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Design of new cholinesterase inhibitors based on phosphorus analogs of tacrine as potential anti-Alzheimer’s disease agents
PublikacjaBased on the analysis of the determined free binding energy (using the AutoDock Vina 1.1.2 docking program), the most potent cholinesterase inhibitors were selected. Moreover, studies of 3D visualization of the results of molecular modeling led to the identification of potential sites for the interaction of new potential inhibitors with amino acid residues building active sites of investigated cholinesterases.
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Chloroacridine derivatives as potential anticancer agents which may act as tricarboxylic acid cycle enzyme inhibitors
PublikacjaThe chloroacridines affect biological forms of melanoma in different ways. Amelanotic (Ab) melanoma (with inhibited melanogenesis and higher malignancy) was particularly sensitive to the action of the chloroacridines. The Ab melanoma cells died through apoptosis and through death without caspase activation. Diminished activity of TAC enzymes was noticed among Ab melanoma cells together with ATP/NAD depletion, especially in the...
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DNA methylation in cancer development, diagnosis and therapy-multiple opportunities for genotoxic agents to act as methylome disruptors or remediators
PublikacjaThe role of DNA methylation and recently discovered hydroxymethylation in the function of the human epigenome is currently one of the hottest topics in the life sciences. Progress in this field of research has been further accelerated by the discovery that alterations in the methylome are not only associated with key functions of cells and organisms, such as development, differentiation and gene expression, but may underlie a number...
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Electrochemical simulation of metabolic reduction and conjugation reactions of unsymmetrical bisacridine antitumor agents, C-2028 and C-2053
PublikacjaElectrochemistry (EC) coupled with analysis techniques such as liquid chromatography (LC) and mass spectrometry (MS) has been developed as a powerful tool for drug metabolism simulation. The application of EC in metabolic studies is particularly favourable due to the low matrix contribution compared to in vitro or in vivo biological models. In this paper, the EC(/LC)/MS system was applied to simulate phase I metabolism of the representative...
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Synthesis of new antrapyridazone derivatives - a novel group of anticancer agents active on a multidrugresistant(MDR) tumor cell lines
PublikacjaNovel antrapyridazone derivatives were synthesized and biologically evaluated in order tobroaden the data on structure-activity relationship of this class of cytostatics. Recent literaturedata prove that acetamides react better with aryl chlorides. A new approach based onintroduction of other amides form into aromatic ring in Ullmann was tested. This new methodcould give better yields and make purification step more convenient.
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Silicon polypodands: powerful metal cation complexing agents and solid–liquid phase-transfer catalysts of new generation
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N-Substituted piperazine derivatives as potential multitarget agents acting on histamine H3 receptor and cancer resistance proteins
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Pd-catalysed general access to 7-membered N/O-heterocyclic compounds as potential agents against inflammation
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Absence of 6-Hydroxydopamine in the Rat Brain After Treatment with Stimulants and Other Dopaminergic Agents: A Mass Fragmentographic Study
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The hydration of the protein stabilizing agents: trimethylamine-N-oxide, glycine and its N-methylderivatives - the volumetric and compressibility studies
PublikacjaThe densities at T = (288.15, 293.15, 298.15, 303.15, and 308.15) K and sound velocities at T = 298.15 K have been measured for aqueous solutions of trimethylamine-N-oxide, glycine, N-methylglycine (sarcosine), N,N-dimethylglycine, N,N,N-trimethylglycine (betaine). From these data the apparent molar volumes, VΦ, the apparent molar isentropic compressions, KS,Φ, and the solvation numbers of solutes have been determined. The concentration...
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Novel molecules containing structural features of NSAIDs and 1,2,3-triazole ring: Design, synthesis and evaluation as potential cytotoxic agents
PublikacjaFor the first time the template containing structural features of more than one NSAIDs and the 1,2,3-triazole ring was explored for the identification of potential cytotoxic agents. These new and complex molecules were predicted to be effective inhibitors of PDE4B by molecular modelling studies in silico. The multi-step synthesis of these compounds were carried out starting from the well-known drug nimesulide and involved the use...
