Publications by authors named "Leentje Persoons"

22 Publications

  • Page 1 of 1

Broad spectrum anti-coronavirus activity of a series of anti-malaria quinoline analogues.

Antiviral Res 2021 Jul 1;193:105127. Epub 2021 Jul 1.

KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, Leuven, Belgium.

In this study, a series of 10 quinoline analogues was evaluated for their in vitro antiviral activity against a panel of alpha- and beta-coronaviruses, including the severe acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2), as well as the human coronaviruses (HCoV) 229E and OC43. Chloroquine and hydroxychloroquine were the most potent with antiviral EC values in the range of 0.12-12 μM. Chloroquine displayed the most favorable selectivity index (i.e. ratio cytotoxic versus antiviral concentration), being 165 for HCoV-OC43 in HEL cells. Potent anti-coronavirus activity was also observed with amodiaquine, ferroquine and mefloquine, although this was associated with substantial cytotoxicity for mefloquine. Primaquine, quinidine, quinine and tafenoquine only blocked coronavirus replication at higher concentrations, while piperaquine completely lacked antiviral and cytotoxic effects. A time-of-addition experiment in HCoV-229E-infected HEL cells revealed that chloroquine interferes with viral entry at a post-attachment stage. Using confocal microscopy, no viral RNA synthesis could be detected upon treatment of SARS-CoV-2-infected cells with chloroquine. The inhibition of SARS-CoV-2 replication by chloroquine and hydroxychloroquine coincided with an inhibitory effect on the autophagy pathway as visualized by a dose-dependent increase in LC3-positive puncta. The latter effect was less pronounced or even absent with the other quinolines. In summary, we showed that several quinoline analogues, including chloroquine, hydroxychloroquine, amodiaquine, ferroquine and mefloquine, exhibit broad anti-coronavirus activity in vitro.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.antiviral.2021.105127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8247284PMC
July 2021

Discovery of ( ±)-3-(1H-pyrazol-1-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazine derivatives with promising in vitro anticoronavirus and antitumoral activity.

Mol Divers 2021 Jun 24. Epub 2021 Jun 24.

Department of Chemistry, National Institute of Technology, Warangal, Telangana, 506004, India.

A new series of ( ±)-(3-(3,5-dimethyl-1H-pyrazol-1-yl)-6-phenyl-6,7-dihydro-5H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-7-yl)(phenyl)methanones were efficiently synthesized starting from 4-amino-5-hydrazinyl-4H-1,2,4-triazole-3-thiol 1, acetyl acetone 2, various aromatic and heterocyclic aldehydes 3 and phenacyl bromides 4. All the newly synthesized compounds were tested for their antiviral and antitumoral activity. It was shown that subtle structural variations on the phenyl moiety allowed to tune biological properties toward antiviral or antitumoral activity. Mode-of-action studies revealed that the antitumoral activity was due to inhibition of tubulin polymerization.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11030-021-10258-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8223195PMC
June 2021

Genome-wide CRISPR screening identifies TMEM106B as a proviral host factor for SARS-CoV-2.

Nat Genet 2021 04 8;53(4):435-444. Epub 2021 Mar 8.

KU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, Leuven, Belgium.

The ongoing COVID-19 pandemic has caused a global economic and health crisis. To identify host factors essential for coronavirus infection, we performed genome-wide functional genetic screens with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human coronavirus 229E. These screens uncovered virus-specific as well as shared host factors, including TMEM41B and PI3K type 3. We discovered that SARS-CoV-2 requires the lysosomal protein TMEM106B to infect human cell lines and primary lung cells. TMEM106B overexpression enhanced SARS-CoV-2 infection as well as pseudovirus infection, suggesting a role in viral entry. Furthermore, single-cell RNA-sequencing of airway cells from patients with COVID-19 demonstrated that TMEM106B expression correlates with SARS-CoV-2 infection. The present study uncovered a collection of coronavirus host factors that may be exploited to develop drugs against SARS-CoV-2 infection or future zoonotic coronavirus outbreaks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00805-2DOI Listing
April 2021

Synthesis, in silico ADME, molecular docking and in vitro cytotoxicity evaluation of stilbene linked 1,2,3-triazoles.

Heliyon 2021 Jan 30;7(1):e05893. Epub 2021 Jan 30.

Department of Pharmaceutical Chemistry, KLE College of Pharmacy, Bengaluru, 560010, Karnataka, India.

