105 results on '"BALZARINI, J."'
Search Results
2. Novel NSAID 1-acyl-4-cycloalkyl/arylsemicarbazides and 1-acyl-5-benzyloxy/hydroxy carbamoylcarbazides as potential anticancer agents and antioxidants
- Author
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Perković, I., Butula, I., Kralj, M., Martin-Kleiner, I., Balzarini, J., Hadjipavlou-Litina, D., Katsori, A.-M., and Zorc, B.
- Published
- 2012
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3. Synthesis, antibacterial and antiviral properties of curcumin bioconjugates bearing dipeptide, fatty acids and folic acid
- Author
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Singh, Ramendra K., Rai, Diwakar, Yadav, Dipti, Bhargava, A., Balzarini, J., and De Clercq, E.
- Published
- 2010
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4. The novel phosphoramidate derivatives of NSAID 3-hydroxypropylamides: Synthesis, cytostatic and antiviral activity evaluations
- Author
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Wittine, K., Benci, K., Rajić, Z., Zorc, B., Kralj, M., Marjanović, M., Pavelić, K., De Clercq, E., Andrei, G., Snoeck, R., Balzarini, J., and Mintas, M.
- Published
- 2009
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5. The novel primaquine derivatives of N-alkyl, cycloalkyl or aryl urea: Synthesis, cytostatic and antiviral activity evaluations
- Author
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Džimbeg, G., Zorc, B., Kralj, M., Ester, K., Pavelić, K., Andrei, G., Snoeck, R., Balzarini, J., De Clercq, E., and Mintas, M.
- Published
- 2008
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6. Evaluation of the semicarbazones, thiosemicarbazones and bis-carbohydrazones of some aryl alicycylic ketones for anticonvulsant and other biological propertie
- Author
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Dimmock, JR, primary, Pandeya, SN, additional, Quail, JW, additional, Pugazhenthi, U, additional, Allen, TM, additional, Kao, GY, additional, Balzarini, J, additional, and DeClercq, E, additional
- Published
- 1995
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7. Synthesis and cytotoxic evaluation of some styryl ketones and related compounds
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Dimmock, JR, primary, Kumar, P, additional, Quail, JW, additional, Pugazhenthi, U, additional, Yang, J, additional, Chen, M, additional, Reid, RS, additional, Allen, TM, additional, Kao, GY, additional, Cole, SPC, additional, Batist, G, additional, Balzarini, J, additional, and De Clercq, E, additional
- Published
- 1995
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8. Synthesis, determination of sequence selective DNA minor groove binding and biological evaluation of hybrid bithiazole-linked netropsin derivatives
- Author
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Mrani, D, primary, Gosselin, G, additional, Bailly, C, additional, Houssin, R, additional, Rao, KE, additional, Zimmermann, J, additional, Balzarini, J, additional, De Clercq, E, additional, Hénichart, JP, additional, Imbach, JL, additional, and Lown, JW, additional
- Published
- 1992
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9. Synthesis, DNA binding and biological activity of oxazolopyridocarbazole-netropsin hybrid molecules
- Author
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Mrani, D, primary, Gosselin, G, additional, Auclair, C, additional, Balzarini, J, additional, De Clercq, E, additional, Paoletti, C, additional, and Imbach, JL, additional
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- 1991
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10. Synthesis, DNA binding properties and biological evaluation of novel oligo-meta-benzamides related to netropsin
- Author
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Debart, F, primary, Gosselin, G, additional, Rayner, B, additional, Le Ber, P, additional, Auclair, C, additional, Balzarini, J, additional, De Clercq, E, additional, Paoletti, C, additional, and Imbach, JL, additional
- Published
- 1991
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11. Stereospecific synthesis and biological evaluations of b-l-pentofuranonucleoside derivatives of 5-fluorouracil and 5-fluorocytosine
- Author
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Griffon, J. F., Mathe, C., Faraj, A., Aubertin, A. M., Clercq, E. De, Balzarini, J., Sommadossi, J. P., and Gosselin, G.
- Published
- 2001
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12. 5-(Acylethynyl)uracils, 5-(Acylethynyl)-2'-deoxyuridines and 5-(Acylethynyl)-1-(2-hydroxyethoxy)methyluracils. Their synthesis, antiviral and cytotoxic activities
- Author
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Kundu, N. G., Mahanty, J. S., Chowdhury, C., Dasgupta, S. K., Das, B., Spears, C. P., Balzarini, J., and Clercq, E. De
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- 1999
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13. Synthesis and antiviral activity of imidazo[l,2-a]pyridines
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Lhassani, M., Chavignon, O., Chezal, J.-M., Teulade, J.-C., Chapat, J.-P., Snoeck, R., Andrei, G., Balzarini, J., Clercq, E. De, and Gueiffier, A.
- Published
- 1999
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14. Mannich bases of phenolic azobenzenes possessing cytotoxic activity
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Dimmock, JR, Erciyas, E, Kumar, P, Hetherington, M, Quail, JW, Pugazhenthi, U, Arpin, SA, Hayes, SJ, Allen, TM, Halleran, S, Clercq, E De, Balzarini, J, and Stables, JP
- Published
- 1997
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15. Isoxazolidine analogs of nucleosides
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Tronchet, JMJ, Iznaden, M, Barbalat-Rey, F, Dhimane, H, Ricca, A, Balzarini, J, and De Clercq, E
- Published
- 1992
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16. 2-Alkoxycarbonyl-3-arylamino-5-substituted thiophenes as a novel class of antimicrotubule agents: Design, synthesis, cell growth and tubulin polymerization inhibition.
- Author
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Romagnoli R, Kimatrai Salvador M, Schiaffino Ortega S, Baraldi PG, Oliva P, Baraldi S, Lopez-Cara LC, Brancale A, Ferla S, Hamel E, Balzarini J, Liekens S, Mattiuzzo E, Basso G, and Viola G
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Membrane Potential, Mitochondrial drug effects, Mice, Models, Molecular, Molecular Structure, Polymerization drug effects, Reactive Oxygen Species metabolism, Structure-Activity Relationship, Thiophenes chemical synthesis, Thiophenes chemistry, Tubulin Modulators chemical synthesis, Tubulin Modulators chemistry, Antineoplastic Agents pharmacology, Drug Design, Microtubules drug effects, Thiophenes pharmacology, Tubulin metabolism, Tubulin Modulators pharmacology
- Abstract
Microtubules are recognized as crucial components of the mitotic spindle during cell division, and, for this reason, the microtubule system is an attractive target for the development of anticancer agents. Continuing our search strategy for novel tubulin targeting-compounds, a new series of 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)-5-aryl/heteroarylthiophene derivatives was designed, synthesized and demonstrated to act as tubulin polymerization inhibitors at the colchicine site. A structure-activity relationship study on the phenyl at the 5-position of the thiophene ring was performed by introducing a variety of substituents containing electron-releasing and electron-withdrawing groups, with the 2-alkoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold being the minimum structural requirement for activity. Of the tested compounds, derivatives 4a, 4c, 4i and 4k possessed the highest overall potency and displayed high antiproliferative activities at submicromolar concentrations, with IC
50 values ranging from 0.13 to 0.84 μM against four different cancer cell lines. Three agents (4a, 4c and 4i) in the present series had similar effects, and these were comparable to those of the reference compound combretastatin A-4 (CA-4) as inhibitors of tubulin assembly. The antitubulin effects correlated with the cytostatic activities and indicate that these compounds inhibit cell growth through inhibition of tubulin polymerization by binding at the colchicine site. Compound 4c, containing the 2'-thienyl ring at the 5-position of the 2-methoxycarbonyl-3-(3',4',5'-trimethoxyanilino)thiophene scaffold, exhibited substantial antiproliferative activity with a mean IC50 value of 140 nM, inhibited tubulin polymerization with an IC50 value of 1.2 μM, similar to that of CA-4 (IC50 : 1.1 μM), and induced apoptosis in HeLa cells., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)- Published
- 2018
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17. Pronounced anti-proliferative activity and tumor cell selectivity of 5-alkyl-2-amino-3-methylcarboxylate thiophenes.