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Anthra[1,2-d][1,2,3]triazine-4,7,12(3H)-triones as a New Class of Antistaphylococcal Agents: Synthesis and Biological Evaluation
PublikacjaThe development and spread of resistance of human pathogenic bacteria to the action of commonly used antibacterial drugs is one of the key problems in modern medicine. One of the especially dangerous and easily developing antibiotic resistant bacterial species is Staphylococcus aureus. Anthra[1,2-d][1,2,3]triazine-4,7,12(3H)-triones 22–38 have been developed as novel effective antistaphylococcal agents. These compounds have been...
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Rosuvastatin based novel 3-substituted isocoumarins / 3-alkylidenephthalides: Ultrasound assisted synthesis and identification of new anticancer agents
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Discovery of phenylselenoether-hydantoin hybrids as ABCB1 efflux pump modulating agents with cytotoxic and antiproliferative actions in resistant T-lymphoma
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Novel molecules containing structural features of NSAIDs and 1,2,3-triazole ring: Design, synthesis and evaluation as potential cytotoxic agents
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Structure modification of acridine antitumor agents results in changes of enzymatic activity and gene expression of CYP3A4 isoenzyme in HepG2 cells.
PublikacjaEkspresja izoenzymu CYP3A4, który zaangażowany jest w metabolizm ok. 60% leków stosowanych klinicznie, może być modulowana przez takie czynniki jak: polimorfizm, czynniki transkrypcyjne oraz obecność ksenobiotyków. Przykładem induktorów genów kodujących izoenzym CYP3A4 jest fenobarbital i rifampicyna, których obecność w organizmie przyspiesza metabolizm innych leków stosowanych jednocześnie, które są substratami dla CYP3A4. Dlatego...
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Flexible Films as Anode Materials Based on rGO and TiO2/MnO2 in Li-Ion Batteries Free of Non-Active Agents
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The influence of combination of binding agents on fatigue properties of deep cold in-place recycled mixtures in Indirect Tensile Fatigue Test (ITFT)
PublikacjaThe publication presents fatigue properties of cold recycled mixtures for eight combinations of binding agents (cement and bituminous emulsion). Cold recycled mixtures were evaluated in Indirect Tensile Fatigue Test (ITFT) at the temperature of 20 C in controlled stress mode. As a function of horizontal stress, fatigue life is strongly influenced by combination of the binding agents. When fatigue life is analyzed as a function...
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The role of intestine and liver in glucuronidation of the imidazo- and triazoloacridinone antitumor agents, C-1311 and C-1305: High affinity substrates for UGT1A10
PublikacjaCelem przeprowadzonych badań było określenie roli poszczególnych izoform UDP-glukuronylotransferazy (UGT)oraz mikrosomów jelita(HIM)i wątroby (HLM) wyizolowanych od różnych pacjentów w metabolizmie pochodnych akrydonu, związków C-1311 i C-1305. Wykazano, że rodziną UGT katalizującą przemiany C-1305 i C-1311 jest UGT1A, z najwyższą aktywnością wykazywaną przez pozawątrobowy izoenzym UGT1A10. Rozkład aktywności frakcji mikrosomalnych...
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Effects of Alkaline Cleaning Agents on the Long-Term Performance and Aging of Polyethersulfone Ultrafiltration Membranes Applied for Treatment of Car Wash Wastewater
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Discovery of Novel 3-Hydroxyandrosta-5,7-Diene-17-Carboxylic Acid Derivatives as Anti-Inflammatory Bowel Diseases (IBD) Agents
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Cell Density-Dependent Cytological Stage Profile and Its Application for a Screen of Cytostatic Agents Active Toward Leukemic Stem Cells
PublikacjaProliferation and expansion of leukemia is driven by leukemic stem cells (LSCs). Multidrug resistance (MDR) of LSCs is one of the main reasons of failure and relapses in acute myeloid leukemia (AML) treatment. In this study, we show that maintaining HL-60 at low cell culture density or applying a 240-day treatment with anthrapyridazone (BS-121) increased the percentage of primitive cells, which include LSCs determining the overall...