Series of ()1-benzyl-4-((4-styrylphenoxy)methyl)-1-1,2,3-triazoles were obtained by Wittig reaction between 4-((1-benzyl-1-1,2,3-triazol-4-yl)methoxy)benzaldehydes and benzyl triphenylphosphonium halides in benzene. The structures of the synthesized compounds were confirmed by FTIR, NMR (H and C NMR) spectroscopy, and mass spectrometry. All synthesized compounds were screened for their cytotoxic activity against human cancer cell lines including pancreatic carcinoma, colorectal carcinoma, lung carcinoma, and leukemias such as acute lymphoblastic, chronic myeloid, and non-Hodgkinson lymphoma cell lines. cytotoxicity data showed that compounds , , , , , , and were moderately cytotoxic (11.6-19.3 μM) against the selected cancer cell lines. These cytotoxicity findings were supported using molecular docking studies of the compounds against 1TUB receptor. The drug-likeness properties of the compounds evaluated by ADME analyses. Resveratrol linked 1,2,3-triazoles were more sensitive towards human carcinoma cell lines but least sensitive towards leukemia and lymphoma cell lines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.heliyon.2020.e05893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851791PMC
January 2021

Characterization of the Carbohydrate-Binding Agents HHA, GNA, and UDA as Inhibitors of Influenza A and B Virus Replication.

Antimicrob Agents Chemother 2021 02 17;65(3). Epub 2021 Feb 17.

KU Leuven, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Leuven, Belgium.

Here, we report on the anti-influenza virus activity of the mannose-binding agents hybrid agglutinin (HHA) and agglutinin (GNA) and the (-acetylglucosamine) -specific agglutinin (UDA). These carbohydrate-binding agents (CBA) strongly inhibited various influenza A(H1N1), A(H3N2), and B viruses , with 50% effective concentration values ranging from 0.016 to 83 nM, generating selectivity indexes up to 125,000. Somewhat less activity was observed against A/Puerto Rico/8/34 and an A(H1N1)pdm09 strain. In time-of-addition experiments, these CBA lost their inhibitory activity when added 30 min postinfection (p.i.). Interference with virus entry processes was also evident from strong inhibition of virus-induced hemolysis at low pH. However, a direct effect on acid-induced refolding of the viral hemagglutinin (HA) was excluded by the tryptic digestion assay. Instead, HHA treatment of HA-expressing cells led to a significant reduction of plasma membrane mobility. Crosslinking of membrane glycoproteins, through interaction with HA, could also explain the inhibitory effect on the release of newly formed virions when HHA was added at 6 h p.i. These CBA presumably interact with one or more -glycans on the globular head of HA, since their absence led to reduced activity against mutant influenza B viruses and HHA-resistant A(H1N1) viruses. The latter condition emerged only after 33 cell culture passages in the continuous presence of HHA, and the A(H3N2) virus retained full sensitivity even after 50 passages. Thus, these CBA qualify as potent inhibitors of influenza A and B viruses with a pleiotropic mechanism of action and a high barrier for viral resistance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/AAC.01732-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8092504PMC
February 2021

Itaconic acid hybrids as potential anticancer agents.

Mol Divers 2020 Oct 11. Epub 2020 Oct 11.

Department of Medicinal Chemistry, Faculty of Pharmacy and Biochemistry, University of Zagreb, 10 000, Zagreb, Croatia.

In this paper, we report the synthesis of novel hybrids 2-14 based on itaconic acid and fluoroaniline, pyridine, indole and quinoline scaffolds. Itaconic acid is a naturally occurring compound with a Michael acceptor moiety, a key structural feature in several anticancer and antiviral drugs, responsible for the covalent binding of a drug to the cysteine residue of a specific protein. Aromatic parts of the hybrids also come from the substances reported as anticancer or antiviral agents. The synthetic route employed to access the amido-ester hybrids 2-13 used monomethyl itaconate or monomethyl itaconyl chloride and corresponding amines as the starting materials. Dimers 14 and 15 with two aminoindole or mefloquine moieties were prepared from itaconic acid and corresponding amino derivative, using standard coupling conditions (HATU/DIEA). All hybrids exerted anticancer effects in vitro against almost all the tumour cell lines that were evaluated (MCF-7, HCT 116, H460, LN-229, Capan-1, DND-41, HL-60, K-562, Z-138). Solid tumour cells were, in general, more responsive than the haematological cancer cells. The MCF-7 breast adenocarcinoma cell line appeared the most sensitive. Amido-ester 12 with chloroquine core and mefloquine homodimer 15 showed the highest activity with GI values between 0.7 and 8.6 µM. In addition, compound 15 also exerted antiviral activity against Zika virus and Coxsackievirus B4 in low micromolar concentrations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11030-020-10147-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548052PMC
October 2020

Design, synthesis and biological evaluation of pyrazolo[3,4-d]pyrimidine-based protein kinase D inhibitors.

