.

National Medicines Institute, 00-725 Warsaw, Poland.

Interactions of 21 fentanyl derivatives with μ-opioid receptor (μOR) were studied using experimental and theoretical methods. Their binding to μOR was assessed with radioligand competitive binding assay. A uniform set of binding affinity data contains values for two novel and one previously uncharacterized derivative. The data confirms trends known so far and thanks to their uniformity, they facilitate further comparisons. In order to provide structural hypotheses explaining the experimental affinities, the complexes of the studied derivatives with μOR were modeled and subject to molecular dynamics simulations. Five common General Features () of fentanyls' binding modes stemmed from these simulations. They include: ) the ionic interaction between D147 and the ligands' piperidine NH⁺ moiety; ) the N-chain orientation towards the μOR interior; ) the other pole of ligands is directed towards the receptor outlet; ) the aromatic anilide ring penetrates the subpocket formed by TM3, TM4, ECL1 and ECL2; ) the 4-axial substituent (if present) is directed towards W318. Except for the ionic interaction with D147, the majority of fentanyl-μOR contacts is hydrophobic. Interestingly, it was possible to find nonlinear relationships between the binding affinity and the volume of the N-chain and/or anilide's aromatic ring. This kind of relationships is consistent with the apolar character of interactions involved in ligand⁻receptor binding. The affinity reaches the optimum for medium size while it decreases for both large and small substituents. Additionally, a linear correlation between the volumes and the average dihedral angles of W293 and W133 was revealed by the molecular dynamics study. This seems particularly important, as the W293 residue is involved in the activation processes. Further, the Y326 (OH) and D147 (Cγ) distance found in the simulations also depends on the ligands' size. In contrast, neither RMSF measures nor D114/Y336 hydrations show significant structure-based correlations. They also do not differentiate studied fentanyl derivatives. Eventually, none of 14 popular scoring functions yielded a significant correlation between the predicted and observed affinity data (R < 0.30, = 28).
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http://dx.doi.org/10.3390/molecules24040740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6412969PMC
February 2019

The Activity of Urolithin A and M4 Valerolactone, Colonic Microbiota Metabolites of Polyphenols, in a Prostate Cancer In Vitro Model.

Planta Med 2019 Jan 19;85(2):118-125. Epub 2018 Oct 19.

Department of Pharmacognosy and Molecular Basis of Phytotherapy, Faculty of Pharmacy, Medical University of Warsaw, Warsaw, Poland.

The gut microbiota-derived metabolites of ellagitannins and green tea catechins, urolithin A (uroA) and 5-(3',4',5'-trihydroxyphenyl)--valerolactone (M4), respectively, are among the main compounds absorbed into human system after ingestion of these polyphenols. The aim of this study was to establish the effects of M4, uroA, and their combinations on LNCaP cells, an androgen dependent prostate cancer model.. The LNCaP cells were incubated with increasing concentrations of tested metabolites. The cell proliferation was determined by measurement of DNA-bisbenzimide H 33 258 complexes fluorescence. The isobolographic analysis was used to establish the type of interaction between metabolites. The apoptosis, androgen receptor (AR) localization, and phosphorylation of Akt kinase were measured by flow cytometry. Prostate-specific antigen (PSA) secretion was determined by ELISA. M4 showed modest antiproliferative activity in LNCaP cells (IC = 117 µM; CI: 81 - 154). UroA decreased proliferation (IC = 32.7 µM; CI: 24.3 - 41.1) and induced apoptosis of LNCaP cells. The mixture of M4 with uroA had synergistic antiproliferative effect. Moreover, M4 potentiated inhibition of PSA secretion and enhanced retention of AR in cytoplasm caused by uroA. Interestingly, uroA increased levels of pSer473 Akt in LNCaP cells. These results show that colonic metabolites may contribute to chemoprevention of prostate cancer by varied polyphenol-rich diet or composite polyphenol preparations.
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http://dx.doi.org/10.1055/a-0755-7715DOI Listing
January 2019

Donepezil-melatonin hybrids as butyrylcholinesterase inhibitors: Improving binding affinity through varying mode of linking fragments.

Arch Pharm (Weinheim) 2018 Nov 5;351(11):e1800194. Epub 2018 Oct 5.

Faculty of Chemistry, University of Warsaw, Warsaw, Poland.

Hybrid inhibitors of acetyl- and butyrylcholinesterase are compounds that combine structural motifs of two different classical inhibitors, leading to a dual binding ligand. A rapidly growing collection of those compounds involves a wide diversity of structural motifs, but the way of linking two active fragments and its impact on the affinity toward cholinesterases usually remains beyond the extent of investigation. We present hereby a detailed analysis of this aspect using melatonin-donepezil hybrids. A new series of compounds, in which two fragments are connected using a carbamate linker, exhibits excellent activity and selectivity toward butyrylcholinesterase.
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http://dx.doi.org/10.1002/ardp.201800194DOI Listing
November 2018

Some mechanistic aspects regarding the Suzuki-Miyaura reaction between selected -substituted phenylboronic acids and 3,4,5-tribromo-2,6-dimethylpyridine.