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Thomas J, Jecic A, Vanstreels E, van Berckelaer L, Romagnoli R, Dehaen W, Liekens S, and Balzarini J
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- Alkylation, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cell Line, Tumor, Cell Nucleus metabolism, Cell Proliferation drug effects, Endoplasmic Reticulum metabolism, Humans, Structure-Activity Relationship, Thiophenes pharmacokinetics, Thiophenes pharmacology, Tissue Distribution, Antineoplastic Agents pharmacology, Thiophenes chemical synthesis
- Abstract
5-(2-(4-Methoxyphenyl)ethyl)-2-amino-3-methylcarboxylate thiophene (TR560) is the prototype drug of a recently discovered novel class of tumor-selective compounds that preferentially inhibit the proliferation of specific tumor cell types (e.g. leukemia/lymphoma). Here, we further increased tumor selectivity by simplification of the molecule through replacing the 4-methoxyphenyl moiety by an alkyl chain. Several 2-amino-3-methylcarboxylate thiophene derivatives containing at C-5 an alkyl group consisting of at least 6 (hexyl) to 9 (nonyl) carbon units showed pronounced anti-proliferative activity in the mid-nanomolar range with 500- to 1000-fold tumor cell selectivity. The compounds preferentially inhibited the proliferation of T-lymphoma CEM and Molt/4, prostate PC-3, kidney Caki-1 and hepatoma Huh-7 tumor cells, but were virtually inactive against other tumor cell lines including B-lymphoma Raji and cervix carcinoma HeLa cells. The novel prototype drug 3j (containing a 5-heptyl chain) elicited a cytotoxic, rather than cytostatic activity, already after 4 h of exposure. The unusual tumor selectivity could not be explained by a differential uptake (or efflux) of the drug by sensitive versus resistant tumor cells. Exposure of a fluorescent derivative of 3j revealed pronounced uptake of the drug in the cytoplasm, no visible appearance in the nucleus, and a predominant localization in the endoplasmic reticulum. These observations may be helpful to narrow down the intracellular localization and identification of the molecular target of the 5-substituted thiophene derivatives., (Copyright © 2017 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2017
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18. Identification of an indol-based derivative as potent and selective varicella zoster virus (VZV) inhibitor.
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Musella S, di Sarno V, Ciaglia T, Sala M, Spensiero A, Scala MC, Ostacolo C, Andrei G, Balzarini J, Snoeck R, Novellino E, Campiglia P, Bertamino A, and Gomez-Monterrey IM
- Subjects
- Cell Line, Cell Proliferation drug effects, Cells, Cultured, Drug Design, Humans, Molecular Structure, Antiviral Agents chemistry, Antiviral Agents pharmacology, Herpesvirus 3, Human drug effects, Indoles chemistry, Indoles pharmacology, Virus Replication drug effects
- Abstract
We report the synthesis and antiviral activity of a new family of non-nucleoside antivirals, derived from the indole nucleus. Modifications of this template through Mannich and Friedel-Crafts reactions, coupled with nucleophilic displacement and reductive aminations led to 23 final derivatives, which were pharmacologically tested. Tryptamine derivative 17a was found to have a selective inhibitory activity against human varicella zoster virus (VZV) replication in vitro, being inactive against a variety of other DNA and RNA viruses. A structure-activity relationship (SAR) study showed that the presence of a biphenyl ethyl moiety and the acetylation at the amino group of tryptamine are a prerequisite for anti-VZV activity. The novel compound shows the same activity against thymidine kinase (TK)-competent (TK
+ ) and TK-deficient (TK- ) VZV strains, pointing to a novel mechanism of antiviral action., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)- Published
- 2016
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19. Anti-HIV-1 activity of a tripodal receptor that recognizes mannose oligomers.
- Author
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Rivero-Buceta E, Carrero P, Casanova E, Doyagüez EG, Madrona A, Quesada E, Peréz-Pérez MJ, Mateos R, Bravo L, Mathys L, Noppen S, Kiselev E, Marchand C, Pommier Y, Liekens S, Balzarini J, Camarasa MJ, and San-Félix A
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Dose-Response Relationship, Drug, HIV Integrase Inhibitors chemical synthesis, HIV Integrase Inhibitors chemistry, HIV Integrase Inhibitors pharmacology, HIV-1 metabolism, Mannans chemical synthesis, Mannans chemistry, Microbial Sensitivity Tests, Molecular Structure, Structure-Activity Relationship, Anti-HIV Agents pharmacology, HIV Envelope Protein gp120 antagonists & inhibitors, HIV Integrase metabolism, HIV-1 drug effects, HIV-1 enzymology, Mannans pharmacology
- Abstract
The glycoprotein gp120 of the HIV-1 viral envelope has a high content in mannose residues, particularly α-1,2-mannose oligomers. Compounds that interact with these high-mannose type glycans may disturb the interaction between gp120 and its (co)receptors and are considered potential anti-HIV agents. Previously, we demonstrated that a tripodal receptor (1), with a central scaffold of 1,3,5-triethylbenzene substituted with three 2,3,4-trihydroxybenzoyl groups, selectively recognizes α-1,2-mannose polysaccharides. Here we present additional studies to determine the anti-HIV-1 activity and the mechanism of antiviral activity of this compound. Our studies indicate that 1 shows anti-HIV-1 activity in the low micromolar range and has pronounced gp120 binding and HIV-1 integrase inhibitory capacity. However, gp120 binding rather than integrase inhibition seems to be the primary mechanism of antiviral activity of 1., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Published
- 2015
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20. Tryptophan dendrimers that inhibit HIV replication, prevent virus entry and bind to the HIV envelope glycoproteins gp120 and gp41.
- Author
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Rivero-Buceta E, Doyagüez EG, Colomer I, Quesada E, Mathys L, Noppen S, Liekens S, Camarasa MJ, Pérez-Pérez MJ, Balzarini J, and San-Félix A
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Binding Sites, Dendrimers chemical synthesis, Dendrimers chemistry, Dose-Response Relationship, Drug, HIV metabolism, Humans, Microbial Sensitivity Tests, Molecular Structure, Protein Binding drug effects, Receptors, HIV metabolism, Structure-Activity Relationship, Tryptophan chemical synthesis, Tryptophan chemistry, Tumor Cells, Cultured, Anti-HIV Agents pharmacology, Dendrimers pharmacology, HIV drug effects, HIV Envelope Protein gp120 metabolism, HIV Envelope Protein gp41 metabolism, Tryptophan pharmacology, Virus Internalization drug effects, Virus Replication drug effects
- Abstract
Dendrimers containing from 9 to 18 tryptophan residues at the peryphery have been efficiently synthesized and tested against HIV replication. These compounds inhibit an early step of the replicative cycle of HIV, presumably virus entry into its target cell. Our data suggest that HIV inhibition can be achieved by the preferred interaction of the compounds herein described with glycoproteins gp120 and gp41 of the HIV envelope preventing interaction between HIV and the (co)receptors present on the host cells. The results obtained so far indicate that 9 tryptophan residues on the periphery are sufficient for efficient gp120/gp41 binding and anti-HIV activity., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Published
- 2015
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21. Synthesis, antiplasmodial activity and mechanistic studies of pyrimidine-5-carbonitrile and quinoline hybrids.
- Author
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Kaur H, Balzarini J, de Kock C, Smith PJ, Chibale K, and Singh K
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- Animals, Antimalarials chemistry, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Antiviral Agents pharmacology, Cell Line, DNA Viruses drug effects, Dose-Response Relationship, Drug, Heme chemistry, Humans, Mice, Models, Molecular, Molecular Structure, Nitriles chemistry, Parasitic Sensitivity Tests, Pyrimidines chemistry, Quinolines chemistry, RNA Viruses drug effects, Structure-Activity Relationship, Antimalarials chemical synthesis, Antimalarials pharmacology, Nitriles pharmacology, Plasmodium falciparum drug effects, Pyrimidines pharmacology, Quinolines pharmacology
- Abstract
A series of hybrids comprising of 5-cyanopyrimidine and quinoline moiety were synthesized and tested for in vitro antiplasmodial activity against NF54 and Dd2 strains of Plasmodium falciparum. Hybrid bearing m-nitrophenyl substituent at C-4 of pyrimidine displayed the highest antiplasmodial activity [IC50 = 56 nM] against the CQ(R) (Dd2) strain, which is four-fold greater than CQ., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Published
- 2015
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22. Design, synthesis and antiproliferative activity of novel heterobivalent hybrids based on imidazo[2,1-b][1,3,4]thiadiazole and imidazo[2,1-b][1,3]thiazole scaffolds.
