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Piet Herdewijn - One of the best experts on this subject based on the ideXlab platform.
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synthesis of 2 deoxy 5 isothiazol 5 yl uridine and its interaction with the hsv 1 thymidine kinase
Helvetica Chimica Acta, 1996Co-Authors: Ingrid Luyten, Erik De Clercq, Jan Balzarini, Hans De Winter, Roger Busson, Theo Lescrinier, Isabelle Creuven, Franclois Durant, Piet HerdewijnAbstract:2′-Deoxy-5-(isothiazol-5-yl)uridine (12) was synthesized starting from 2′-deoxy-5-iodouridine using a Pd-catalysed cross-coupling reaction with propiolaldehyde diethyl acetal followed by deprotection and ring closure using thiosulfate. 2′-Deoxyuridine 12 has a particular place among the 5-heteroaryl-substituted 2′-Deoxyuridines in that it has a high affinity for herpes simplex virus type 1 (HSV-1)-encoded thymidine kinase (TK) without antiviral activity. Biochemical studies revealed that 12 is a substrate for viral TK. We further investigated the interaction of 12 with the HSV-1 thymidine kinase. The conformation of 12 in solution was established by NMR spectroscopy. The most stable conformer 12A has the S-atom of the isothiazole ring placed in the neighbourhood of the C(4)O group of the pyrimidine moiety. The compound was docked in its most stable conformation in the active site of HSV-1 TK and subjected to energy minimization. This demonstrated that the isothiazole moiety binds in a cavity lined by the side chains of Tyr-132, Arg-163, Ala-167, and Ala-168 and that the C(3) atom of the isothiazole moiety is located in close proximity of the phenolic O-atom of Tyr-132 and the aliphatic part of the Arg-163 side chain.
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Synthesis and antiviral activity of 5-thien-2-yl-2'-Deoxyuridine analogues
Journal of medicinal chemistry, 1993Co-Authors: Piet Wigerinck, L. Kerremans, P. Claes, Robert Snoeck, Maudgal P, De Clercq E, Piet HerdewijnAbstract:A number of 5-heteroaromatic-substituted 2'-Deoxyuridines were synthesized from 5-iodo-2'-Deoxyuridine using tetraorganotin reagents and palladium complexes as catalyst. The palladium-catalyzed cross-coupling reaction between 5-iodo-2'-Deoxyuridine and stannylated heteroaromatics was optimized for the synthesis of the 5-thien-3-yl-2'-Deoxyuridine and 5-furan-3-yl-2'-Deoxyuridine. 5-(5-Iodothien-2-yl)-2'-Deoxyuridine was used as starting material for the synthesis of 5-(5-methylthien-2-yl)-2'-Deoxyuridine, 5-(5-vinylthien-2-yl)-2'-Deoxyuridine, and 5-(5-ethynylthien-2-yl)-2'- Deoxyuridine. 5-(5-Nitrothien-2-yl)-2'-Deoxyuridine was synthesized using ceric ammonium nitrate as reagent. 5-(Isoxazol-5-yl)-2'-Deoxyuridine was synthesized from 5-(3-oxopropyn-1-yl)-2'-Deoxyuridine. Finally, 5-(5-chlorothien-2-yl)-beta-D-arabinofuranosyluracil and 5-(5-bromothien-2-yl)-beta-D-arabinofuranosyluracil were obtained by halogenation of 5-thien-2-yl-beta-D-arabinofuranosyluracil. Introduction of an alkyl substituent in the 5-position of the thienyl group of 5-thien-2-yl-2'-Deoxyuridine or substitution of the 2-deoxyribofuranose ring by an arabinofuranose moiety gave decreased activity against HSV-1 and VZV replication when compared with the 5"-halogenated-5-thien-2-yl-2'-Deoxyuridines. 5-(5-Bromothien-2-yl)-2'-Deoxyuridine caused prompt healing of HSV-1 keratitis when administered as eye drops (0.2%) to rabbits.
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Synthesis and anti-herpes activity of 5-trifluorovinyl-2'-Deoxyuridine
Bioorganic & Medicinal Chemistry Letters, 1992Co-Authors: Piet Herdewijn, L. Kerremans, Robert Snoeck, Aerschot Arthur Van, E. Esmans, E. De ClercqAbstract:Abstract 5-Trifluorovinyl-2′-Deoxyuridine was synthesized from protected 5-iodo-2′-Deoxyuridine and tetrakis(perfluorovinyl)tin. The compound demonstrates significant activity against HSV-1 but activity against HSV-2.