Beilstein J Org Chem 2018 11;14:2384-2393. Epub 2018 Sep 11.

Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.

Atropisomers are very interesting stereoisomers having axial chirality resulting from restricted rotation around single bonds and are found in various classes of compounds. Substituted arylpyridines are an important group of them. A regio- and atropselective Suzuki-Miyaura cross-coupling reaction on 3,4,5-tribromo-2,6-dimethylpyridine was studied. Reactions with various amounts of -substituted phenylboronic acids with 3,4,5-tribromo-2,6-dimethylpyridine gave a series of mono- di- and triarylpyridine derivatives which allowed to draw conclusions about the order of substitution. Also, the observed selectivity in the case of -methoxyphenylboronic acid suggested an additional metal -chelation effect in the transition state, apparently not present in the -chloro analogues. The rotational barrier in selected atropisomers was determined on the basis of HT NMR and thermal epimerisation experiments. The structure of most presented atropisomeric derivatives of 2,6-dimethylpyridine was confirmed by single-crystal X-ray analysis. Racemic chiral, differently substituted atropisomers were also examined by H NMR spectroscopy in the presence of a chiral solvating agent. This regio- and atropselectivity may be generally applicable to other arylpyridine systems. A regio- and atropselective Suzuki-Miyaura cross-coupling process has been observed, giving an efficient access to a class of atropisomeric compounds. An opposite selectivity using a differently -substituted phenylbornic acid was observed.
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http://dx.doi.org/10.3762/bjoc.14.214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6142784PMC
September 2018

Simultaneous induction and blockade of autophagy by a single agent.

Cell Death Dis 2018 03 2;9(3):353. Epub 2018 Mar 2.

Laboratory of Molecular Bases of Aging, Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093, Warsaw, Poland.

Besides cell death, autophagy and cell senescence are the main outcomes of anticancer treatment. We demonstrate that tacrine-melatonin heterodimer C10, a potent anti-Alzheimer's disease drug, has an antiproliferative effect on MCF-7 breast cancer cells. The main cell response to a 24 h-treatment with C10 was autophagy enhancement accompanied by inhibition of mTOR and AKT pathways. Significantly increased autophagy markers, such as LC3B- and ATG16L-positive vesicles, confirmed autophagy induction by C10. However, analysis of autophagic flux using mCherry-GFP-LC3B construct revealed inhibition of autophagy by C10 at the late-stage. Moreover, electron microscopy and analysis of colocalization of LC3B and LAMP-1 proteins provided evidence of autophagosome-lysosome fusion with concomitant inhibition of autolysosomal degradation function. After transient treatment with IC dose of C10 followed by cell culture without the drug, 20% of MCF-7 cells displayed markers of senescence. On the other hand, permanent cell treatment with C10 resulted in massive cell death on the 5th or 6th day. Recently, an approach whereby autophagy is induced by one compound and simultaneously blocked by the use of another one has been proposed as a novel anticancer strategy. We demonstrate that the same effect may be achieved using a single agent, C10. Our findings offer a new, promising strategy for anticancer treatment.
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http://dx.doi.org/10.1038/s41419-018-0383-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834631PMC
March 2018

Flow Photochemistry as a Tool for the Total Synthesis of (+)-Epigalcatin.

Org Lett 2018 02 18;20(3):605-607. Epub 2018 Jan 18.

Faculty of Chemistry, University of Warsaw , Pasteura 1, Warsaw 02-093, Poland.

The first total synthesis of (+)-epigalcatin was completed in a highly stereoselective manner starting from piperonal, 3,4-dimethylbenzaldehyde, and diethyl succinate. l-Prolinol was used as a chiral auxiliary. The crucial step in this procedure involves the construction of the cyclolignan framework by continuous-flow photocyclization of a chiral atropisomeric 1,2-bisbenzylidenesuccinate amide ester.
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http://dx.doi.org/10.1021/acs.orglett.7b03974DOI Listing
February 2018

Molecular cloning of melatonin 3-hydroxylase and its production of cyclic 3-hydroxymelatonin in rice (Oryza sativa).

J Pineal Res 2016 Nov 31;61(4):470-478. Epub 2016 Aug 31.

Department of Biotechnology, Bioenergy Research Center, Chonnam National University, Gwangju, South Korea.