- Author
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Romagnoli R, Baraldi PG, Prencipe F, Balzarini J, Liekens S, and Estévez F
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- Animals, Antineoplastic Agents chemistry, Cell Death drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HeLa Cells, Humans, Imidazoles chemical synthesis, Mice, Models, Molecular, Molecular Structure, Structure-Activity Relationship, Thiadiazoles chemical synthesis, Thiazoles chemical synthesis, Tumor Cells, Cultured, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Drug Design, Imidazoles chemistry, Imidazoles pharmacology, Thiadiazoles chemistry, Thiadiazoles pharmacology, Thiazoles chemistry, Thiazoles pharmacology
- Abstract
Heterobivalent ligands constituted by two different pharmacophores that bind to different molecular targets or to two distinct sites on the same molecular target could be one of the methods used for the treatment of cancer. In view of the importance of imidazo[1,2-b][1,3]thiazole and imidazo[1,2-b][1,3,4]thiadiazole as privileged structures for the preparation of novel anticancer agents, we decided to explore the synthesis and biological evaluation of molecular conjugates comprising these fused bicyclic systems tethered at their C-6 position by a meta-(α-bromoacryloylamido)phenyl moiety. We found that most of the hybrid compounds displayed high antiproliferative activity toward a wide panel of cancer cell lines, with one-digit micromolar to submicromolar 50% inhibitory concentrations (IC50). We have observed that selected compounds 7d, 7e, 7n and 8c induced apoptosis, which was associated with the release of cytochrome c and cleavage of multiple caspases. Overexpression of the protective mitochondrial protein Bcl-2 did not confer protection to cell death induced by these compounds., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Published
- 2015
- Full Text
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23. Linear and branched alkyl-esters and amides of gallic acid and other (mono-, di- and tri-) hydroxy benzoyl derivatives as promising anti-HCV inhibitors.
- Author
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Rivero-Buceta E, Carrero P, Doyagüez EG, Madrona A, Quesada E, Camarasa MJ, Peréz-Pérez MJ, Leyssen P, Paeshuyse J, Balzarini J, Neyts J, and San-Félix A
- Subjects
- Alkylation, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Dose-Response Relationship, Drug, Gallic Acid chemical synthesis, Gallic Acid chemistry, HIV drug effects, Microbial Sensitivity Tests, Molecular Structure, Structure-Activity Relationship, Amides chemistry, Antiviral Agents pharmacology, Esters chemistry, Gallic Acid pharmacology, Hepacivirus drug effects
- Abstract
Linear and branched compounds that contain two, three or five units of galloyl (3,4,5-trihydroxybenzoyl) or its isomer 2,3,4-trihydroxybenzoyl, as well as other mono- or dihydroxybenzoyl moieties have been synthesized. These molecules have been evaluated for their in vitro inhibitory effects against a wide panel of viruses showing preferential activity against HIV and HCV. Our structure-activity relationship studies demonstrated that the 2,3,4-trihydroxybenzoyl moiety provides better antiviral activities than the galloyl (3,4,5-trihydroxybenzoyl) moiety that is present in natural green tea catechins. This observation can be of interest for the further rational exploration of compounds with anti-HCV/HIV properties. The most notable finding with respect to HIV is that the tripodal compounds 43 and 45, with three 2,3,4-trihydroxybenzoyl moieties, showed higher activities than linear compounds with only one or two. With respect to HCV, the linear compounds, 52 and 41, containing a 12 polymethylene chain and two 2,3 di- or 2,3,4 tri-hydroxybenzoyl groups respectively at the ends of the molecule showed good antiviral efficiency. Furthermore, the anti-HCV activity of both compounds was observed at concentrations well below the cytotoxicity threshold. A representative member of these compounds, 41, showed that the anti-HCV activity was largely independent of the genetic make-up of the HCV subgenomic replicon and cell lines used., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Published
- 2015
- Full Text
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24. Design, synthesis and bioevaluation of novel 6-(4-Hydroxypiperidino)naphthalen-2-ol-based potential Selective Estrogen Receptor Modulators for breast cancer.
- Author
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Jha A, Yadav Y, Naidu AB, Rao VK, Kumar A, Parmar VS, MacDonald WJ, Too CK, Balzarini J, Barden CJ, and Cameron TS
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Breast Neoplasms pathology, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, HeLa Cells, Humans, MCF-7 Cells, Mice, Models, Molecular, Molecular Structure, Naphthols chemical synthesis, Naphthols chemistry, Piperidines chemical synthesis, Piperidines chemistry, Receptors, Estrogen metabolism, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Drug Design, Naphthols pharmacology, Piperidines pharmacology, Receptors, Estrogen antagonists & inhibitors
- Abstract
In a study directed towards development of novel Selective Estrogen Receptor Modulators (SERMs), 1-(4-(2-(dialkylamino)ethoxy)benzyl)-6-(4-hydroxypiperidin-1-yl)-2-naphthol and corresponding aryl methyl ethers were synthesized and bioevaluated against the estrogen-responsive human MCF-7 breast cancer cell line. The phenolic analogs displayed little or no activity, but aryl methyl ether analogs showed significant cytotoxic potency. Also, representative compounds from the aryl methyl ether series showed significant binding and antagonistic activity against ERα. Two representative compounds were also evaluated for in vitro membrane permeability, plasma stability as well as in-vivo toxicity in mice. The compounds displayed well-acceptable drug-like in vitro membrane permeability as well as plasma stability and were well-tolerated in experimental mice at 300 mg/kg dose., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2015
- Full Text
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25. Fused heterocycles bearing bridgehead nitrogen as potent HIV-1 NNRTIs. Part 3: optimization of [1,2,4]triazolo[1,5-a]pyrimidine core via structure-based and physicochemical property-driven approaches.
- Author
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Huang B, Li C, Chen W, Liu T, Yu M, Fu L, Sun Y, Liu H, De Clercq E, Pannecouque C, Balzarini J, Zhan P, and Liu X
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Cell Line, Tumor, Dose-Response Relationship, Drug, HIV Reverse Transcriptase metabolism, Heterocyclic Compounds chemical synthesis, Heterocyclic Compounds chemistry, Heterocyclic Compounds, 2-Ring chemical synthesis, Heterocyclic Compounds, 2-Ring chemistry, Humans, Microbial Sensitivity Tests, Models, Molecular, Molecular Structure, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Solubility, Structure-Activity Relationship, Sulfones chemical synthesis, Sulfones chemistry, Anti-HIV Agents pharmacology, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Heterocyclic Compounds pharmacology, Heterocyclic Compounds, 2-Ring pharmacology, Nitrogen chemistry, Reverse Transcriptase Inhibitors pharmacology, Sulfones pharmacology
- Abstract
In our arduous efforts to develop new potent HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs), novel piperidine-linked [1,2,4]triazolo[1,5-a]pyrimidine derivatives were designed, synthesized and evaluated for their antiviral activities in MT-4 cell cultures. Biological results showed that all of the title compounds displayed moderate to excellent activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 8.1 nM to 2284 nM in a cell-based assay. Among them, the most promising analog 7d possessed an EC50 value of 8.1 nM against wt HIV-1, which was much more potent than the reference drugs DDI, 3 TC, NVP and DLV. Additionally, 7d demonstrated weak activity against the double mutant HIV-1 strain (K103N + Y181C), and was more efficient than NVP in a RT inhibition assay. Besides, some measured and calculated physicochemical properties of 7d, like log P and water solubility, as well as the structure-activity relationships (SARs) analysis have been discussed in detail. Furthermore, the binding mode of the active compound 7d was rationalized by molecular simulation studies., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)
- Published
- 2015
- Full Text
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26. Hairpin oligonucleotides forming G-quadruplexes: new aptamers with anti-HIV activity.
- Author
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Romanucci V, Gaglione M, Messere A, Potenza N, Zarrelli A, Noppen S, Liekens S, Balzarini J, and Di Fabio G
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Aptamers, Nucleotide chemical synthesis, Aptamers, Nucleotide chemistry, Microbial Sensitivity Tests, Molecular Structure, Oligonucleotides chemical synthesis, Oligonucleotides chemistry, Surface Plasmon Resonance, Anti-HIV Agents pharmacology, Aptamers, Nucleotide pharmacology, G-Quadruplexes, HIV-1 drug effects, HIV-2 drug effects, Oligonucleotides pharmacology
- Abstract
We describe the facile syntheses of new modified oligonucleotides based on d(TG3AG) that form bimolecular G-quadruplexes and possess a HEG loop as an inversion of polarity site 3'-3' or 5'-5' and aromatic residues conjugated to the 5'-end through phosphodiester bonds. The conjugated hairpin G-quadruplexes exhibited parallel orientation, high thermal stability, elevated resistance in human serum and high or moderate anti-HIV-1 activity with low cytotoxicity. Further, these molecules showed significant binding to HIV envelope glycoproteins gp120, gp41 and HSA, as revealed by SPR assays. As a result, these conjugated hairpins represent the first active anti-HIV-1 bimolecular G-quadruplexes based on the d(TG3AG) sequence., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2015
- Full Text
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27. All trans 1-(3-arylacryloyl)-3,5-bis(pyridin-4-ylmethylene)piperidin-4-ones as curcumin-inspired antineoplastics.
