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dr hab. inż. Grzegorz Cholewiński
Employment
- Associate professor at Department of Organic Chemistry
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total: 39
Catalog Publications
Year 2024
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Approaches Towards Better Immunosuppressive Agents
PublicationSeveral classes of compounds are applied in clinics due to their immunosuppressive properties in transplantology and the treatment of autoimmune diseases. Derivatives of mycophe-nolic acid, corticosteroids and chemotherapeutics bearing heterocyclic moieties like methotrexate, azathioprine, mizoribine, and ruxolitinib are active substances with investigated mechanisms of action. However, improved synthetic approaches of known drugs...
Year 2022
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Novel amides of mycophenolic acid and some heterocyclic derivatives as immunosuppressive agents
PublicationThe group of new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5'-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis employed uronium-type activating system (TBTU/HOBt/DIPEA) while or phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without...
Year 2021
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Anticancer Properties of Amino Acid and Peptide Derivatives of Mycophenolic Acid
PublicationBackground: Although Mycophenolic Acid (MPA) is applied as prodrugs in clinic as an immunosuppressant, it also possesses anticancer activity. MPA acts as Inosine-5’-Monophosphate Dehydrogenase (IMPDH) inhibitor, where the carboxylic group at the end of the side chain interacts with Ser 276 of the enzyme via hydrogen bonds. Therefore, MPA derivatives with other polar groups indicated high inhibition too. On the other hand, potent...
Year 2020
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Immunosuppressive properties of amino acid and peptide derivatives of mycophenolic acid
PublicationMycophenolic acid (MPA) was coupled with amino acids and biologically active peptides including derivatives of tuftsin to modify its immunosuppressive properties. Both amino acid unit in the case of simple MPA amides and modifications within peptide moiety of MPA - tuftsin conjugates influenced the observed activity. Antiproliferative potential of the obtained conjugates was investigated in vitro and MPA amides with threonine methyl...
Year 2019
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Synthesis and antiproliferative activity of new mycophenolic acid conjugates with adenosine derivatives
PublicationNew conjugates of mycophenolic acid (MPA) and adenosine derivatives were synthesized and assessed as potential immunosuppressants on Jurkat cell line and peripheral blood mononuclear cells (PBMC) from healthy donors. As compared to MPA, all compounds were found to be more active against Jurkat cell line. The antiproliferative activities were compared with MPA and adenosine, in both 2′,3′-O-isopropylidene protected and free hydroxyl...
Year 2018
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Modifications of total synthesis of mycophenolic acid
PublicationThe total synthesis of mycophenolic acid (MPA), a potent immunosuppressant, was modified. The obtained mycophenolic acid was suitable for further preparation of new prospective immunosuppressants with improved therapeutic properties.
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Synthesis and antimicrobial activity of amino acid and peptide derivatives of mycophenolic acid
PublicationThe series of 16 novel amino acid and peptide mycophenolic acid (MPA) derivatives was obtained as potential antibacterial agents. Coupling of MPA with respective amines was optimized with condensing reagents such as EDCI/DMAP and T3P/TEA. Amino acid analogs were received both as methyl esters and also with the free carboxylic group. The biological activity of the products was tested on five references bacterial strains: Klebsiella...
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The synthesis and structure of a potential immunosuppressant: N-mycophenoyl malonic acid dimethyl ester
PublicationThe synthesis of a potential immunosuppressant, i.e. dimethyl ester of N-mycophenoyl malonic acid was optimized in the reaction of mycophenolic acid (MPA) with amino malonic dimethyl ester in the presence of propanephosphonic anhydride (T3P) as a coupling reagent. The structural properties of the obtained MPA derivative were investigated by NMR, MS and single crystal X-ray diffraction methods. Theoretical considerations of conformational...
Year 2017
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Investigations on the immunosuppressive activity of derivatives of mycophenolic acid in immature dendritic cell
PublicationThe main activity of mycophenolic acid (MPA) and its analogs is the inhibition of proliferation of T cells. Here, we hypothesized that MPA and its conjugates inhibits also the activity of antigen-presenting cells (APC) including dendritic cells (DCs). We tested the effect of novel amino acid derivatives of MPA and conjugates of MPA with acridines/acridones on DCs by flow cytometry, ELISA and MLR assay. Both acridines/acridone derivatives...
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New Analogues of Mycophenolic Acid
PublicationMycophenolic acid (MPA) possesses antibacterial, antifungal, antiviral, immunosuppressive and anticancer properties. It is a non-competitive and reversible inhibitor of dehydrogenase inosine-5'-monophosphate (IMPDH). This compound belongs to the immunosuppressive drugs used for the prevention of both acute and chronic transplant rejection. Until now, two derivatives of MPA have been used clinically: mycophenolate mofetil (MMF,...