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Amphotericin B derivatives: novel strategy for the development of non-toxic, broad spectrum, fungicidal and overcoming multidrug resistance antifungal agents.
PublikacjaZaprezentowano porównawczą charakterystykę działania amfoterycyny B (AmB) oraz jej pochodnych o różnym stopniu selektywnej toksyczności na szczepy grzybów reperezentujących różne mechanizmy oporności. Były to mutanty C. albicans posiadające defekt w szlaku biosyntezy ergosterolu oraz wielolekooporne szczepy S. cerevisiae wyposażone w pompy eksportujące typu ABC i MFS. Badania obejmowały: 1)porównanie aktywności przeciwgrzybowej...
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NADPH-Cytochrome P-450 reductase in strongly involved in activating metabolic transformatios of 9-amino-1-nitroacridine antitumor agents
PublikacjaCelem pracy było wyjaśnienie roli reduktazy cytochromu P-450 jaką odgrywa ten enzym w przemianach metabolicznych dwóch związków przeciwnowotworowych z grupy pochodnych 1-nitroakrydyny. Zastosowano metodę HPLC do rozdziału metabolitów, a badania struktur przeprowadzono stosując metodę ESI-MS. Wykazano, że badana reduktaza jest zaangażowana bardziej w metabolizm aktywacyjny 1-nitroakrydyn niż metabolizm detoksykacyjny.
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A new pH/organic modifier gradient RP HPLC method for convenient determination of lipophilicity and acidity of drugs as applied to established imidazoline agents
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Synthesis of 7-oxo-7h-naphto[1,2,3-de]quinoline derivatives as potential anticancer agents active on multidrug resistant cell lines
PublikacjaOpierając się na naszym wcześniejszym stwierdzeniu, że tetracykliczne analogi antrachinonów z wbudowanym pierścieniem pirydynowym wykazują aktywną cytotoksyczność względem komórek z indukowaną opornością, przeprowadzono syntezę pochodnych 7-oxo-7h-nafto[1,2,3-de]chinoliny (3, 6-8, 10-12, 14,15 i 18) posiadających jeden lub dwa zasadowe łańcuchy boczne i różne podstawniki w pierścieniu pirydynowym, związków o potencjalnym działaniu...
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Acridinone antitumor agents, C-1305 and C-1299 are metabolized rather by flavin-containing monooxygenases and UDP-glucuronosyltransferases than cytochromes P450
PublikacjaStwierdzono, że to monooksygenazy flawinowe, a nie enzymy cytochromu P450, są głównymi enzymami frakcji mikrosomalnej, odpowiedzialnymi za detoksyfikacyjny metabolizm dwóch badanych pochodnych triazoloakrydonu. Dodatkowo C-1305 ulega sprzęganiu w czasie drugiej fazy metabolizmu z kwasem glukuronowym do postaci O-glukuronidu
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Carbon Dioxide Adsorption over Activated Carbons Produced from Molasses Using H2SO4, H3PO4, HCl, NaOH, and KOH as Activating Agents
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Carbon Dioxide Adsorption Over Activated Carbons Produced from Molasses Using H2so4, H3po4, Hcl, Naoh, and Koh as Activating Agents
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Prophylaxis of Non-communicable Diseases: Why Fruits and Vegetables may be Better Chemopreventive Agents than Dietary Supplements Based on Isolated Phytochemicals?
PublikacjaThe World Health Organization (WHO) report from 2014 documented that non-communicable socalled civilization diseases such as cardiovascular disease, chronic respiratory diseases, cancer or type 2 diabetes are responsible for over 50% of all premature deaths in the world. Research carried out over the past 20 years has provided data suggesting that diet is an essential factor influencing the risk of development of these diseases....