- Author
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Paul NK, Jha M, Bhullar KS, Rupasinghe HP, Balzarini J, and Jha A
- Subjects
- Animals, Antineoplastic Agents chemistry, Antioxidants chemistry, Antioxidants pharmacology, Carbon-13 Magnetic Resonance Spectroscopy, Cell Line, Curcumin chemistry, Drug Screening Assays, Antitumor, Humans, Mice, Piperidines chemistry, Proton Magnetic Resonance Spectroscopy, Spectrometry, Mass, Electrospray Ionization, Spectrophotometry, Ultraviolet, Antineoplastic Agents pharmacology, Curcumin pharmacology, Piperidines pharmacology
- Abstract
A series of eleven N-acryloyl/N-cinnamoyl 3,5-bis(pyridin-4-yl)methylene-4-piperidones were synthesized as curcumin-based candidate antineoplastic agents. The cytostatic potency of these compounds was evaluated against three representative cell lines and all compounds were found to exhibit significant anti-cancer cell activity in vitro. QSAR studies using several physicochemical parameters and 50% inhibitory concentration (IC50) values resulted in certain important correlations which will aid design of more potent analogs. Representative test compounds were investigated in the NCI 60-cell line panel where they were found to display a profound cytotoxicity. These compounds were also potent anti-oxidants and inhibitors of human topoisomerase IIα. Representative compounds were well-tolerated by human fibroblasts and by mice during the survival/toxicity studies., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2014
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28. Synthesis and evaluation of new antitumor 3-aminomethyl-4,11-dihydroxynaphtho[2,3-f]indole-5,10-diones.
- Author
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Shchekotikhin AE, Glazunova VA, Dezhenkova LG, Luzikov YN, Buyanov VN, Treshalina HM, Lesnaya NA, Romanenko VI, Kaluzhny DN, Balzarini J, Agama K, Pommier Y, Shtil AA, and Preobrazhenskaya MN
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Cattle, Cell Proliferation drug effects, Cell Survival drug effects, DNA drug effects, DNA Cleavage drug effects, DNA Topoisomerases, Type I metabolism, DNA Topoisomerases, Type II metabolism, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, Humans, Indoles chemical synthesis, Indoles chemistry, K562 Cells, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Molecular Structure, Naphthols chemical synthesis, Naphthols chemistry, Structure-Activity Relationship, Topoisomerase Inhibitors chemical synthesis, Topoisomerase Inhibitors chemistry, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Indoles pharmacology, Naphthols pharmacology, Topoisomerase Inhibitors pharmacology
- Abstract
A series of new 3-aminomethyl-4,11-dihydroxynaphtho[2,3-f]indole-5,10-diones 6-13 bearing the cyclic diamine in the position 3 of the indole ring was synthesized. The majority of new compounds demonstrated a superior cytotoxicity than doxorubicin against a panel of mammalian tumor cells with determinants of altered drug response, that is, Pgp expression or p53 inactivation. For naphtho[2,3-f]indole-5,10-diones 6-9 bearing 3-aminopyrrolidine in the side chains, the ability to bind double-stranded DNA and inhibit topoisomerases 1 and 2 mediated relaxation of supercoiled DNA were demonstrated. Only one isomer, (R)-4,11-dihydroxy-3-((pyrrolidin-3-ylamino)methyl)-1H-naphtho[2,3-f]indole-5,10-dione (7) induced the formation of specific DNA cleavage products similar to the known topoisomerase 1 inhibitors camptothecin and indenoisoquinoline MJ-III-65, suggesting a role of the structure of the side chain of 3-aminomethylnaphtho[2,3-f]indole-5,10-diones in interaction with the target. Compound 7 demonstrated an antitumor activity in mice with P388 leukemia transplants whereas its enantiomer 6 was inactive. Thus, 3-aminomethyl derivatives of 4,11-dihydroxynaphtho[2,3-f]indole-5,10-dione emerge as a new prospective chemotype for the search of antitumor agents., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2014
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29. Novel multi-targeting anthra[2,3-b]thiophene-5,10-diones with guanidine-containing side chains: interaction with telomeric G-quadruplex, inhibition of telomerase and topoisomerase I and cytotoxic properties.
- Author
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Ilyinsky NS, Shchyolkina AK, Borisova OF, Mamaeva OK, Zvereva MI, Azhibek DM, Livshits MA, Mitkevich VA, Balzarini J, Sinkevich YB, Luzikov YN, Dezhenkova LG, Kolotova ES, Shtil AA, Shchekotikhin AE, and Kaluzhny DN
- Subjects
- Animals, Antineoplastic Agents chemistry, Antineoplastic Agents metabolism, Antineoplastic Agents pharmacology, Cell Line, Tumor, Humans, Intracellular Space metabolism, Mice, Thiophenes chemistry, Topoisomerase I Inhibitors chemistry, Topoisomerase I Inhibitors metabolism, Topoisomerase I Inhibitors pharmacology, G-Quadruplexes, Guanidine chemistry, Telomerase antagonists & inhibitors, Thiophenes metabolism, Thiophenes pharmacology
- Abstract
Novel generations of antitumor anthraquinones are expected to be advantageous over the conventional chemotherapeutic agents. Previous structure-activity relationship studies demonstrated an importance of the positively charged side chains conjugated to anthra[2,3-b]thiophene-5,10-dione scaffolds. Exploring a role of individual side chain moieties in binding to the duplex and G-quadruplex DNA, modulation of telomerase and topoisomerase I activities, intracellular accumulation and cytostatic potency, we herein analyzed a series of reported and newly synthesized guanidine-containing derivatives of anthra[2,3-b]thiophene-5,10-dione. We found that the number of cationic side chains (namely, two) is critical for a tight interaction with human telomeric G-quadruplex (TelQ). Along with a larger drug-TelQ association constant, the telomerase attenuation by anthrathiophenediones with two basic groups in the side chains was more pronounced than by the analogs bearing one basic group. For mono-guanidinated compounds the substituent with the amino group in the side chain provided better TelQ affinity than the methylamine residue. The intracellular uptake of the mono-guanidino derivative with two side chains was >2-fold higher than the respective value for the bis(guanidino) derivative. This difference can explain a lower antiproliferative potency of bis(guanidine) containing compounds. Thus, the modifications of side chains of anthra[2,3-b]thiophene-5,10-dione differently modulated drug-target interactions and cellular effects. Nevertheless, the selected compound 11-(3-aminopropylamino)-4-(2-guanidinoethylamino)anthra[2,3-b]thiophene-5,10-dione 13 demonstrated a high affinity to TelQ and the ability to stabilize the quadruplex structure. These properties were paralleled by reasonable potency of 13 as a telomerase/topoisomerase I inhibitor and an antiproliferative agent. These results indicate that the structural elements of anthra[2,3-b]thiophene-5,10-dione derivatives can be balanced to yield a candidate for further preclinical study., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2014
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30. Discovery and SAR studies of a novel class of cytotoxic 1,4-disubstituted piperidines via Ugi reaction.
- Author
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de Castro S, Camarasa MJ, Balzarini J, and Velázquez S
- Subjects
- Animals, Antineoplastic Agents chemistry, Cell Line, Tumor, Humans, Mice, Piperidines chemical synthesis, Structure-Activity Relationship, Antineoplastic Agents chemical synthesis, Antineoplastic Agents pharmacology, Drug Design, Piperidines chemistry, Piperidines pharmacology
- Abstract
Herein we report a novel class of 1,4-disubstituted piperidines as potential anticancer agents. One-step and efficient synthesis of a structurally diverse library of piperidine-based analogs with five points of diversity has been developed using the Ugi four-component reaction. A structure-activity relationship (SAR) study showed that the presence of a benzyl or a Boc group at the N-1 position together with two or three aromatic groups at the C-4 position of the piperidine ring are important for optimal cytostatic properties. Compounds 20, 22, 27 and 29 were found to be the most potent with a 50% inhibitory concentration (IC50) ranging between 3 and 9.5 μM in the cancer cell lines evaluated. The NCI60 screen confirmed this 50% cytostatic concentration range for compound 20, irrespective of the nature of the tumor cell lines evaluated. The NCI COMPARE algorithm did not show any significant correlation between the growth inhibition profile of compound 20 with the NCI database compound profiles suggesting a potential novel mechanism of action., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2014
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31. Microwave-assisted synthesis of C-8 aryl and heteroaryl inosines and determination of their inhibitory activities against Plasmodium falciparum purine nucleoside phosphorylase.