Melatonin is metabolized in animals to cyclic 3-hydroxymelatonin (3-OHM) not by an enzymatic pathway, but by interaction with hydroxyl radicals. The production of 3-OHM in animals suggests the possible presence of 3-OHM in plants. Prior to the identification of 3-OHM in plants, we directly cloned the corresponding gene(s) responsible for 3-OHM synthesis using Escherichia coli library strains expressing genes belonging to the 2-oxoglutarate-dependent dioxygenase (2-ODD) superfamily from rice. Three of 35 E. coli library strains supplemented with 1 mmol/L melatonin were found to produce 3-OHM in their extracellular medium, suggestive of three 2-ODD genes involved in 3-OHM production. The purified recombinant 2-ODD 11, 2-ODD 26, and 2-ODD 33 proteins were shown to catalyze the metabolism of melatonin to 3-OHM, with 2-ODD 11 showing the highest melatonin 3-hydroxylase (M3H) catalytic activity. Consistent with the presence of M3H genes, rice leaves supplemented with 5 mmol/L melatonin produced 3-OHM [233 μg/g fresh weight (FW)], 2-hydroxymelatonin (21 μg/g FW), and N -acetyl-N -formyl-5-methoxykynuramine (5 μg/g FW). Three M3H transcripts were induced upon the treatment of rice leaves with cadmium followed by an increase in M3H enzyme activity. Cloning of M3H genes in plants has paved the way for the studies of melatonin in plants in terms of its multiple physiological roles.
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http://dx.doi.org/10.1111/jpi.12361DOI Listing
November 2016

SYNTHETIC DERIVATIVES OF ISOQUINOLINE, DICARBOXYLIC ACID IMIDES AND THIOIMIDES AS BIOACTIVE COMPOUNDS.

Acta Pol Pharm 2016 Sep;73(5):1181-1189

This study is a continuation of a research program aimed at identifying potent drugs against bacterial infections, in which a series of organic compounds: dicarboxylic acid imides and thioimides, isoquinoline derivatives and open chain compounds, were examined for antimicrobial properties against Staphylococcus auneus and Escheiichia coli. In effect of this investigation, the most active compounds (35-40, 47) were selected for in vitiv tests against fourteen clinically important pathogenic isolates, the methicillin resistant Staphylococcus aueus (MRSA) and several reference Gram-negative bacteria: Prteus vulgaris, Pseudomonas aeruginosa, Klebsiella pneumonia, Stenonophoinonas inaltophilia, and Acinetobacter baumannii. The obtained data revealed that seven compounds (three dithioimides, 35, 39, 47, and four thioimides, 36-38, 40) exhibit effective antibacterial activity against the tested Staphylococcus auirus MSSA and MRSA strains. Among them, dicarboxylic acid thioimides 37 and 38 were proven to be the most active.
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September 2016

A convenient route to symmetrically and unsymmetrically substituted 3,5-diaryl-2,4,6-trimethylpyridines via Suzuki-Miyaura cross-coupling reaction.

Beilstein J Org Chem 2016 28;12:835-45. Epub 2016 Apr 28.

Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.

A series of differently substituted 3,5-diaryl-2,4,6-trimethylpyridines were prepared and characterized using the Suzuki-Miyaura coupling reaction with accordingly selected bromo-derivatives and arylboronic acids. The reaction conditions were carefully optimized allowing high yield of isolated products and also the construction of unsymmetrically substituted diarylpyridines, difficult to access by other methods.
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http://dx.doi.org/10.3762/bjoc.12.82DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4901938PMC
June 2016

Isoprenoid Alcohols are Susceptible to Oxidation with Singlet Oxygen and Hydroxyl Radicals.

Lipids 2016 Feb 30;51(2):229-44. Epub 2015 Dec 30.

Department of Lipid Biochemistry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences (PAS), Pawinskiego 5a, 02-106, Warsaw, Poland.

Isoprenoids, as common constituents of all living cells, are exposed to oxidative agents--reactive oxygen species, for example, singlet oxygen or hydroxyl radicals. Despite this fact, products of oxidation of polyisoprenoids have never been characterized. In this study, chemical oxidation of isoprenoid alcohols (Prenol-2 and -10) was performed using singlet oxygen (generated in the presence of hydrogen peroxide/molybdate or upon photochemical reaction in the presence of porphyrin), oxygen (formed upon hydrogen peroxide dismutation) or hydroxyl radical (generated by the hydrogen peroxide/sonication, UV/titanium dioxide or UV/hydrogen peroxide) systems. The structure of the obtained products, hydroxy-, peroxy- and heterocyclic derivatives, was studied with the aid of mass spectrometry (MS) and nuclear magnetic resonance (NMR) methods. Furthermore, mass spectrometry with electrospray ionization appeared to be a useful analytical tool to detect the products of oxidation of isoprenoids (ESI-MS analysis), as well as to establish their structure on the basis of the fragmentation spectra of selected ions (ESI-MS/MS analysis). Taken together, susceptibility of polyisoprenoid alcohols to various oxidizing agents was shown for the first time.
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http://dx.doi.org/10.1007/s11745-015-4104-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735226PMC
February 2016

Formal synthesis of (-)-podophyllotoxin through the photocyclization of an axially chiral 3,4-bisbenzylidene succinate amide ester--a flow photochemistry approach.