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Recent developmentsinthesynthesisand biological activityofacridine/acridoneanalogues
PublicationMany people in the world struggle with cancer or bacterial, parasitic, viral, Alzheimer's and other diseases. Therefore, many scientists seek new, more effective, more selective and less toxic drugs. Acridine/acridone derivatives constitute a class of compounds with a broad spectrum of biological activity and are of great interest to scientists. Todate, many acridine/acridone analogues have been obtained,which, inter alia, exhibit...
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Tuftsin-Properties and Analogs
PublicationImmunomodulation is one of the significant therapeutic strategies. It includes both stimulation or suppression of the immune system by a variety of substances called immunomodulators, designed to regulate the immune response of the organism to infections of varying etiology. An example of such a substance is tuftsin (TKPA) 3 (Fig. (1)). Tuftsin is an endogenous immunomodulator of a wide spectrum of biological activity. Tetrapeptide...
Year 2016
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New conjugates of mycophenolic acid and their antiproliferative activity
PublicationThe new conjugates of mycophenolic acid (MPA) were obtained in the reaction of N6-(ω-aminoalkyl)adenosines with MPA in the presence of EDCI as a coupling reagent. New compounds 4a–h were evaluated on leukemia cell line (Jurkat) and PBMC from healthy donors. Length of the linker influenced observed activity. The compound 4b possessing 1,3-diamine spacer exhibited the most promising results and can be considered to further investigations.
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Synthesis and biological activity of ester derivatives of mycophenolic acid and acridines/acridones as potential immunosuppressive agents
PublicationImproved derivatives of mycophenolic acid (MPA) are necessary to reduce the frequency of adverse effects, this drug exerts in treated patients. In this study, MPA was coupled with N-(x-hydroxyalkyl)-9-acridone-4-carboxamides or N-(x-hydroxyalkyl)acridine-4-carboxamides to give respective ester conjugates upon Yamaguchi protocol. This esterification required protection of phenol group in MPA. Designed conjugates revealed higher...
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Synthesis and biological evaluation of novel analogues of batracylin with synthetic amino acids and adenosine: an unexpected effect on centromere segregation in tumor cells through a dual inhibition of topoisomerase IIa and Aurora B
PublicationIn the search for new anticancer agents we designed and synthesized batracylin derivatives with linking synthetic amino acid side chains of different lengths and adenosine. Unexpectedly, we have found that in water and the culture media adenosine–amino acid–BAT conjugates form supramolecular structures and this prevents these compounds from entering cells. Consequently, these compounds exerted no biological activity when tested...
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Synthesis of Combretastatin A-4 Analogs and their Biological Activities
PublicationCombretastatin A-4 (CA-4) is a natural product, which consists of two phenyl rings, linked by an ethylene bridge. CA-4, inhibitor of polymerization of tubulin to microtubules, possesses a strong antitumor and anti-vascular properties both in vitro and in vivo. Previous studies showed that disodium phosphate salt of CA-4, a water-soluble prodrug is well tolerated at therapeutically useful doses. However, it should be noted that...
Year 2015
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Inhibitors of angiogenesis in cancer therapy – synthesis and biological activity
PublicationAngiogenesis is the process of formation of new capillaries from preexisting blood vessels. Angiogenesis is involved in normal physiological processes, and plays an important role in tumor invasion and development of metastases. Vascular endothelial growth factor (VEGF) plays a key role in angiogenesis. VEGF is a mitogen for vascular endothelial cells and stimulates their proliferation. By inhibiting the biological activity of...
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Synthesis of functionalized new conjugates of batracylin with tuftsin/ retro-tuftsin derivatives and their biological evaluation
PublicationNew batracylin conjugates with tuftsin/retro-tuftsin derivatives were designed and synthesized using T3P as a coupling agent. The conjugates possess an amide bond formed between the carboxyl group of heterocyclic molecule and the N-termini of the tuftsin/retro-tuftsin chain. The in vitro cytotoxic activity of the new analogues and their precursors was evaluated using a series of human and murine tumor cells. BAT conjugates containing...
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Synthesis of the inosine 5'-monophosphate dehydrogenase (IMPDH) inhibitors
PublicationIn this review are summrized newly described IMPDH inhibitors. The article concerns both synthetic pathways and biological activities of the most promising compounds.