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Role of Human UDP-Glucuronosyltransferases in the Biotransformation of the Triazoloacridinone and Imidazoacridinone Antitumor Agents C-1305 and C-1311 : Highly Selective Substrates for UGT1A10
Publikacja5-Diethylaminoethylamino-8-hydroxyimidazoacridinone, C-1311 (NSC-645809), is an antitumor agent shown to be effective against breast cancer in phase II clinical trials. A similar compound, 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone, C-1305, shows high activity against experimental tumors and is expected to have even more beneficial pharmacological properties than C-1311. Previously published studies showed that these...
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CYP3A4-dependent cellular response does not relate to CYP3A4-catalysed metabolites of C-1748 and C-1305 acridine antitumor agents in HepG2 cells
PublikacjaHigh CYP3A4 expression sensitizes tumor cells to certain antitumor agents while for others it can lower their therapeutic ef fi cacy. We have elucidated the in fl uence of CYP3A4 overexpression on the cellular response induced by antitumor acridine derivatives, C-1305 and C-1748, in two hepatocellular carcinoma (HepG2) cell lines, Hep3A4 stably transfected with CYP3A4 isoenzyme, and HepC34 expressing empty vector. The compounds...
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Elucidation of chemical compounds in different extracts of two Lavandula taxa and their biological potentials: Walking with versatile agents on the road from nature to functional applications
PublikacjaDue to their health-promoting and nutraceutical properties, lavenders are frequently employed in the food and pharmaceutical industries. Here, we focused on investigate the chemical profile of hexane, MeOH, and water extracts of leaf, flower, and root of L. pedunculata and L. stoechas and to assess their antioxidant, enzyme inhibitory, and antibacterial properties. The highest total polyphenolic and flavonoids contents were recorded...
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Cancer stem cells in drug resistance and drug screening: can we exploit the cancer stem cell paradigm in search for new antitumor agents?
PublikacjaPraca przedstawia przegląd literatury dotyczącej hipotezy komórek pierwotnych nowotworu, w szczególności w ich oporności na istniejące terapie. Dyskutowane jest także zagadnienie możliwości wykorzystania wiedzy o tych komórkach do konstrukcji nowych testów do badań przesiewowych in vitro w celu poszukiwania nowych leków przeciwnowotworowych.
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Nanoemulsion Structural Design in Co-Encapsulation of Hybrid Multifunctional Agents: Influence of the Smart PLGA Polymers on the Nanosystem-Enhanced Delivery and Electro-Photodynamic Treatment
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Peptide dendrimers as antifungal agents and carriers for potential antifungal agent—N3‐(4‐methoxyfumaroyl)‐(S)‐2,3‐ diaminopropanoic acid—synthesis and antimicrobial activity
PublikacjaA series of peptide dendrimers and their conjugates with antimicrobial agent FMDP (N3‐(4‐methoxyfumaroyl)‐(S)‐2,3‐diamino‐propanoic acid) were synthesized. The obtained compounds were tested for the antibacterial and antifungal activity. All novel dendrimers displayed much better activity against the tested strains than FMDP itself. Moreover, their conjugates with FMDP also exhibited antimicrobial activity. The most promising molecules...
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Essential Oils, Silver Nanoparticles and Propolis as Alternative Agents Against Fluconazole Resistant Candida albicans, Candida glabrata and Candida krusei Clinical Isolates
PublikacjaDevelopment of effective and safe therapeutic treatment of fungal infections remains one of the major challenge for modern medicine. The aim of presented investigation was to analyze the in vitro antifungal activity of selected essential oils, ethanolic extracts of propolis and silver nanoparticles dropped on TiO2 against azole-resistant C. albicans (n = 20), C. glabrata (n = 14) and C. krusei (n = 10) clinical isolates. Among...
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Acridinone antitumor agents: C-1311, C-1330 and C-1305 are metabolized by flavin-containing monooxygenase isoenzymes: FMO1, FMO3 and FMO5 with different rates
PublikacjaRekombinantowe ludzkie monooksygenazy flawinowe: FMO1, FMO3, FMO5 indukują przemiany metaboliczne wybranych do badań pochodnych akrydonu. Biotransformacja związków C-1311, C-1330 i C-1305 przez FMO prowadzi do jednego produktu o strukturze N-tlenku. Wyniki badań wskazują, że najbardziej podatna na przemiany wobec FMO jest pochodna triazoloakrydonu C-1305. Wydaje się więc, że głównymi enzymami pierwszej fazy przemian metabolicznych...