Org Biomol Chem 2016 Jan;14(2):460-469

Faculty of Chemistry, University of Warsaw, Pasteura 1, Warsaw 02-093, Poland.

We have developed a strategy for the stereoselective synthesis of cyclolignans related to podophyllotoxin and its derivatives. The crucial step of the synthesis is the photocyclization of a chiral atropoisomeric 1,2-bisbenzylidenesuccinate amide ester, which can be prepared from suitable aromatic aldehydes, diethyl succinate and l-prolinol. The photocyclization was found to be more efficient when irradiation was performed in a home-built continuous flow photochemical reactor. The in-flow irradiation also allowed us to perform the reaction on a multigram scale. The chiral auxiliary was removed by reductive cleavage with the Schwartz's reagent to give the cytotoxic 1R,2R-cis-podophyllic aldehyde, which in turn could be easily reduced to the corresponding alcohol, completing the formal synthesis of (-)-podophyllotoxin.
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http://dx.doi.org/10.1039/c5ob01844gDOI Listing
January 2016

The enantioselective synthesis of (S)-(+)-mianserin and (S)-(+)-epinastine.

Beilstein J Org Chem 2015 28;11:1509-13. Epub 2015 Aug 28.

Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093, Warsaw, Poland.

A simple enantioselective synthetic procedure for the preparation of mianserin and epinastine in optically pure form is described. The key step in the synthetic pathway is the asymmetric reduction of the cyclic imine using asymmetric transfer hydrogenation conditions.
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http://dx.doi.org/10.3762/bjoc.11.164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4578372PMC
October 2015

Metabolism of N-acylated-dopamine.

PLoS One 2014 22;9(1):e85259. Epub 2014 Jan 22.

Department of Respiratory Research, Medical Research Center, Polish Academy of Sciences, Warsaw, Poland.

N-oleoyl-dopamine (OLDA) is a novel lipid derivative of dopamine. Its biological action includes the interaction with dopamine and the transient receptor potential vanilloid (TRPV1) receptors. It seems to be synthesized in a dopamine-like manner, but there has been no information on its degradation. The aim of the study was, therefore, to determine whether OLDA metabolism proceeds the way dopamine proper does. We addressed the issue by examining the occurrence of O-methylation of exogenously supplemented OLDA via catechol-O-methyltransferase (COMT) under in vitro, ex vivo, and in vivo conditions using rat brain tissue. The results show that OLDA was methylated by COMT in all conditions studied, yielding the O-methylated derivative. The methylation was reversed by tolcapone, a potent COMT inhibitor, in a dose-dependent manner. We conclude that OLDA enters the metabolic pathway of dopamine. Methylation of OLDA may enhance its bioactive properties, such as the ability to interact with TRPV1 receptors.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0085259PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3899008PMC
December 2014

Chemical aspects of the primary ionization mechanisms in matrix-assisted laser desorption ionization.

Eur J Mass Spectrom (Chichester) 2014 ;20(6):437-44

National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland.

It has been proposed that the primary ionization mechanism occurring in matrix-assisted laser desorption ionization (MALDI) experiments originates from the presence, in the solid-state matrix-analytes sample, of matrix dimers. These species are formed by the interaction of carboxylic groups present in the matrix molecules with the formation of strong hydrogen bonds. Theoretical calculations proved that the laser irradiation of these structures leads to one or two H-bridge cleavages, giving rise to an "open" dimer structure or to disproportionation with the formation of MH(+) and [M-H](-) species. The ions so formed can be considered highly effective in their reaction with analyte ions, leading to their protonation (or deprotonation). To achieve further evidence for these proposals, in the present study the energetics of the reactions of ions from different aromatic carboxylic acids with two amino acids (glycine and lysine) and three multipeptides (gly-gly, gly-gly-gly and gly-gly-gly-gly) was investigated. The lowest ∆G values were obtained for 2,5- dihydroxybenzoic acid, widely employed as the MALDI matrix. Also, for p-nitrobenzoic acid the reaction is slightly exothermic, while for the other aromatic carboxylic acids derivatives positives values of ∆G are present.
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http://dx.doi.org/10.1255/ejms.1296DOI Listing
May 2015

Highly selective inhibition of butyrylcholinesterase by a novel melatonin-tacrine heterodimers.

J Pineal Res 2013 May;54(4):435-41

Faculty of Chemistry, University of Warsaw, Warsaw, Poland.

Novel inhibitors of cholinesterases, especially butyrylcholinesterase (BuChE), were obtained by coupling melatonin-tacrine heterodimers via the carbamate bond. Compounds 14a-i possessed potent cholinesterase inhibitory activity (with IC50 values as low as 1.18 nM for acetylcholinesterase (AChE) and 0.24 nM for butyrylcholinesterase (BuChE)). These heterodimers exhibit selectivity toward BuChE, being from 4- to 256-fold more active toward BuChE than AChE, but still acting as better AChE inhibitors than tacrine 4.
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http://dx.doi.org/10.1111/jpi.12006DOI Listing
May 2013

Metallomics for drug development: a further insight into intracellular activation chemistry of a ruthenium(III)-based anticancer drug gained using a multidimensional analytical approach.