- Author
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Gigante A, Priego EM, Sánchez-Carrasco P, Ruiz-Pérez LM, Vande Voorde J, Camarasa MJ, Balzarini J, González-Pacanowska D, and Pérez-Pérez MJ
- Subjects
- Animals, Anti-Bacterial Agents chemical synthesis, Anti-Bacterial Agents chemistry, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Cell Line, Tumor, Chlorocebus aethiops, DNA Viruses drug effects, Dogs, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors chemistry, Escherichia coli drug effects, HeLa Cells, Humans, Inosine analogs & derivatives, Inosine chemical synthesis, Madin Darby Canine Kidney Cells, Microbial Sensitivity Tests, Microwaves, Molecular Conformation, Mycoplasma hyorhinis drug effects, Purine-Nucleoside Phosphorylase metabolism, RNA Viruses drug effects, Vero Cells, Anti-Bacterial Agents pharmacology, Antiviral Agents pharmacology, Enzyme Inhibitors pharmacology, Inosine pharmacology, Plasmodium falciparum enzymology, Purine-Nucleoside Phosphorylase antagonists & inhibitors
- Abstract
8-Arylinosines have been scarcely studied for therapeutic purposes, probably due to difficulties in their synthesis. The recently described direct arylation reaction at position 8 of purine nucleosides has been employed to synthesize a series of 8-aryl and 8-pyridylinosines. These compounds have been studied for hydrolytic stability and subjected to biological evaluation. Three compounds have shown a pronounced specific inhibition of Plasmodium falciparum-encoded purine nucleoside phosphorylase, an important target for antimalarial chemotherapy., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2014
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32. Design and synthesis of a new series of modified CH-diarylpyrimidines as drug-resistant HIV non-nucleoside reverse transcriptase inhibitors.
- Author
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Meng G, Liu Y, Zheng A, Chen F, Chen W, De Clercq E, Pannecouque C, and Balzarini J
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Dose-Response Relationship, Drug, HIV Reverse Transcriptase metabolism, HIV-1 drug effects, HIV-2 drug effects, Microbial Sensitivity Tests, Molecular Structure, Pyrimidines chemical synthesis, Pyrimidines chemistry, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Structure-Activity Relationship, Anti-HIV Agents pharmacology, Drug Design, HIV Reverse Transcriptase antagonists & inhibitors, Pyrimidines pharmacology, Reverse Transcriptase Inhibitors pharmacology
- Abstract
This article reports the design, synthesis and antiviral evaluation of a new series of non-nucleoside reverse transcriptase inhibitors (NNRTIs). The basic skeleton of these target 18 molecules is diarylpyrimidine featuring a substituted amino group between the pyrimidine scaffold and the aryl wing. All of the new compounds have been characterized by spectra analysis. The entire target molecules were evaluated for their in vitro anti-HIV activity with controlling group of FDA approved drugs. Most of them showed good to potent activities against wild-type (WT) HIV-1 with IC50 values in the range of 0.0175-69.21 μM. 2-(4-Cyanophenylamino)-4-(2-cyanovinylphenylhydrazonomethyl)pyrimidine (1d) displayed potent anti-HIV-1 activity against WT HIV-1 with a selectivity index (SI) of 106367 and an IC50 value of 1.75 nM, which was 47 fold lower than that of AZT. Compound 1d also showed a broad-spectrum inhibitory activity, with an IC50 value of 5.33 μM and 5.05 μM against both HIV-1 double-mutated (K103N/Y181C) strain and HIV-2 strain, respectively. The preliminary structure-activity relationship (SAR) was also investigated. The binding modes with HIV-1 RT for both the wild type and mutant type have also been discussed., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2014
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33. Discovery of novel diarylpyrimidines as potent HIV NNRTIs via a structure-guided core-refining approach.
- Author
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Li X, Chen W, Tian Y, Liu H, Zhan P, De Clercq E, Pannecouque C, Balzarini J, and Liu X
- Subjects
- HIV Reverse Transcriptase chemistry, HIV Reverse Transcriptase metabolism, HIV-1 drug effects, HIV-1 physiology, Molecular Docking Simulation, Protein Conformation, Pyrimidines metabolism, Reverse Transcriptase Inhibitors metabolism, Structure-Activity Relationship, Virus Replication drug effects, Drug Design, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 enzymology, Pyrimidines chemistry, Pyrimidines pharmacology, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors pharmacology
- Abstract
Guided by crystal structures of HIV-1 RT/DAPY complex and molecular modeling studies, a series of novel DAPY derivatives were rationally designed, synthesized and evaluated for their anti-HIV activities. Among them, 16 compounds significantly inhibited HIV-1 IIIB replication with EC50 values lower than 66 nM. Particularly, compound 7a was the most potent inhibitor against HIV-1 wild-type and double RT mutant HIV-1 strain K103N/Y181C, with an EC50 value of 2.5 nM (SI = 13,740) and 0.33 μM (SI = 107), respectively. Unexpectedly, compound 8c was found to show moderate anti-HIV-2 potency (EC50 = 5.57 μM). Preliminary structure-activity relationships (SARs) and molecular modeling of these new analogues were also discussed in detail., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2014
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34. PMPA and PMEA prodrugs for the treatment of HIV infections and human papillomavirus (HPV) associated neoplasia and cancer.
- Author
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Pertusati F, Hinsinger K, Flynn ÁS, Powell N, Tristram A, Balzarini J, and McGuigan C
- Subjects
- Adenine chemical synthesis, Adenine chemistry, Adenine pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HIV drug effects, HeLa Cells, Humans, Microbial Sensitivity Tests, Molecular Structure, Organophosphonates chemical synthesis, Organophosphonates chemistry, Prodrugs chemical synthesis, Prodrugs chemistry, Structure-Activity Relationship, Tenofovir, Tumor Cells, Cultured, Adenine analogs & derivatives, Antineoplastic Agents pharmacology, Antiviral Agents pharmacology, HIV Infections drug therapy, Organophosphonates pharmacology, Papillomavirus Infections drug therapy, Prodrugs pharmacology
- Abstract
The synthesis and in vitro biological evaluation of novel phosphonamidate and phosphonodiamidate prodrugs of adefovir and tenofovir are reported. The selected synthetic approach from free phosphonic acid via bis-trimethylsilyl ester intermediates affords (L)-alanine ester derivatives in 10-70% yields. When assessed for their anti-HIV activity, all the prodrugs showed submicromolar activity. Noteworthy, the most potent derivative in the adefovir series contained a 5,6,7,8-tetrahydronaphtyl group, herein reported for the first time as an aryl moiety in a ProTide. A pronounced cytostatic activity of the above prodrugs is also reported. Selected compounds were tested for their antiproliferative activity against HPV-transformed cells and they were found significantly more active in comparison to their parent compounds. In this study a slightly improved activity of the adefovir derivatives over those of tenofovir was also noticed. However, no specificity for naturally HPV-transformed cell lines was observed., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2014
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35. Novel 3,5-bis(arylidene)-4-oxo-1-piperidinyl dimers: structure-activity relationships and potent antileukemic and antilymphoma cytotoxicity.
- Author
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Santiago-Vazquez Y, Das S, Das U, Robles-Escajeda E, Ortega NM, Lema C, Varela-Ramírez A, Aguilera RJ, Balzarini J, De Clercq E, Dimmock SG, Gorecki DK, and Dimmock JR
- Subjects
- Antineoplastic Agents chemical synthesis, Antineoplastic Agents toxicity, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dimerization, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HL-60 Cells, HeLa Cells, Humans, Molecular Structure, Piperidines chemical synthesis, Piperidines toxicity, Structure-Activity Relationship, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Leukemia pathology, Lymphoma pathology, Piperidines chemistry, Piperidines pharmacology
- Abstract
Novel clusters of 3,5-bis(benzylidene)-4-oxo-1-piperidinyl dimers 3-5 were evaluated against human Molt4/C8 and CEM T-lymphocytes and human HeLa cervix adenocarcinoma cells as well as murine L1210 leukemia neoplasms. Several of these compounds demonstrated IC50 values in the submicromolar and low micromolar range and compounds possessing 4-fluoro, 4-chloro and 3,4,5-trimethoxy substituents in the series 3 and 4 were identified as potent molecules. A heat map revealed the very high cytotoxic potencies of representative compounds against a number of additional leukemic and lymphoma cell lines and displayed greater toxicity to these cells than nonmalignant MCF10A and Hs-27 neoplasms. These dienones are more refractory to breast and prostate cancers. The evaluation of representative compounds in series 3-5 against a panel of human cancer cell lines revealed them to be potent cytotoxins with average IC50 values ranging from 0.05 to 8.51 μM. In particular, the most potent compound 4g demonstrated over 382-fold and 590-fold greater average cytotoxic potencies in this screen than the reference drugs, melphalan and 5-fluorouracil, respectively. A mode of action investigation of two representative compounds 3f and 4f indicated that they induce apoptosis which is due, at least in part, to the activation of caspase-3 and depolarization of the mitochondrial membrane potential., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)
- Published
- 2014
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36. Regioselective synthesis of 6-substituted-2-amino-5-bromo-4(3H)-pyrimidinones and evaluation of their antiviral activity.