Eur J Med Chem 2020 Nov 29;205:112638. Epub 2020 Jul 29.

KU Leuven, Department of Chemistry, Molecular Design and Synthesis, Celestijnenlaan 200F - Box 2404, B-3001, Leuven, Belgium. Electronic address:

The multiple roles of protein kinase D (PKD) in various cancer hallmarks have been repeatedly reported. Therefore, the search for novel PKD inhibitors and their evaluation as antitumor agents has gained considerable attention. In this work, novel pyrazolo[3,4-d]pyrimidine based pan-PKD inhibitors with structural variety at position 1 were synthesized and evaluated for biological activity. Starting from 3-IN-PP1, a known PKD inhibitor with IC values in the range of 94-108 nM, compound 17m was identified with an improved biochemical inhibitory activity against PKD (IC = 17-35 nM). Subsequent cellular assays demonstrated that 3-IN-PP1 and 17m inhibited PKD-dependent cortactin phosphorylation. Furthermore, 3-IN-PP1 displayed potent anti-proliferative activity against PANC-1 cells. Finally, a screening against different cancer cell lines demonstrated that 3-IN-PP1 is a potent and versatile antitumoral agent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmech.2020.112638DOI Listing
November 2020

Synthesis and Antitumor Activity of C-7-Alkynylated and Arylated Pyrrolotriazine C-Ribonucleosides.

ACS Med Chem Lett 2020 Aug 9;11(8):1605-1610. Epub 2020 Jul 9.

Medicinal Chemistry, KU Leuven, Rega Institute for Medical Research, Herestraat 49-box 1041, 3000 Leuven, Belgium.

A number of biologically active nucleoside analogues contain the adenine isostere 4-amino-pyrrolo[2,1-][1,2,4]triazine connected to various sugar moieties through a C-C anomeric linkage. We employed palladium-catalyzed cross-coupling chemistry to promptly functionalize the 7-position of such a heterocyclic scaffold with various alkynyl and aryl groups starting from a common 7-iodo-pyrrolotriazine C-ribonucleoside intermediate. Analogues bearing a 7-cyclopropyl-, 7-propyl-, and 7-butylacetylene moiety displayed potent cytotoxic activity, with the latest being the most selective of this series toward cancer cells. Further insights revealed that such C-nucleosides could exert their antiproliferative action by causing dose-dependent DNA damage.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acsmedchemlett.0c00269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429976PMC
August 2020

Synthesis of Novel Nitroxoline Analogs with Potent Cathepsin B Exopeptidase Inhibitory Activity.

ChemMedChem 2020 Dec 21;15(24):2477-2490. Epub 2020 Sep 21.

SynbioC Research Group, Department of Green Chemistry and Technology, Faculty of Bioscience Engineering, Ghent University, Coupure Links 653, 9000, Ghent, Belgium.

Nitroxoline, a well-known antimicrobial agent, has been identified in several independent studies, and on different molecular targets, as a promising candidate to be repurposed for cancer treatment. One specific target of interest concerns cathepsin B, a lysosomal peptidase involved in the degradation of the extracellular matrix (ECM), leading to tumor invasion, metastasis and angiogenesis. However, dedicated optimization of the nitroxoline core is needed to actually deliver a nitroxoline-based antitumor drug candidate. Within that context, 34 novel nitroxoline analogs were synthesized and evaluated for their relative cathepsin B inhibitory activity, their antiproliferative properties and their antimicrobial activity. More than twenty analogs were shown to exert a similar or even slightly higher cathepsin B inhibitory activity compared to nitroxoline. The implemented modifications of the nitroxoline scaffold and the resulting SAR information can form an eligible basis for further optimization toward more potent cathepsin B inhibitors in the quest for a clinical nitroxoline-based antitumor agent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cmdc.202000402DOI Listing
December 2020

Drug repurposing: phosphate prodrugs of anticancer and antiviral FDA-approved nucleosides as novel antimicrobials.