Metallomics 2014 Jan;6(1):147-53

Chair of Analytical Chemistry, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland.

The mechanism by which the most relevant ruthenium anticancer drugs are activated in tumors to commence their tumor-inhibiting action remains one of the challenging research tasks of present-day metallomics. This contribution aims to capture and identify eventually more reactive species of one of two bis-indazole tetrachloridoruthenate(III) compounds that are progressing in clinical trials. In view of the fact that the transport of ruthenium into cancer cells is governed by transferrin receptors, the susceptibility of the Ru drug adduct with holo-transferrin to exposure by glutathione and ascorbic acid (at their cancer cytosol concentrations) was studied by inductively coupled plasma mass spectrometry (ICP-MS), following isolation of the reaction products by ultrafiltration. Next, capillary electrophoresis coupled to ICP-MS was applied to monitor changes in the Ru speciation both under simulated cancer cytosol conditions and in real cytosol and to assign the charge state of novel metal species. The latter were identified by using tandem electrospray ionization MS in the respective ion mode. The formation of ruthenium(II) species was for the first time revealed, in which the central metal is coordinated by the reduced (GSH) or the oxidized (GSSG) form of glutathione, i.e. [Ru(II)HindCl4(GSH)](2-) and [Ru(II)HindCl4(GSSG)](2-), respectively (Hind = indazole). Ascorbic acid released the ruthenium functionality from the protein-bound form in a different way, the products of adduct cleavage containing aqua ligands. Distribution of low-molecular mass species of Ru in human cytosol was found to have very much in common with the ruthenium speciation assayed under simulated cytosol conditions.
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http://dx.doi.org/10.1039/c3mt00252gDOI Listing
January 2014

Synthesis of imperatorin analogs and their evaluation as acetylcholinesterase and butyrylcholinesterase inhibitors.

Arch Pharm (Weinheim) 2013 Nov 14;346(11):775-82. Epub 2013 Oct 14.

Faculty of Chemistry, University of Warsaw, Warsaw, Poland; Faculty of Pharmacy, Department of Pharmacognosy and Molecular Basis of Phytotherapy, Medical University of Warsaw, Warsaw, Poland.

In this study, we synthesized several imperatorin analogs using imperatorin and xanthotoxin as substrates. The anti-cholinesterase activities of all compounds were evaluated in in vitro experiments according to the modified Ellman's method. For each synthesized compound, IC50 values for both enzymes were established. Galantamine hydrobromide was used as a positive control in the enzymatic experiments. All active compounds showed selectivity toward butyrylcholinesterase (BuChE) rather than acetylcholinesterase. The most active ones were 8-(3-methylbutoxy)-psoralen and 8-hexoxypsoralen with IC50 values for BuChE of around 16.5 and 16.4 µM, respectively. The results of our study may be considered as the beginning of a search for potential anti-Alzheimer's disease drugs based on the structure of natural furocoumarins.
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http://dx.doi.org/10.1002/ardp.201300259DOI Listing
November 2013

On the Primary Ionization Mechanism(s) in Matrix-Assisted Laser Desorption Ionization.

J Anal Methods Chem 2012 27;2012:161865. Epub 2012 Nov 27.

National Council of Researches, Institute of Molecular Sciences and Technologies, Corso Stati Uniti 4, I35100 Padova, Italy.

A mechanism is proposed for the first step of ionization occurring in matrix-assisted laser desorption ionization, leading to protonated and deprotonated matrix (Ma) molecules ([Ma + H](+) and [Ma - H](-) ions). It is based on observation that in solid state, for carboxyl-containing MALDI matrices, the molecules form strong hydrogen bonds and their carboxylic groups can act as both donors and acceptors. This behavior leads to stable dimeric structures. The laser irradiation leads to the cleavage of these hydrogen bonds, and theoretical calculations show that both [Ma + H](+) and [Ma - H](-) ions can be formed through a two-photon absorption process. Alternatively, by the absorption of one photon only, a heterodissociation of one of the O-H bonds can lead to a stable structure containing both cationic and anionic sites. This structure could be considered an intermediate that, through the absorption of a further photon, leads to the formation of matrix ions. Some experiments have been performed to evaluate the role of thermal ionization and indicate that its effect is negligible. Some differences have been observed for different matrices in the formation of analyte molecule (M) ion [M + H](+), [M - H](-), M(+•), and [M - 2H](-•), and they have been explained in terms of ionization energies, pKa values, and thermodynamic stability.
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http://dx.doi.org/10.1155/2012/161865DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515899PMC
December 2012

3-(2-Acetamido-eth-yl)-1H-indol-5-yl 4-nitro-phenyl carbonate.