- Author
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Singh K, Singh K, and Balzarini J
- Subjects
- Animals, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Cells, Cultured, Chlorocebus aethiops, Dogs, Dose-Response Relationship, Drug, HeLa Cells, Humans, Microbial Sensitivity Tests, Molecular Structure, Pyrimidinones chemical synthesis, Pyrimidinones chemistry, Stereoisomerism, Structure-Activity Relationship, Vero Cells, Antiviral Agents pharmacology, Pyrimidinones pharmacology, Viruses drug effects
- Abstract
A series of 2-amino-5-bromo-4(3H)-pyrimidinone derivatives bearing different substituents at the C-6 position were synthesized using a highly regioselective lithiation-substitution protocol, and the effect of structural variation at the C-6 position on their antiviral activity in cell culture was evaluated. Although some of the derivatives were found to be active against various virus strains, they were effective only close to their toxicity threshold., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
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37. Synthesis and broad spectrum antiviral evaluation of bis(POM) prodrugs of novel acyclic nucleosides.
- Author
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Hamada M, Roy V, McBrayer TR, Whitaker T, Urbina-Blanco C, Nolan SP, Balzarini J, Snoeck R, Andrei G, Schinazi RF, and Agrofoglio LA
- Subjects
- Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Cells, Cultured, Dose-Response Relationship, Drug, Humans, Microbial Sensitivity Tests, Molecular Structure, Nucleosides chemical synthesis, Nucleosides chemistry, Prodrugs chemical synthesis, Prodrugs chemistry, Structure-Activity Relationship, Antiviral Agents pharmacology, Nucleosides pharmacology, Prodrugs pharmacology, Viruses drug effects
- Abstract
A series of seventeen hitherto unknown ANP analogs bearing the (E)-but-2-enyl aliphatic side chain and modified heterocyclic base such as cytosine and 5-fluorocytosine, 2-pyrazinecarboxamide, 1,2,4-triazole-3-carboxamide or 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as key synthetic step. All novel compounds were evaluated for their antiviral activities against a large number of DNA and RNA viruses including herpes simplex virus type 1 and 2, varicella zoster virus, feline herpes virus, human cytomegalovirus, hepatitis C virus (HCV), HIV-1 and HIV-2. Among these molecules, only compound 31 showed activity against human cytomegalovirus in HEL cell cultures with at EC50 of ∼10 μM. Compounds 8a, 13, 14, and 24 demonstrated pronounced anti-HCV activity without significant cytotoxicity at 100 μM., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
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38. Synthesis of 4-aminoquinoline-pyrimidine hybrids as potent antimalarials and their mode of action studies.
- Author
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Singh K, Kaur H, Chibale K, and Balzarini J
- Subjects
- Antimalarials metabolism, Antimalarials toxicity, Antiviral Agents metabolism, Antiviral Agents toxicity, Cell Line, Chemistry Techniques, Synthetic, DNA metabolism, Heme metabolism, Humans, Plasmodium falciparum drug effects, Pyrimidines metabolism, Pyrimidines toxicity, Structure-Activity Relationship, Antimalarials chemical synthesis, Antimalarials pharmacology, Antiviral Agents chemical synthesis, Antiviral Agents pharmacology, Pyrimidines chemical synthesis, Pyrimidines pharmacology
- Abstract
One of the most viable options to tackle the growing resistance to the antimalarial drugs such as artemisinin is to resort to synthetic drugs. The multi-target strategy involving the use of hybrid drugs has shown promise. In line with this, new hybrids of quinoline with pyrimidine have been synthesized and evaluated for their antiplasmodial activity against both CQ(S) and CQ(R) strains of Plasmodium falciparum. These depicted activity in nanomolar range and were found to bind to heme as well as AT rich pUC18 DNA., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
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39. Ester prodrugs of acyclic nucleoside thiophosphonates compared to phosphonates: synthesis, antiviral activity and decomposition study.
- Author
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Roux L, Priet S, Payrot N, Weck C, Fournier M, Zoulim F, Balzarini J, Canard B, and Alvarez K
- Subjects
- Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Cell Line, Tumor, Cell Survival drug effects, DNA Viruses drug effects, Dose-Response Relationship, Drug, Esters chemical synthesis, Esters chemistry, Esters pharmacology, HIV-1 drug effects, HIV-2 drug effects, Hepatitis B virus drug effects, Humans, Models, Chemical, Molecular Structure, Nucleosides chemistry, Organophosphonates chemical synthesis, Organophosphonates chemistry, Organothiophosphonates chemical synthesis, Organothiophosphonates chemistry, Prodrugs chemical synthesis, Prodrugs chemistry, Antiviral Agents pharmacology, Organophosphonates pharmacology, Organothiophosphonates pharmacology, Prodrugs pharmacology
- Abstract
9-[2-(Thiophosphonomethoxy)ethyl]adenine [S-PMEA, 8] and (R)-9-[2-(Thiophosphonomethoxy)propyl]adenine [S-PMPA, 9] are acyclic nucleoside thiophosphonates we described recently that display the same antiviral spectrum (DNA viruses) as approved and potent phosphonates PMEA and (R)-PMPA. Here, we describe the synthesis, antiviral activities in infected cell cultures and decomposition study of bis(pivaloyloxymethoxy)-S-PMEA [Bis-POM-S-PMEA, 13] and bis(isopropyloxymethylcarbonyl)-S-PMPA [Bis-POC-S-PMPA, 14] as orally bioavailable prodrugs of the S-PMEA 8 and S-PMPA 9, in comparison to the equivalent "non-thio" derivatives [Bis-POM-PMEA, 11] and [Bis-POC-PMPA, 12]. Compounds 11, 12, 13 and 14 were evaluated for their in vitro antiviral activity against HIV-1-, HIV-2-, HBV- and a broad panel of DNA viruses, and found to exhibit moderate to potent antiviral activity. In order to determine the decomposition pathway of the prodrugs 11, 12, 13 and 14 into parent compounds PMEA, PMPA, 8 and 9, kinetic data and decomposition pathways in several media are presented. As expected, bis-POM-S-PMEA 13 and bis-POC-S-PMPA 14 behaved as prodrugs of S-PMEA 8 and S-PMPA 9. However, thiophosphonates 8 and 9 were released very smoothly in cell extracts, in contrast to the release of PMEA and PMPA from "non-thio" prodrugs 11 and 12., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
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40. Anticancer activity of novel hybrid molecules containing 5-benzylidene thiazolidine-2,4-dione.
- Author
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Romagnoli R, Baraldi PG, Salvador MK, Camacho ME, Balzarini J, Bermejo J, and Estévez F
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Apoptosis drug effects, Benzylidene Compounds chemical synthesis, Benzylidene Compounds chemistry, Blotting, Western, Caspases metabolism, Cell Line, Tumor, Cell Survival drug effects, Cytochromes c metabolism, DNA Fragmentation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Flow Cytometry, HL-60 Cells, HeLa Cells, Humans, Mice, Microscopy, Fluorescence, Models, Chemical, Molecular Structure, Thiazolidinediones chemical synthesis, Thiazolidinediones chemistry, U937 Cells, Antineoplastic Agents pharmacology, Benzylidene Compounds pharmacology, Cell Proliferation drug effects, Thiazolidinediones pharmacology
- Abstract
Hybridization of two different bioactive molecules with different mechanism of action is one of the methods that are being adopted to treat cancer. Molecules bearing a thiazolidine-2,4-dione scaffold have been recognized as antineoplastic agents with a broad spectrum of activity against many cancer cell lines. In this manuscript we have described the synthesis and biological evaluation of two series of N-3-substituted-5-arylidene thiazolidine-2,4-diones, bearing the α-bromoacryloylamido moiety at the para- or meta-position on the phenyl of the arylidene portion. We have observed that selected compounds 5a, 5c and 5g suppress proliferation of human myeloid leukaemia HL-60 and U937 cells by triggering morphological changes and internucleosomal DNA fragmentation, which are well-known features of apoptosis. Finally, our results indicated that the investigated compounds induced apoptotic cell death through a mechanism that involved activation of multiple caspases and was also associated with the release of cytochrome c from the mitochondria., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
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41. Novel water-soluble prodrugs of acyclovir cleavable by the dipeptidyl-peptidase IV (DPP IV/CD26) enzyme.