J Antimicrob Chemother 2020 10;75(10):2864-2878

School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.

Objectives: Following a drug repurposing approach, we aimed to investigate and compare the antibacterial and antibiofilm activities of different classes of phosphate prodrugs (HepDirect, cycloSal, SATE and mix SATE) of antiviral and anticancer FDA-approved nucleoside drugs [zidovudine (AZT), floxouridine (FUDR) and gemcitabine (GEM)] against a variety of pathogenic Gram-positive and -negative bacteria.

Methods: Ten prodrugs were synthesized and screened for antibacterial activity against seven Gram-negative and two Gram-positive isolates fully susceptible to traditional antibiotics, alongside six Gram-negative and five Gram-positive isolates with resistance mechanisms. Their ability to prevent and eradicate biofilms of different bacterial pathogens in relation to planktonic growth inhibition was also evaluated, together with their effect on proliferation, viability and apoptosis of different eukaryotic cells.

Results: The prodrugs showed decreased antibacterial activity compared with the parent nucleosides. cycloSal-GEM-monophosphate (MP) prodrugs 20a and 20b were the most active agents against Gram-positive bacteria (Enterococcus faecalis and Staphylococcus aureus) and retained their activity against antibiotic-resistant isolates. cycloSal-FUDR-MP 21a partially retained good activity against the Gram-positive bacteria E. faecalis, Enterococcus faecium and S. aureus. Most of the prodrugs tested displayed very potent preventive antibiofilm specific activity, but not curative. In terms of cytotoxicity, AZT prodrugs did not affect apoptosis or cell viability at the highest concentration tested, and only weak effects on apoptosis and/or cell viability were observed for GEM and FUDR prodrugs.

Conclusions: Among the different prodrug approaches, the cycloSal prodrugs appeared the most effective. In particular, cycloSal (17a) and mix SATE (26) AZT prodrugs combine the lowest cytotoxicity with high and broad antibacterial and antibiofilm activity against Gram-negative bacteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jac/dkaa268DOI Listing
October 2020

Design, synthesis and biological evaluation of 2-alkoxycarbonyl-3-anilinoindoles as a new class of potent inhibitors of tubulin polymerization.

Bioorg Chem 2020 04 18;97:103665. Epub 2020 Feb 18.

Rega Institute for Medical Research, KU Leuven, Laboratory of Virology and Chemotherapy, Leuven, Belgium.

A new class of inhibitors of tubulin polymerization based on the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)indole molecular skeleton was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization and cell cycle effects. The results presented show that the methoxy substitution and location on the indole nucleus plays an important role in inhibition of cell growth, and the most favorable position for the substituent was at C-6. In addition, a small-size ester function (methoxy/ethoxycarbonyl) at the 2-position of the indole core was desirable. Also, analogues that were alkylated with methyl, ethyl or n-propyl groups or had a benzyl moiety on the N-1 indolic nitrogen retained activity equivalent to those observed in the parent N-1H analogues. The most promising compounds of the series were 2-methoxycarbonyl-3-(3',4'.5'-trimethoxyanilino)-5-methoxyindole 3f and 1-methyl-2-methoxycarbonyl-3-(3',4'.5'-trimethoxyanilino)-6-methoxy-indole 3w, both of which target tubulin at the colchicine site with antitubulin activities comparable to that of the reference compound combretastatin A-4.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bioorg.2020.103665DOI Listing
April 2020

Iron/Copper Co-Catalyzed Cross-Coupling Reaction for the Synthesis of 6-Substituted 7-Deazapurines and the Corresponding Nucleosides.

J Org Chem 2020 01 20;85(2):403-418. Epub 2019 Dec 20.

KU Leuven , Rega Institute for Medical Research, Medicinal Chemistry , Herestraat 49-bus 1041 , 3000 Leuven , Belgium.

An efficient access to 6-substituted 7-deazapurine and the corresponding nucleosides by coupling aryl or alkyl Grignard reagents and halogenated purine nucleosides in the presence of Fe(acac)/CuI is described. A series of 6-substituted 7-deazapurines and the corresponding nucleosides were obtained in medium to good yields. For the synthesis of modified nucleosides that will be the subject of biological testing, we propose to use iron-catalyzed instead of palladium-catalyzed reaction. The synthesized compounds were tested for their antiproliferative activity. The cytotoxicity study of compounds - shows that by modifying the 6-position of 7-deazapurine ribonucleosides, the compounds may become selective for certain cancer cell lines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.joc.9b02414DOI Listing
January 2020

Design and Synthesis of New 6-Nitro and 6-Amino-3,3a,4,5-Tetrahydro-2-Benzo[]indazole Derivatives: Antiproliferative and Antibacterial Activity.