Acta Crystallogr Sect E Struct Rep Online 2012 Oct 12;68(Pt 10):o2915. Epub 2012 Sep 12.

National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland ; NationalCentre for Nuclear Research, 05-400 Otwock-Świerk, Poland.

In the title mol-ecule, C(19)H(17)N(3)O(6), the indole ring system is essentially planar (r.m.s. deviation = 0.009 Å) and forms a dihedral angle of 31.96 (9)° with the nitro-substituted benzene ring. In the crystal, mol-ecules are linked by pairs of N-H⋯O hydrogen bonds, forming inversion dimers which are connected by further N-H⋯O hydrogen bonds into a two-dimensional network parallel to (102).
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http://dx.doi.org/10.1107/S1600536812038238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3470262PMC
October 2012

On the mechanisms of the reactions between some perfluorinated compounds and CH(5) (+) --experimental and theoretical approaches.

J Mass Spectrom 2011 Dec;46(12):1211-22

CNR-ISTM, Sezione di Padova, Corso Stati Uniti 4, 35127, Padova, Italy.

Five perfluorocompounds [perfluoropentane, 4-(perfluoroethoxy)-perfluorobutane, 5-(perfluoroethyl)-perfluorotetrahydrofuran, 2-(trifluoromethyl)-perfluorotetrahydropyran, and 4-(trifluoromethyl)-perfluorotetrahydropyran] were analyzed by electron ionization (EI) and chemical ionization (CI), using methane and isobutane as reagent gases. Under CI conditions, isobutane does not lead to significative results whereas methane leads to high ionic yields [with respect to both CI (isobutane) and EI]. Under EI conditions, practically only fragment ions are observed, with the complete loss of molecular weight. In contrast under CI(CH(4) ) conditions, [M-F](+) ions are produced. Under these conditions, the behavior of oxygen-containing molecules is strongly different from that of perfluoropentane. This is because oxygen can greatly stabilize the formation of the [M-F](+) carbocation by a π-electron donor effect, especially in the case of cyclic structures. Moreover, π-stabilization can be considered a useful tool to rationalize the position of tertiary carbon atom in trifluoromethyl-perfluoro-pyrane isomeric ions. The experimental data formed the starting point for the theoretical calculation, which allowed us to explore the mechanisms of the reactions of CH(5) (+) ions with selected perfluorocompounds. The computational methods used show that a direct protonation of the perfluoroethers (PFEs) by CH(5) (+) as well as iBu(+) is very unlikely. In the theoretical calculations, the PFE molecule served rather as the F(-) donor, and the elimination of HF molecule occurred when the PFE molecule was placed close to H(+) or CH(5) (+) ions. The fact that the latter is very unstable and decomposes to a proton and methane molecule explains why the use of methane in CI is so successful in the generation of [M-F](+) ion. In contrast, the isobutonium cation rearranges to an isopropyl cation/methane complex rather than that it abstracts F(-) from the PFE molecule. Similar results can be expected for other PFEs and perfluoroalkanes (PFAs) because both CH(5) (+) and H(+) were able to abstract the HF molecule also by attacking along the perfluoroalkyl chain of the PFE.
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http://dx.doi.org/10.1002/jms.1995DOI Listing
December 2011

Identification of common impurities present in the synthetic routes leading to 4-methylthioamphetamine (4-MTA). Part II: Reductive amination and nitropropene route.

Forensic Sci Int 2012 Apr 22;217(1-3):60-70. Epub 2011 Nov 22.

Forensic Laboratory, Internal Security Agency, 1 Sierpnia 30A, 02-134 Warsaw, Poland.

In this paper the by-products arising during the synthesis of 4-methylthioamphetamine (4-MTA) by LiAlH(4) reduction of 1-(4-methylthiophenyl)-2-nitropropene (nitropropene route) and reductive amination of 4-methylthiophenyl-2-propanone in the presence of NaCNBH(4) are investigated. The identification of 4-methylthio derivatives of N-(β-phenylisopropyl)benzaldimine, 4-methylthio derivative of N-(β-phenylisopropyl)benzyl methyl ketimine, 1-(4-methylthiophenyl)-N-(4-methylthiobenzyl)-2-propanamine, (RS) and (SS/RR)-N,N-di-[β-(4-methylthiophenyl)isopropyl]amine, 4-methylthiobenzyl ether and methylthiobenzoic acid methyl ester as most prominent impurities in crude 4-MTA synthesised by reductive amination of 4-methylthiophenyl-2-propanone, is reported. Methylthio derivatives of 2-methyl-3-phenylaziridine, 2-benzylaziridine, and 4-methylthio derivative of BMK oxime as route-specific markers of nitropropene route leading to 4-MTA, were also characterized. The identity of these compounds was confirmed by their independent synthesis.
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http://dx.doi.org/10.1016/j.forsciint.2011.09.026DOI Listing
April 2012

Identification and synthesis of by-products found in 4-methylthioamphetamine (4-MTA) produced by the Leuckart method.