Year 2014
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Design and synthesis of new analogues of batracylin linked to tuftsin and retro-tuftsin derivatives
PublicationThe synthesis of derivatives of batracylin with several peptides was elaborated followed by their cytotoxic activity investigation.
Year 2013
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Synthesis and biological activity of mycophenolic acid-amino acid derivatives
PublicationIn search of new immunosuppressants, mycophenolic acid (MPA) was coupled with amino acid methyl esters followed by hydrolysis to analogs bearing free carboxylic groups. The obtained compunds were tested in vitro as growth inhibitors of lymphoid cell line (Jurkat) and human peripheral blood mononuclear cells (PBMC) from healthy donors. According to obtained results recovering of free carboxylic group increased their activity. Additionally,...
Year 2012
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Synthesis and biological activity of novel mycophenolic acid conjugates containing nitro-acridine/acridone derivatives
PublicationOpracowano warunki reakcji kwasu mykofenolowego z aminowymi pochodnymi akrydyn i akrydonów. Tak otrzymane koniugaty zostały scharakteryzowane, a następnie przebadane in vitro pod względem aktywności przeciwbiałaczkowej oraz immunosupresyjnej.
Year 2011
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4-[(tert-Butyldimethylsilyl)oxy]-6-methoxy-7-methyl-5-(oxiran-2-ylmethyl)-2-benzofuran-3(1H)-one
PublicationThe title compound, C19H28O5Si, was obtained in the reaction of 1,3-dihydro-4-[(tert-butyldimethylsilyl)oxy]-6-methoxy-7-methyl-3-oxo-5-(prop-2-enyl)isobenzofuran with meta-chloroperbenzoic acid. This reaction is one of the stages of the total synthesis of mycophenolic acid, which we attempted to modify. The title compound forms crystals with only weak intermolecular interactions. The strongest stacking interaction is found between...
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Natural and synthetic acridines/acridones as antitumor agents: their biological activities and methods of synthesis.
PublicationPraca stanowi przegląd opisanych w literaturze chemicznej modyfikacji struktur naturalnych i syntetycznych pochodnych akrydyny i akrydonu. Artykuł obejmuje swym zakresem metody syntezy, a także wpływ budowy cząsteczek tych związków na ich aktywność przeciwnowotworową oraz mechanizm działania.
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Poszukiwanie nowych leków immunosupresyjnych = Quest for new immunosuppressive drugs
PublicationNiniejsza praca przeglądowa dotyczy znanych leków immunosupresyjnych, a także nowych związków o potencjalnym zastosowaniu klinicznym. Wybrane pochodne przedstawiono z uwzględnieniem mechanizmu ich działania oraz metod otrzymywania.
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Reaktywność wybranych siarkowych i selenowych pochodnych kwasu fosforowego
PublicationKilka lat temu byliśmy w stanie zademonstrować, nowa reakcję redukcji wiązania N-O pod wpływem anionu kwasu tio oraz seleno fosforowego, biegnącą mechanizmem SET. W toku dalszych naszych prac ustaliliśmy, że kwas ditiofosforowy jest donorem zarówno protonu jak i atomu wodoru, natomiast anion kwasu ditiofosforowego jest doskonałym nukleofugiem oraz donorem pojedynczego elektronu. W kolejnym etapie badań stwierdziliśmy, że zarówno...
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Synteza aminokwasowych pochodnych MPA
PublicationKwas mykofenolowy (MPA) jest związkiem o działaniu immunosupresyjnym i ma zastosowaniu w zapobieganiu odrzucania przeszczepów narządów. Zaprezentowano nowe pochodne MPA, które posiadają przyłączony do grupy karboksylowej fragment aminokwasowy. Celem tych badań jest określenie wpływu konfiguracji na chiralnym atomie węgla oraz podstawnika w reszcie aminokwasowej na aktywność immunosupresyjną.
Year 2010
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5,5-Dimethyl-2-methylseleno-1,3,2-dioxaphosphorinan-2-one
PublicationTytułowy związek otrzymano w reakcji soli potasowej kwasu O,O-neopentylidenomonoselenofosforowego z jodkiem metylu. Analiza krystalograficzna tego estru wykazała, że grupa selenometylowa zajmuje pozycję aksjalną względem sześcioczłonowego pierścienia dioksafosforinanu.
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The Chemistry of Mycophenolic Acid-Synthesis and Modifictions Towards Desired Biological Activity
PublicationDokonano przeglądu literatury chemicznej na temat metod syntezy kwasu mykofenolowego oraz jego pochodnych, a także zależności pomiędzy ich strukturą i aktywnością biologiczną.