Molecules 2019 Nov 21;24(23). Epub 2019 Nov 21.

Instituto de Química Médica (IQM, CSIC), Juan de la Cierva 3, 28006 Madrid, Spain.

New substituted benzo[g]indazoles functionalized with a 6-nitro and 6-amino groups have been synthesized by the reaction of benzylidene tetralones with hydrazine in acetic acid. The resulting conformationally-constrained compounds were evaluated for their antiproliferative activity against selected cancer cell lines. The nitro-based indazoles , , and have shown IC values between 5-15 μM against the lung carcinoma cell line NCI-H460. Moreover, the nitro compounds were tested for antibacterial activity where compounds and have shown MIC values of 250 and 62.5 μg/mL against with no hemolytic activity in human red blood cells (RBC).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules24234236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930490PMC
November 2019

Superior inhibition of influenza virus hemagglutinin-mediated fusion by indole-substituted spirothiazolidinones.

Bioorg Med Chem 2020 01 8;28(1):115130. Epub 2019 Nov 8.

Rega Institute for Medical Research, KU Leuven, Department of Microbiology, Immunology and Transplantation, B-3000 Leuven, Belgium. Electronic address:

The influenza virus hemagglutinin (HA) mediates membrane fusion after viral entry by endocytosis. The fusion process requires drastic low pH-induced HA refolding and is prevented by arbidol and tert-butylhydroquinone (TBHQ). We here report a class of superior inhibitors with indole-substituted spirothiazolidinone structure. The most active analogue 5f has an EC value against influenza A/H3N2 virus of 1 nM and selectivity index of almost 2000. Resistance data and in silico modeling indicate that 5f combines optimized fitting in the TBHQ/arbidol HA binding pocket with a capability for endosomal accumulation. Both criteria appear relevant to achieve superior inhibitors of HA-mediated fusion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2019.115130DOI Listing
January 2020

Synthesis, biological evaluation and molecular modeling of a novel series of fused 1,2,3-triazoles as potential anti-coronavirus agents.

Bioorg Med Chem Lett 2018 11 22;28(21):3472-3476. Epub 2018 Sep 22.

Molecular Design and Synthesis, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium. Electronic address:

Synthesis and biological evaluation of a novel library of fused 1,2,3-triazole derivatives are described. The in-house developed multicomponent reaction based on commercially available starting materials was applied and broad biological screening against various viruses was performed, showing promising antiviral properties for compounds 14d, 14n, 14q, 18f and 18i against human coronavirus 229E. Further in silico studies identified the key molecular interactions between those compounds and the 3-chymotrypsin-like protease, which is essential to the intracellular replication of the virus, supporting the hypothesis that the protease is the target molecule of the potential antiviral derivatives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmcl.2018.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127349PMC
November 2018

Asymmetric Primaquine and Halogenaniline Fumardiamides as Novel Biologically Active Michael Acceptors.

Molecules 2018 Jul 14;23(7). Epub 2018 Jul 14.

Faculty of Pharmacy and Biochemistry, University of Zagreb, A. Kovačića 1, 10000 Zagreb, Croatia.

Novel primaquine (PQ) and halogenaniline asymmetric fumardiamides ⁻, potential Michael acceptors, and their reduced analogues succindiamides ⁻ were prepared by simple three-step reactions: coupling reaction between PQ and mono-ethyl fumarate () or mono-methyl succinate (), hydrolysis of PQ-dicarboxylic acid mono-ester conjugates , to corresponding acids ,, and a coupling reaction with halogenanilines. 1-[bis(Dimethylamino)methylene]-1-1,2,3-triazolo[4,5-]pyridinium 3-oxide hexafluorophosphate (HATU) was used as a coupling reagent along with Hünig's base. Compounds and were evaluated against a panel of bacteria, several strains, fungi, a set of viruses, and nine different human tumor cell lines. -Chlorofumardiamide showed significant activity against and , but also against (minimum inhibitory concentration (MIC) 6.1⁻12.5 µg/mL). Together with -fluoro and -CF₃ fumardiamides ,, compound showed activity against and , against . In biofilm eradication assay, most of the bacteria, particularly , showed susceptibility to fumardiamides. -CF₃ and -chloroaniline fumardiamides and showed significant antiviral activity against reovirus-1, sindbis virus and Punta Toro virus (EC = 3.1⁻5.5 µM), while was active against coxsackie virus B4 (EC = 3.1 µM). -Fluoro derivative exerted significant cytostatic activity (IC = 5.7⁻31.2 μM). Acute lymphoblastic leukemia cells were highly susceptible towards -substituted derivatives ,, (IC = 6.7⁻8.9 μM). Biological evaluations revealed that fumardiamides were more active than succindiamides indicating importance of Michael conjugated system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/molecules23071724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100582PMC
July 2018