Forensic Sci Int 2012 Mar 6;216(1-3):108-20. Epub 2011 Oct 6.

Forensic Laboratory, Internal Security Agency, 1 Sierpnia 30A, 02-134 Warsaw, Poland.

The synthesis of the designer drug 4-methylthioamphetamine (4-MTA) has been carried out using the well-known Leuckart reaction in four versions. The treatment of 4-methylthiophenylacetone with formamide, mixture of formamide/formic acid, ammonium formate, and mixture of ammonium formate and formic acid followed by acid hydrolysis brought about the formation of 4-MTA contaminated with a number of impurities. The gas chromatography mass-spectrometry (GC-MS) analysis of the reaction mixtures allowed identification of the most prominent impurities, such as diasteromers of N,N-di-[β-(4-methylthiophenyl)isopropyl]amine, N,N-di-[β-(4-methylthiophenyl)isopropyl]methylamine, N,N-di-[β-(4-methylthiophenyl)isopropyl]formamide, the Schiff bases derived from 4-MTA and 4-methylbenzaldehyde (benzaldimine) and 4-methylthiophenylacetone (ketimine) as well as some heterocycles: 4-methyl-5-(4'-methylthiophenyl)pyrimidine, 4-(4'-methylthiobenzyl)pyrimidine, 2,6-dimethyl-3,5-di-(4'-methylthiophenyl)pyridine, 2,4-dimethyl-3,5-di-(4'-methylthiophenyl)pyridine. The correctness of identification was confirmed by independent synthesis of these compounds. Each synthesized reference compound was characterized by means of MS, (1)H and (13)C NMR, and IR methods. The stereochemistry of (RR/SS) diasteromer of N,N-di-[β-(4-methylthiophenyl)isopropyl]amine was confirmed by a crystallographic method.
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http://dx.doi.org/10.1016/j.forsciint.2011.09.005DOI Listing
March 2012

The synthesis, mass spectrometric properties and identification of some N,N-di-(β-arylisopropyl)formamides related to the synthesis of ring-modified amphetamines.

Forensic Sci Int 2011 Mar 16;206(1-3):197-206. Epub 2010 Sep 16.

Forensic Laboratory, Internal Security Agency, 1 Sierpnia 30A, 02-134 Warsaw, Poland.

This study examines the electron impact (EI) induced mass spectrometric behavior of several N,N-di-(β-arylisopropyl)formamides, which are connected to the Leuckart synthesis of some amphetamine analogues. Emphasis is laid on the fragmentation paths, which are common for all compounds under investigation and may be used in construction of the prediction scheme useful for identification of similar impurities, especially in absence of desirable authentic material. On the basis of this scheme several new N,N-di-(β-arylisopropyl)formamides have been identified in selected amphetamine analogues synthesized by the Leuckart method, including 4-methylthioamphetamine (4-MTA), 4-fluoroamphetamine (4-FA), 4-methylamphetamine, 3-trifluoromethylamphetamine, 3,4-methylenedioxyamphetamine (MDA), 2,5-dimethoxyamphetamine (2,5-DMA), 2,4,5- and 3,4,5-trimethoxyamphetamines (2-TMA and 3-TMA).
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http://dx.doi.org/10.1016/j.forsciint.2010.08.007DOI Listing
March 2011

Selective inhibition of butyrylcholinesterase by singlet oxygen-generated melatonin derivatives.

J Pineal Res 2010 Aug 29;49(1):55-9. Epub 2010 Apr 29.

Faculty of Chemistry, University of Warsaw, Warsaw, Poland.

The inhibition of cholinesterases plays a crucial role in a therapy of neurodegenerative diseases, including Alzheimer's disease. Especially, butyrylcholinesterase (BChE) has recently gained special interest. On the other hand, compounds having antioxidative properties may have a beneficial role in slowing down neurodegeneration processes. To combine these two effects, we synthesized a series of new derivatives of melatonin, which is a strong antioxidant, possessing structural elements essential for the inhibitory activity against cholinesterase. The structure of the new compounds was confirmed by NMR spectroscopy and mass spectrometry, and their activity against cholinesterases was measured in vitro using modified Ellman's method. The compounds obtained showed a high inhibitory activity, together with a strong selectivity against BChE. These results may point at new area of interest in a research on cholinesterase inhibitors.
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http://dx.doi.org/10.1111/j.1600-079X.2010.00766.xDOI Listing
August 2010

Trimethyl-3-meth-oxy-4-oxo-5-triphenyl-phospho-ranyl-idene-cyclo-pent-1-ene-1,2,3-tricarboxyl-ate.