- Author
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Diez-Torrubia A, Cabrera S, de Castro S, García-Aparicio C, Mulder G, De Meester I, Camarasa MJ, Balzarini J, and Velázquez S
- Subjects
- Acyclovir chemistry, Acyclovir pharmacology, Adamantane analogs & derivatives, Adamantane pharmacology, Animals, Antiviral Agents chemistry, Antiviral Agents pharmacology, Biocatalysis drug effects, Cattle, Cells, Cultured, Dipeptidyl Peptidase 4 chemistry, Dipeptidyl-Peptidase IV Inhibitors pharmacology, Dose-Response Relationship, Drug, Fibroblasts drug effects, Fibroblasts virology, Herpesvirus 1, Human drug effects, Herpesvirus 2, Human drug effects, Humans, Hydrolysis, Microbial Sensitivity Tests, Nitriles pharmacology, Prodrugs chemistry, Prodrugs pharmacology, Pyrrolidines pharmacology, Solubility, Structure-Activity Relationship, Vildagliptin, Water chemistry, Acyclovir metabolism, Antiviral Agents metabolism, Dipeptidyl Peptidase 4 metabolism, Prodrugs metabolism
- Abstract
We herein report for the first time the successful use of the dipeptidyl peptidase IV (DPPIV/CD26) prodrug approach to guanine derivatives such as the antiviral acyclovir (ACV). The solution- and solid-phase synthesis of the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of acyclovir are reported. The synthesis of the demanding tetrapeptide amide prodrug of ACV 3 was first established in solution and successfully transferred onto solid support by using Ellman's dihydropyran (DHP) resin. In contrast with the valyl ester prodrug (valacyclovir, VACV), the tetrapeptide amide prodrug 3 and the tripeptide ester conjugate 4 of ACV proved fully stable in PBS. Both prodrugs converted to VACV (for 4) or ACV (for 3) upon exposure to purified DPPIV/CD26 or human or bovine serum. Vildagliptin, a potent inhibitor of DPPIV/CD26 efficiently inhibited the DPPIV/CD26-catalysed hydrolysis reaction. Both amide and ester prodrugs of ACV showed pronounced anti-herpetic activity in cell culture and significantly improved the water solubility in comparison with the parent drug., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
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42. The synthesis, antiviral, cytostatic and cytotoxic evaluation of a new series of acyclonucleotide analogues with a 1,2,3-triazole linker.
- Author
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Głowacka IE, Balzarini J, and Wróblewski AE
- Subjects
- Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Cell Line, Tumor, Cell Proliferation drug effects, Cytostatic Agents chemical synthesis, Cytostatic Agents chemistry, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HeLa Cells, Humans, Mice, Molecular Structure, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Antiviral Agents pharmacology, Cytostatic Agents pharmacology, Herpesvirus 1, Human drug effects, Herpesvirus 2, Human drug effects, T-Lymphocytes drug effects
- Abstract
The efficient synthesis of a new series of acyclonucleotide analogues with a 1,2,3-triazole linker is described starting from diethyl azidomethyl-, 2-azidoethyl-, 3-azidopropyl-, 4-azidobutyl-, 2-azido-1-hydroxyethyl-, 3-azido-2-hydroxypropyl- and 3-azido-1-hydroxypropylphosphonates and selected alkynes under microwave irradiation. Several O,O-diethylphosphonate acyclonucleotides were transformed into the respective phosphonic acids. All compounds were evaluated in vitro for activity against a broad variety of DNA and RNA viruses and cytostatic activity against murine leukaemia L1210, human T-lymphocyte CEM and human cervix carcinoma HeLa cells. Acyclonucleotide 22e exhibited activity against both herpes simplex viruses (HSV-1, HSV-2) in HEL cell cultures (EC₅₀ = 17 μM) and feline herpes virus (EC₅₀ = 24 μM) in CRFK cell cultures, while compounds 20k, 21k, 22k and 23k preferentially inhibited proliferation of human T-lymphocyte CEM cells at IC₅₀ in the 2.8-12 μM range., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
- Full Text
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43. Design, synthesis and biological evaluation of phosphorodiamidate prodrugs of antiviral and anticancer nucleosides.
- Author
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McGuigan C, Bourdin C, Derudas M, Hamon N, Hinsinger K, Kandil S, Madela K, Meneghesso S, Pertusati F, Serpi M, Slusarczyk M, Chamberlain S, Kolykhalov A, Vernachio J, Vanpouille C, Introini A, Margolis L, and Balzarini J
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Anti-HIV Agents pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Caco-2 Cells, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, HeLa Cells, Humans, Microbial Sensitivity Tests, Molecular Structure, Prodrugs chemical synthesis, Prodrugs chemistry, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Drug Design, HIV-1 drug effects, HIV-2 drug effects, Nucleosides chemistry, Prodrugs pharmacology
- Abstract
We herein report the application of the phosphorodiamidate phosphate prodrug approach to a series of thirteen nucleoside analogs with antiviral or anticancer activity. Twenty-five symmetrical phosphorodiamidates were synthesized, bearing esterified l-Alanine (and in one case d-Alanine) in the prodrug moiety, each as single stereoisomer. The presence of an achiral phosphorus represents a potential advantage over the phosphoramidate ProTide approach, where diastereoisomeric mixtures are routinely obtained, and different biological profiles may be expected from the diastereoisomers. Optimization of the synthetic pathway allowed us to identify two general methods depending on the particular nucleoside analogs. All the compounds were biologically evaluated in antiviral and anticancer assays and several showed improvement of activity compared to their parent nucleosides, as in the case of ddA, d4T, abacavir and acyclovir against HIV-1 and/or HIV-2. The biological results were supported by metabolism studies with carboxypeptidase Y monitored by (31)P NMR to investigate their bioactivation. This work further validates the phosphorodiamidate approach as a monophosphate prodrug motif with broad application in the antiviral and anticancer fields., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)
- Published
- 2013
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44. Synthesis and antiviral evaluation of bis(POM) prodrugs of (E)-[4'-phosphono-but-2'-en-1'-yl]purine nucleosides.
- Author
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Pradère U, Roy V, Montagu A, Sari O, Hamada M, Balzarini J, Snoeck R, Andrei G, and Agrofoglio LA
- Subjects
- Animals, Antiviral Agents pharmacology, Chlorocebus aethiops, DNA Viruses growth & development, Dogs, Drug Design, Drug Discovery, HeLa Cells, Humans, Madin Darby Canine Kidney Cells, Organophosphonates pharmacology, Prodrugs pharmacology, Purine Nucleosides pharmacology, RNA Viruses growth & development, Vero Cells, Viral Plaque Assay, Antiviral Agents chemical synthesis, DNA Viruses drug effects, Organophosphonates chemical synthesis, Prodrugs chemical synthesis, Purine Nucleosides chemical synthesis, RNA Viruses drug effects
- Abstract
Seventeen hitherto unknown bis(POM) prodrugs of novel (E)-[4'-phosphono-but-2'-en-1'-yl]purine nucleosides were prepared in a straight approach and at good yields. Those compounds were synthesized by the reaction of purine nucleobases directly with the phosphonate synthon 3 bearing POM biolabile groups under Mitsunobu conditions. All obtained compounds were evaluated for their antiviral activities against a large number of DNA and RNA viruses including herpes simplex viruses 1 and 2, varicella zoster virus, Feline herpes virus, human cytomegalovirus, HIV-1 and HIV-2. Among these molecules, some of them exhibit anti-VZV and anti-HIV activity at submicromolar concentrations. This class of compound will be of further interest for lead optimization as anti-infectious agents., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)
- Published
- 2012
- Full Text
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45. Synthesis and antiviral activities of hexadecyloxypropyl prodrugs of acyclic nucleoside phosphonates containing guanine or hypoxanthine and a (S)-HPMP or PEE acyclic moiety.
- Author
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Tichý T, Andrei G, Snoeck R, Balzarini J, Dračínský M, and Krečmerová M
- Subjects
- Animals, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Antiviral Agents metabolism, Antiviral Agents pharmacology, Cell Line, Chemistry Techniques, Synthetic, DNA Viruses drug effects, Humans, Organophosphonates chemistry, Organophosphonates metabolism, Structure-Activity Relationship, Guanine analogs & derivatives, Guanine chemistry, Hypoxanthine chemistry, Hypoxanthines chemistry, Nucleosides chemistry, Organophosphonates chemical synthesis, Organophosphonates pharmacology, Phosphorous Acids chemistry, Prodrugs metabolism
- Abstract
Hexadecyloxypropyl esters of acyclic nucleoside phosphonates containing guanine (G) or hypoxanthine (Hx) and a (S)-[3-hydroxy-2-(phosphonomethoxy)propyl] [(S)-HPMP] or 2-(2-phosphonoethoxy)ethyl (PEE) acyclic moiety have been prepared. The activity of the prodrugs was evaluated in vitro against different virus families. Whereas ester derivatives of PEEHx and (S)-HPMPHx were antivirally inactive, monoesters of PEEG, and mono- and diesters of (S)-HPMPG showed pronounced antiviral activity against vaccinia virus and/or herpesviruses. Monoesters of (S)-HPMPG emerged as the most potent and selective derivatives against these DNA viruses. None of the compounds were inhibitory against RNA viruses and retroviruses., (Crown Copyright © 2012. Published by Elsevier Masson SAS. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
46. Chiral resolution, absolute configuration assignment and biological activity of racemic diarylpyrimidine CH(OH)-DAPY as potent nonnucleoside HIV-1 reverse transcriptase inhibitors.