Year 2009
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Core-Shell Nanoparticles with Hyperbranched Poly(arylene-oxindole) Interiors
PublicationCore-shell type star polymers composed of poly(tert-butyl acrylate) (poly(t-BuA)) arms and 100% hyperbranched poly(arylene-oxindole) interiors were synthesized via the "core-first" method. Atom transfer radical polymerization of t-BuA initiated by 2-bromopropionyl terminal groups of the hyperbranched core was applied for the synthesis of the stars. The resultant star structures were characterized by gel permeation chromatography...
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Kwas mykofenolowy i jego analogi. Synteza i aktywność biologiczna = Mycophenolic acid (MPA) and its analogues. Synthesis and biological activity
PublicationW artykule opisano kwas mykofenolowy (MPA)oraz jego analogi. Kwas MPA został odkryty ponad 100 lat temu i nadal pozostaje atrakcyjnym celem badań biologicznych. Z uwagi na bardzo dużą tendencję do ulegania glukuronidyzacji in vivo, ograniczone są jego możliwości zastosowań jako potencjalnego chemoterapeutyka. Otrzymane dotychczas analogi m.in. zawierające różne cykliczne ugrupowania, monocykliczne fenole i niefenolowe analogi oraz...
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O-4-Chlorobenzoyl diphenylselenophosphinate
PublicationTytułowy związek difenyloselenofosfinian O-4-chlorobenzoilu krystalizuje w układzie jednoskośnym, w grupie P21/c. Upakowanie molekuł w krysztale wskazuje na oddziaływania van der Waalsa pomiędzy pierścieniami aromatycznymi reszt acylowych. Z kolei kąt dwuścienny pomiędzy pierścieniami fenylowymi reszty fosforowej wynosi 72.64 (14) stopni. Geometrię cząsteczki badanego związku porównano z opisanymi w litaraturze chemicznej estrami...
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O-Pivaloyl diphenylselenophosphinate
PublicationTytułowy związek difenyloselenofosfinian O-piwaloilu krystalizuje w układzie jednoskośnym, w grupie P21/c. Jeden z pierścieni fenylowych jest w pozycji periplanarnej do płaszczyzny wiązań Se-P-C, podczas gdy kąt dwuścienny pomiędzy dwoma pierścieniami aromatycznymi wynosi ok. 73 stopni. Geometrię cząsteczki badanego związku porównano z opisanymi w literaturze chemicznej estrami O-alkilowymi i O-arylowymi kwasu difenyloselenofosfinowego.
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Synthesis and structural investigation of N-acyl selenophosphoramides
PublicationN-acylowane amidy kwasu O,O-neopentylidenomonoselenofosforowego, w zależności od podstawnika na atomie azotu, krystalizują jako konformery zawierające selen w pozycji ekwatorialnej bądź aksjalnej. Wyniki tych eksperymentów wyjaśniono działaniem efektu anomerycznego.
Year 2007
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Reaction of thio and seleno phosphoric acid derivatives with O-thioacylated hydroxylamine
PublicationZbadano reakcję siarkowych i selenowych analogów kwasu O,O-neopentylidenofosforowego z O-tiopiwaloilo-N-tert-butylohydroksyloaminą, w której to następuje rozszczepienie wiązania N-O. Znaleziono korelację pomiędzy potencjałem utleniającym anionu pochodnej kwasu fosforowego a przebiegiem badanej reakcji.
Year 2006
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Otrzymywanie i reaktywność selenofosforanów acylu
Publication.
Year 2005
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Synthesis and reactivity of O-acyl selenophosphates
PublicationThe synthesis of several new O-acyl selenophosphates were investigated. The stability and reactivity of the products were studied and related to their structure.
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Synthesis and reactivity of O-acyl selenophosphates.
PublicationMieszane bezwodniki kwasów monoselenofosforowych >P(Se)O-C(O)- w zależności od podstawników na atomie fosforu oraz karbonylowym atomie węgla izomeryzują do układów Se-mostkowych >P(O)Se-(O)C- oraz ulegają dekarboksylacji (dekarbonylacji i dekarboksylacji) do estrów Se-alkilowych >P(O)Se-. W eksperymantach krzyżowych następuje wzajemna wymiana grup acylowych pomiędzy cząsteczkami bezwodników.
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Synthesis and reactivity of O-acyl selenophosphates
PublicationPrzeprowadzono syntezę nowych selenofosforanów acylu. Badano stabilność i reaktywność tych bezwodników w odniesieniu do ich struktury.
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