Acta Crystallogr Sect E Struct Rep Online 2010 Oct 9;66(Pt 11):o2792. Epub 2010 Oct 9.

The title compound, C(30)H(27)O(8)P (2), was formed as one of two products {(1) [Krawczyk et al. (2010 ▶). Acta Cryst. E66 (cv2752)] and (2)} in the reaction of dimethyl acetyl-enedicarboxyl-ate with triphenyl-phosphine. The mol-ecule of (2) consists of a five-membered carbocyclic ring. The P atom is a part of a triphenylphosphoranylidene substituent. In contrast to (1), the five-membered ring of (2) is planar, the r.m.s. deviation being only 0.009 (2) Å.
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http://dx.doi.org/10.1107/S1600536810037815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3009217PMC
October 2010

Tetra-methyl 1,1,2-triphenyl-2H-1λ-phosphole-2,3,4,5-tetra-carboxyl-ate.

Acta Crystallogr Sect E Struct Rep Online 2010 Oct 9;66(Pt 11):o2791. Epub 2010 Oct 9.

The title compound, C(30)H(27)O(8)P (1), was formed as one of two products {(1) and (2) [Krawczyk et al. (2010 ▶). Acta Cryst. E66 (cv2753)]} in the reaction of dimethyl acetyl-enedicarboxyl-ate with triphenyl-phosphine. The mol-ecule of (1) consists of a five-membered ring, in which the P atom is incorporated. One of the phenyl groups of the triphenyl-phosphine migrated to a vicinal C atom during the reaction. The five-membered ring of (1) is corrugated [r.m.s. deviation = 0.0719 (8) Å], whereas that in compound (2) is planar, the r.m.s. deviation being only 0.009 (2) Å.
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http://dx.doi.org/10.1107/S1600536810037827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3008977PMC
October 2010

The analytical profile of some 4-methylthioamphetamine (4-MTA) homologues.

Forensic Sci Int 2009 Nov 18;192(1-3):98-114. Epub 2009 Sep 18.

Forensic Laboratory, Internal Security Agency, 1 Sierpnia 30A, Warsaw, Poland.

The 4-methylthioamphetamine (4-MTA) is a sulphur-containing amphetamine-type stimulant (ATS), which appeared on the illicit market in Europe at the end of 90s. For the purpose of this study, several N-alkyl homologues of 4-MTA, including 4-methylthiomethamphetamine (4-MTMA), 4-methylthioethylamphetamine (4-MTEA), 4-methylthiodimethamphetamine (4-MTDMA), 4-methylthiopropylamphetamine (4-MTPA) and 4-methylthiobutylamphetamine (4-MTBA) were synthesized. The homologues were characterized by means of gas chromatography/mass spectrometry (GC-MS), infrared (IR) spectroscopy and the magnetic resonance spectroscopy ((1)H and (13)C NMR). The gas chromatography and mass spectrometry properties of their acetyl, trifluoroacyl (TFA), pentafluoropropionyl (PFP) and heptafluorobutyryl (HFB) derivatives were also investigated and discussed.
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http://dx.doi.org/10.1016/j.forsciint.2009.08.009DOI Listing
November 2009

The oxidation products of melatonin derivatives exhibit acetylcholinesterase and butyrylcholinesterase inhibitory activity.

J Pineal Res 2008 Aug 12;45(1):40-9. Epub 2008 Feb 12.

Faculty of Chemistry, Warsaw University, Warsaw, Poland.

It is already well documented that melatonin exhibits strong antioxidant properties. It traps several reactive oxygen species including singlet oxygen, peroxyl and hydroxyl radicals. Also, peroxynitrite-induced reactions are inhibited by melatonin. The oxidation of melatonin by singlet molecular oxygen [O(2) ((1)Delta(g))] may produce cyclic 3-hydroxymelatonin whose structure we have already studied. In this investigation we report on the synthesis of several melatonin analogues having a carbamate substituent instead of the methoxy group at 5 position of the indole ring. These compounds behave analogously to melatonin with respect to singlet oxygen and produce the corresponding cyclic 3-hydroxymelatonin analogues. The structures of the products were investigated with spectral methods and X-ray crystallography. The compounds obtained possess the 2,3,8,8a-tetrahydropyrrolo[2,3-b]indole heterocyclic system which is a structural motif characteristic of alkaloids, physostigmine and phenserine, that are potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors used in the Alzheimer's disease treatment. We measured the inhibitory activity of the obtained compounds against AChE and BChE from human erythrocytes and serum. In the case of the compounds having a phenylcarbamate and methoxyphenylcarbamate substituents, the inhibitory activity (IC(50)) ranged from 0.252 +/- 0.033 to 3.804 +/- 0.581 microM. Other compounds were less active and showed rather complex interactions with the structure-activity relationship in need of further investigation.
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http://dx.doi.org/10.1111/j.1600-079X.2008.00554.xDOI Listing
August 2008
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