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Reactive metabolites of acridinone antitumor agents, C-1311 and C-1305, are trapped within the active site of CYP1A2 and CYP3A4, causing irreversible enzymes inactivation
PublikacjaZwiązki C-1305 i C-1311, zsyntetyzowane w Katedrze Technologii Leków i Biochemii, wykazują najsilniejsze właściwości przeciwnowotworowe wśród pochodnych, odpowiednio, triazolo- i imidazoakrydonu. Obecnie prowadzone są badania mające na celu określenie biochemicznego mechanizmu działania, jak również potencjalnych szlaków biotransformacji C-1305 i C-1311.W bieżącym etapie podjęto próbę określenia mechanizmu obserwowanej inhibicji...
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Modulation of UDP-glucuronidation by acridinone antitumor agents C-1305 and C-1311 in HepG2 and HT29 cell lines, despite slight impact in noncellular systems.
PublikacjaBackground Among the studied antitumor acridinone derivatives developed in our laboratory, 5-dimethylaminopropylamino-8-hydroxytriazoloacridinone (C-1305) and 5-diethylaminoethylamino-8-hydroxyimidazoacridinone (C-1311) exhibited cytotoxic and antitumor properties against several cancer types and were selected to be evaluated in preclinical and early-phase clinical trials. In the present work, we investigated the impact of C-1305...
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Down-regulation of DNA topoisomerase IIalpha leads to prolonged cell cycle transit in G2 and early M phases and increased survival to microtubule-interacting agents
PublikacjaInhibitory polimeryzacji mikrotubul wykazują preferencyjną toksyczność wobec komórek mitotycznych. W ramach tego projektu badaliśmy czy oporność komórek ludzkich białaczek na inhibitor mikrotubul, winkrystynę, prowadzi do zmian w regulacji progresji cyklu komórkowego. Nasze wyniki wskazują, że oporności na winkrystynę towarzyszą zmiany w długości fazy G2 i M w nieobecności i obecności inhibitora wrzeciona mitotycznego, nokodazolu....
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Contribution of UDP-glucuronosyltransferases (UGTs) in metabolism of acridinone antitumor agents, C-1311, C-1305, and their less active structural analogues, C-1330 and C-1299
PublikacjaCelem prowadzonych badań było określenie roli UDP-glukuronylotransferaz, uważanych za najważniejsze enzymy detoksykujące, w metabolizmie pochodnych imidazo- i triazoloakrydonu. Wykazano, że najbardziej aktywne przeciwnowotworowo związki z obu grup, tj. C-1311 i C-1305 są transformowane do O-glukuronidów, w przeciwieństwie do ich metoksylowych analogów, odpowiednio związku C-1330 i C-1299. Analiza składu mieszanin reakcyjnych zawierających...
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Novel 2-(2-alkylthiobenzenesulfonyl)-3-(phenylprop-2-ynylideneamino)guanidine derivatives as potent anticancer agents – Synthesis, molecular structure, QSAR studies and metabolic stability
PublikacjaA series of new 2-(2-alkylthiobenzenesulfonyl)-3-(phenylprop-2-ynylideneamino)guanidine derivatives have been synthesized and evaluated in vitro by MTT assays for their antiproliferative activity against cell lines of colon cancer HCT-116, cervical cancer HeLa and breast cancer MCF-7. The obtained results indicated that these compounds display prominent cytotoxic effect. The best anticancer properties have been observed for derivatives...