Synthesis and Biological Evaluation of Pyrrolo[2,1-f][1,2,4]triazine C-Nucleosides with a Ribose, 2'-Deoxyribose, and 2',3'-Dideoxyribose Sugar Moiety.

ChemMedChem 2018 01 12;13(1):97-104. Epub 2017 Dec 12.

Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49-bus 1043, 3000, Leuven, Belgium.

The synthesis of hitherto unknown pyrrolo[2,1-f][1,2,4]triazine C-nucleosides is described. Structural variations (chlorine, bromine, iodine, and cyano groups) were introduced at position 7 of 4-aza-7,9-dideazaadenine. In addition, pyrrolo[2,1-f][1,2,4]triazine C-nucleosides bearing a 2'-deoxy-, 2',3'-dideoxy-, and 2',3'-dehydrodideoxyribose moiety were also prepared. Among these analogues, the pyrrolo[2,1-f][1,2,4]triazine C-ribonucleosides with either a hydrogen atom or cyano group at position 7 of the nucleobase displayed potent cytotoxic activity in a panel of various cancer cell lines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cmdc.201700657DOI Listing
January 2018

Chlorogenic Compounds from Coffee Beans Exert Activity against Respiratory Viruses.

Planta Med 2017 May 2;83(7):615-623. Epub 2016 Nov 2.

Rega Institute for Medical Research, KU Leuven - University of Leuven, Leuven, Belgium.

Chlorogenic acids are secondary metabolites in diverse plants. Some chlorogenic acids extracted from traditional medicinal plants are known for their healing properties, e.g., against viral infections. Also, green coffee beans are a rich source of chlorogenic acids, with 5--caffeoylquinic acid being the most abundant chlorogenic acid in coffee. We previously reported the synthesis of the regioisomers of lactones, bearing different substituents on the quinidic core. Here, 3,4--dicaffeoyl-1,5--quinide and three dimethoxycinnamoyl--quinides were investigated for antiviral activities against a panel of 14 human viruses. Whereas the dimethoxycinnamoyl--quinides did not show any antiviral potency in cytopathogenic effect reduction assays, 3,4--dicaffeoyl-1,5--quinide exerted mild antiviral activity against herpes simplex viruses, adenovirus, and influenza virus. Interestingly, when the compounds were evaluated against respiratory syncytial virus, a potent antiviral effect of 3,4--dicaffeoyl-1,5--quinide was observed against both subtypes of respiratory syncytial virus, with EC values in the submicromolar range. Time-of-addition experiments revealed that this compound acts on an intracellular post-entry replication step. Our data show that 3,4--dicaffeoyl-1,5--quinide is a relevant candidate for lead optimization and further mechanistic studies, and warrants clinical development as a potential anti-respiratory syncytial virus drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0042-119449DOI Listing
May 2017

Photochemical studies and nanomolar photodynamic activities of phthalocyanines functionalized with 1,4,7-trioxanonyl moieties at their non-peripheral positions.

J Inorg Biochem 2016 Feb 14;155:76-81. Epub 2015 Nov 14.

Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium. Electronic address:

Manganese(III), cobalt(II), copper(II), magnesium(II), zinc(II) and metal-free phthalocyanines, possessing 1,4,7-trioxanonyl substituents, at their non-peripheral positions, were subjected to photochemical, photodynamic and biological activity studies. Demetallated phthalocyanine and its metallated d-block analogues, with copper(II), cobalt(II), manganese(III) chloride, were found to be less efficient singlet oxygen generators in comparison to the zinc(II) analogue and zinc(II) phthalocyanine reference. Irradiation of several phthalocyanines for short time periods resulted in a substantially increased cytostatic activity against both suspension (leukemic/lymphoma at 85nM) and solid (cervix carcinoma at 72nM and melanoma at 81nM) tumour cell lines (up to 200-fold). Noteworthy is that enveloped viruses, such as for herpesvirus and influenza A virus, but not, non-enveloped virus strains, such as Coxsackie B4 virus and reovirus-1, exposed to irradiation in the presence of the phthalocyanines, markedly lost their infectivity potential.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jinorgbio.2015.11.006DOI Listing
February 2016

Synthesis and anti-herpetic activity of phosphoramidate ProTides.

ChemMedChem 2013 Jun 18;8(6):985-93. Epub 2013 Apr 18.

Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.

Among the many prodrug approaches aimed at delivering nucleoside monophosphates into cells, the phosphoramidate ProTide approach is one that has shown success, which has made it possible for some of the phosphoramidates to enter into clinical trials. Herein, we report the synthesis and antiviral activity of a series of phosphoramidate ProTides designed to bypass the thymidine kinase (TK) dependence of the parent nucleoside analogues. Phosphoramidate derivatives of (E)-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) that contain L-alanine or pivaloyloxymethyl iminodiacetate (IDA-POM) exhibit anti-HSV-1 and anti-VZV activity in cell cultures, but they largely lost antiviral potency against TK-deficient virus strains. Among deazapurine nucleosides and their phosphoramidate derivatives, the 7-deazaadenine containing nucleosides and their phosphoramidate triester derivatives showed weak antiviral activity against VZV. Apparently, intracellular nucleotide delivery with these phosphoramidates is partly successful. However, none of the compound prodrugs showed superior activity to their parent drugs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cmdc.201300035DOI Listing
June 2013

Interaction between mouse adenovirus type 1 and cell surface heparan sulfate proteoglycans.

PLoS One 2012 7;7(2):e31454. Epub 2012 Feb 7.

Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium.

Application of human adenovirus type 5 (Ad5) derived vectors for cancer gene therapy has been limited by the poor cell surface expression, on some tumor cell types, of the primary Ad5 receptor, the coxsackie-adenovirus-receptor (CAR), as well as the accumulation of Ad5 in the liver following interaction with blood coagulation factor X (FX) and subsequent tethering of the FX-Ad5 complex to heparan sulfate proteoglycan (HSPG) on liver cells. As an alternative vector, mouse adenovirus type 1 (MAV-1) is particularly attractive, since this non-human adenovirus displays pronounced endothelial cell tropism and does not use CAR as a cellular attachment receptor. We here demonstrate that MAV-1 uses cell surface heparan sulfate proteoglycans (HSPGs) as primary cellular attachment receptor. Direct binding of MAV-1 to heparan sulfate-coated plates proved to be markedly more efficient compared to that of Ad5. Experiments with modified heparins revealed that the interaction of MAV-1 to HSPGs depends on their N-sulfation and, to a lesser extent, 6-O-sulfation rate. Whereas the interaction between Ad5 and HSPGs was enhanced by FX, this was not the case for MAV-1. A slot blot assay demonstrated the ability of MAV-1 to directly interact with FX, although the amount of FX complexed to MAV-1 was much lower than observed for Ad5. Analysis of the binding of MAV-1 and Ad5 to the NCI-60 panel of different human tumor cell lines revealed the preference of MAV-1 for ovarian carcinoma cells. Together, the data presented here enlarge our insight into the HSPG receptor usage of MAV-1 and support the development of an MAV-1-derived gene vector for human cancer therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031454PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3274534PMC
July 2012

Design, synthesis and biological evaluation of 2'-deoxy-2',2'-difluoro-5-halouridine phosphoramidate ProTides.

Bioorg Med Chem 2011 Jul 27;19(14):4338-45. Epub 2011 May 27.

Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.

We report the synthesis of a series of novel 2'-deoxy-2',2'-difluoro-5-halouridines and their corresponding phosphoramidate ProTides. All compounds were evaluated for antiviral activity and for cellular toxicity. Interestingly, 2'-deoxy-2',2'-difluoro-5-iodo- and -5-bromo-uridines showed selective activity against feline herpes virus replication in cell culture due to a specific recognition (activation) by the virus-encoded thymidine kinase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2011.05.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127735PMC
July 2011
-->