- Author
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Gu SX, Li ZM, Ma XD, Yang SQ, He QQ, Chen FE, De Clercq E, Balzarini J, and Pannecouque C
- Subjects
- HIV Reverse Transcriptase chemistry, HIV-1 drug effects, HIV-2 drug effects, Models, Molecular, Protein Conformation, Pyrimidines chemical synthesis, Reverse Transcriptase Inhibitors chemical synthesis, Stereoisomerism, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 enzymology, Pyrimidines chemistry, Pyrimidines pharmacology, Reverse Transcriptase Inhibitors chemistry, Reverse Transcriptase Inhibitors pharmacology
- Abstract
(+)-3a and (-)-3a were successfully separated from racemate (±)-3a by the chiral technique of supercritical fluid chromatography (SCF) with enantiomeric excess (ee%) >99% and purity >99%, and assigned for their absolute configuration as R and S, respectively, by the experimental electronic circular dichroism (ECD) spectrum and simulated ECD spectra calculated by time-dependent density functional theory (TDDFT) calculations. (+)-(R)-3a displayed excellent activity with an EC(50) of 5.3 nM against wild-type HIV-1, which was 12-fold more potent than (-)-(S)-3a. However, (-)-(S)-3a showed higher potency than (+)-(R)-3a against the double HIV-1 RT mutant (K103N+Y181C) as well as HIV-2 strain ROD. The possible reason for the difference of (R)- and (S)-3a in anti-HIV-1 activity was interpreted by molecular docking., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
47. Synthesis and antiviral evaluation of C5-substituted-(1,3-diyne)-2'-deoxyuridines.
- Author
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Sari O, Roy V, Balzarini J, Snoeck R, Andrei G, and Agrofoglio LA
- Subjects
- Antiviral Agents chemistry, Cell Line, Chemistry Techniques, Synthetic, Deoxyuridine chemistry, Humans, Inhibitory Concentration 50, Virus Replication drug effects, Antiviral Agents chemical synthesis, Antiviral Agents pharmacology, Deoxyuridine chemical synthesis, Deoxyuridine pharmacology, Viruses drug effects
- Abstract
Starting from acetylated 5-ethynyl-2'-deoxyuridine (3), 14 hitherto unknown C5-substituted-(1,3-diyne)-2'-deoxyuridines (with cyclopropyl, hydroxymethyl, methylcyclopentane, p-(substituted)phenyl and disubstituted-phenyl substituents) have been synthesized via a nickel-copper catalyzed C-H activation between two terminal alkynes, in yields ranging from 19% to 67%. Their antiviral activities were measured against a large number of DNA and RNA viruses including herpes simplex virus type 1 and type 2, varicella-zoster virus, human cytomegalovirus and vaccinia virus. The 5-[4-(4-trifluoromethoxyphenyl)buta-1,3-diynyl]-2'-deoxyuridine (26) is the most potent inhibitor of this series against VZV with an EC(50) of ~1 μM and a CC(50) of 55 μM. Their cytostatic activities were determined against murine leukemia cells, human T-lymphocyte cells and cervix carcinoma cells. Compounds were also evaluated on a wide panel of RNA viruses, including influenza virus A (H1N1 and H3N2) and B in MDCK cell cultures, parainfluenza-3 virus, reovirus-1, Sindbis virus and Punta Toro virus in Vero cell cultures and vesicular stomatitis, coxsackie B4 and respiratory syncytial virus in HeLa cell cultures and against human immunodeficiency virus type 1 and 2 in CEM cell cultures, with no specific antiviral effect. This class of compounds could be of further interest for lead optimization as anti-infectious (i.e. herpetic) agents., (Copyright © 2012. Published by Elsevier Masson SAS.)
- Published
- 2012
- Full Text
- View/download PDF
48. 2-Aminopyrimidine based 4-aminoquinoline anti-plasmodial agents. Synthesis, biological activity, structure-activity relationship and mode of action studies.
- Author
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Singh K, Kaur H, Chibale K, Balzarini J, Little S, and Bharatam PV
- Subjects
- Aminoquinolines metabolism, Aminoquinolines toxicity, Animals, Antimalarials metabolism, Antimalarials toxicity, Cell Line, DNA metabolism, Dogs, Heme metabolism, Humans, Hydrogen Bonding, Hydrophobic and Hydrophilic Interactions, Protoporphyrins metabolism, Structure-Activity Relationship, Viruses drug effects, Aminoquinolines chemical synthesis, Aminoquinolines pharmacology, Antimalarials chemical synthesis, Antimalarials pharmacology, Plasmodium falciparum drug effects, Pyrimidines chemistry
- Abstract
2-Aminopyrimidine based 4-aminoquinolines were synthesized using an efficacious protocol. Some of the compounds showed in vitro anti-plasmodial activity against drug-sensitive CQ(S) (3D7) and drug-resistant CQ(R) (K1) strains of Plasmodium falciparum in the nM range. In particular, 5-isopropyloxycarbonyl-6-methyl-4-(2-nitrophenyl)-2-[(7-chloroquinolin-4-ylamino)butylamino] pyrimidine depicted the lowest IC(50) (3.6 nM) value (56-fold less than CQ) against CQ(R) strain. Structure-activity profile and binding with heme, μ-oxo-heme have been studied. Binding assays with DNA revealed better binding with target parasite type AT rich pUC18 DNA. Most compounds were somewhat cytotoxic, but especially cytostatic. Molecular docking analysis with Pf DHFR allowed identification of stabilizing interactions., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)
- Published
- 2012
- Full Text
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49. Synthesis and biological evaluation of piperidine-substituted triazine derivatives as HIV-1 non-nucleoside reverse transcriptase inhibitors.
- Author
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Chen X, Zhan P, Pannecouque C, Balzarini J, De Clercq E, and Liu X
- Subjects
- Anti-HIV Agents chemical synthesis, Anti-HIV Agents chemistry, Cell Line, Chemistry Techniques, Synthetic, HIV-1 enzymology, Inhibitory Concentration 50, Reverse Transcriptase Inhibitors chemical synthesis, Reverse Transcriptase Inhibitors chemistry, Structure-Activity Relationship, Triazines chemistry, Anti-HIV Agents pharmacology, HIV Reverse Transcriptase antagonists & inhibitors, HIV-1 drug effects, Piperidines chemistry, Reverse Transcriptase Inhibitors pharmacology, Triazines chemical synthesis, Triazines pharmacology
- Abstract
A novel series of piperidine-substituted triazine derivatives have been synthesized and evaluated for anti-HIV activities in MT-4 cells. Most compounds displayed extremely promising activity against wild-type HIV-1 with EC(50) values in low nanomolar concentration, better than that of Nevirapine, Delavirdine, Zidovudine and Dideoxycitidine, and higher potency towards the resistant mutant strain K103N/Y181C than that of Nevirapine and Delavirdine. Selected compounds were also assayed against reverse transcriptase with lower IC(50) values than that of Nevirapine. The structure-activity relationship (SAR) of these novel structural congeners was also discussed., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
50. Design, synthesis, antiviral and cytostatic evaluation of novel isoxazolidine nucleotide analogues with a 1,2,3-triazole linker.
- Author
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Piotrowska DG, Balzarini J, and Głowacka IE
- Subjects
- Animals, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Antiviral Agents pharmacology, Antiviral Agents toxicity, Cell Line, Cytostatic Agents chemical synthesis, Cytostatic Agents chemistry, Cytostatic Agents pharmacology, Cytostatic Agents toxicity, Humans, Inhibitory Concentration 50, Mice, Nucleotides chemical synthesis, Nucleotides chemistry, Drug Design, Nucleotides pharmacology, Nucleotides toxicity, Triazoles chemistry, Viruses drug effects
- Abstract
Azidation (TMSN(3), SnCl(4)) of a 9:1 mixture of trans- and cis-5-acetoxy-2-methylisoxazolidin-3-yl-3-phosphonates at the anomeric carbon atom led to the formation of the equimolar mixture of cis- and trans-5-azido-2-methylisoxazolidin-3-yl-3-phosphonates, which were efficiently separated. The 1,3-dipolar cycloaddition of pure trans- and cis-5-azidoisoxazolidin-3-yl-3-phosphonates with selected alkynes gave the respective nucleoside mimetics containing a 1,2,3-triazole linker. The (1,2,3-triazolyl)isoxazolidine phosphonates obtained herein were evaluated in vitro for activity against a variety of DNA and RNA viruses. None of the compounds were endowed with antiviral activity at subtoxic concentrations. Compounds 15f-j and 16f-j were cytostatic in the higher micromolar range., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)
- Published
- 2012
- Full Text
- View/download PDF
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