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Pregnane X receptor dependent up-regulation of CYP2C9 and CYP3A4 in tumor cells by antitumor acridine agents, C-1748 and C-1305, selectively diminished under hypoxia
PublikacjaInduction of proteins involved in drug metabolism and in drug delivery has a significant impact on drug-drug interactions and on the final therapeutic effects. Two antitumor acridine derivatives selected for present studies, C-1748 (9-(2’-hydroxyethylamino)-4-methyl-1-nitroacridine) and C-1305 (5-dimethylaminopropylamino-8-hydroxy-triazoloacridinone), expressed high and low susceptibility to metabolic transformations with liver...
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2,7-Dihydro-3H-pyridazino[5,4,3-kl]acridin-3-one derivatives, novel type of cytotoxic agents active on multidrug-resistant cell lines. Synthesis and biological evaluation.
PublikacjaOtrzymano serię pirydazyno akrydyn-3-onów w reakcji 9-okso-9,10-dihydroakrydyno-1-karboksylanu etylu z POCl3, następnie dodanie odpowiedniej alkiloaminoalkilohydrazyny. Badane związki wykazują w porównaniu z referencyjnymi cytostatykami DX, MIT niższe wartości indeksu RI, a także niższe aktywności cytotoksyczne.
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Human CYP2 family of cytochrome P-450 takes part in metabolism of two acridine antitumor agents, C-1311 and C-1748, selected for I phase of clinical trials
PublikacjaPraca zawiera wyniki badań metabolicznej transformacji przeciwnowotworowych pochodnych akrydyny wobec zestawu 16 prób enzymów mikrosomalnych, pochodzących z wątroby 16 różnych pacjentów. Wykazano, że za metabolizm tych związków u człowieka odpowiedzialne są głównie izoenzymy z rodziny CYP2.
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Antibiotic resistance in Staphylococcus aureus strains isolated from cows with mastitis in the eastern Poland and analysis of susceptibility of resistant strains to alternative non-antibiotic agents: lysostaphin, nisin and polymyxin B.
PublikacjaThe aim of the studies was analysis of resistance of Staphylococcus aureus isolates from bovine mastitis in eastern part of Poland to a set of 20 antibiotics and three alternative agents: lysostaphin, nisin and polymyxin B. Eighty-six out of 123 examined isolates were susceptible to all of 20 tested antibiotics (70 %). The highest percentage of resistance was observed in the case of β-lactam antibiotics: amoxicillin (n=22, 17.9...
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Synthesis and biological evaluation of 2,7-Dihydro-3H-dibenzo[de,h]cinnoli- ne-3,7-done derivatives a novel group of anticancer agents active on a multidrug resistance cell line.
PublikacjaZsyntezowano serię pochodnych pirydazonu z jednym lub dwoma łańcuchami bocznymi w różnych pozycjach chromoforu tetracyklicznego. Związki wykazały aktywność cytoksyczną na mysią białaczkę L1210 i ludzką k562 oraz na linii komórkowej oporności krzyżowej MDR (k562/DX). Dwa najbardziej aktywne związki przetestowano in vivo na mysiej białaczce P388. Wykazały one aktywność przeciwnowotworową porównywalną z aktywnością Mitoxantronu.
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Phytotoxic Metabolites from Three Neofusicoccum Species Causal Agents of Botryosphaeria Dieback in Australia, Luteopyroxin, Neoanthraquinone, and Luteoxepinone, a Disubstituted Furo-α-pyrone, a Hexasubstituted Anthraquinone, and a Trisubstituted Oxepi-2-one from Neofusicoccum luteum
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Synthesis, molecular structure, and metabolic stability of new series of N' -(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-1-(5-phenyl-1 H -pyrazol-1-yl)amidine as potential anti-cancer agents
PublikacjaA series of new N'-(2-alkylthio-4-chloro-5-methylbenzenesulfonyl)-1-(5-phenyl-1H-pyrazol-1-yl)amidine derivatives have been synthesized and evaluated in vitro by MTT assays for their antiproliferative activity against cell lines of colon cancer HCT-116, cervical cancer HeLa and breast cancer MCF-7. The studied compounds display selective activity mainly against HCT-116 and HeLa cells. Thus, five compounds show selective cytotoxic...