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5-(5-Bromothien-2-yl)-2'-Deoxyuridine and 5-(5-chlorothien-2-yl)-2'-Deoxyuridine are equipotent to (E)-5-(2-bromovinyl)-2'-Deoxyuridine in the inhibition of herpes simplex virus type I replication.
Journal of medicinal chemistry, 1991Co-Authors: Piet Wigerinck, Robert Snoeck, E. De Clercq, Christophe Pannecouque, Paul Claes, Piet HerdewijnAbstract:2'-Deoxyuridines with a five-membered heterocyclic substituent in the 5-position were synthesized by palladium-catalyzed coupling reactions of 5-iodo-2'-Deoxyuridine with the activated heteroaromatics. Further modification of the compound with the 5-thien-2-yl substituent gave 5-(5-bromothien-2-yl)-2'-Deoxyuridine and 5-(5-chlorothienyl-2-yl)-2'-Deoxyuridine. Both compounds show potent and selective activity against herpes simplex virus type 1 and varicella-zoster virus.
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Synthesis and antiviral activity of 5-heteroaryl-substituted 2'-Deoxyuridines.
Journal of medicinal chemistry, 1991Co-Authors: Piet Wigerinck, Robert Snoeck, E. De Clercq, Paul Claes, Piet HerdewijnAbstract:The synthesis of 5-heteroaryl-substituted 2'-Deoxyuridines is described. The heteroaromatics were obtained from three different 5-substituted 2'-Deoxyuridines. Cycloaddition reaction of nitrile oxides on the 5-ethynyl derivative 1 gave the isoxazoles 4a-e. The thiazole derivatives 14a-c were obtained from the 5-thiocarboxamide 11, while 5-pyrrol-1-yl-2'-Deoxyuridine (17) could be synthesized directly from 5-amino-2'-Deoxyuridine. The compounds were evaluated for antiviral activity. Selective activity against herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) was noted for 5-(3-bromoisoxazol-5-yl)-2'-Deoxyuridine (4c). The compound was inactive against herpes simplex virus type 2, cytomegalovirus, and thymidine kinase (TK)-deficient mutants of HSV-1 and VZV, which indicates that, most likely, its antiviral activity depends on phosphorylation by the virus-specified TK.
Christophe Len - One of the best experts on this subject based on the ideXlab platform.
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improved microwave assisted ligand free suzuki miyaura cross coupling of 5 iodo 2 Deoxyuridine in pure water
New Journal of Chemistry, 2013Co-Authors: Shawn Gallagherduval, Guillaume Sartori, G Herve, Gerald Enderlin, Christophe LenAbstract:A facile and efficient methodology for direct synthesis of 5-aryl-2′-Deoxyuridines was developed through ligand-free Suzuki–Miyaura cross-coupling reactions starting from totally deprotected 5-iodo-2′-Deoxyuridine and various boronic acids. Reactions were performed, in pure water, in the presence of very low loading of palladium either by classical thermal heating or with the assistance of microwave irradiation yielding 5-arylated uridine derivatives in moderate to good yields within short reaction times.
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new efficient approach for the ligand free suzuki miyaura reaction of 5 iodo 2 Deoxyuridine in water
Synthesis, 2013Co-Authors: Guillaume Sartori, G Herve, Gerald Enderlin, Christophe LenAbstract:A series of 5-aryl-2′-Deoxyuridines was prepared, using ligandless Suzuki–Miyaura cross-coupling reactions in neat water, starting from 5-iodo-2′-Deoxyuridine as totally deprotected starting material. This ligand-free process gave good to high isolated yields within short reaction times and with low loadings of palladium.
Robert Snoeck - One of the best experts on this subject based on the ideXlab platform.
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5 alkynyl analogs of arabinouridine and 2 Deoxyuridine cytostatic activity against herpes simplex virus and varicella zoster thymidine kinase gene transfected cells
Journal of Medicinal Chemistry, 2007Co-Authors: Walter A Cristofoli, Erik De Clercq, Jan Balzarini, Leonard I. Wiebe, Robert Snoeck, Graciela Andrei, Edward E. KnausAbstract:A group of arabinouridines (TMSEAU, EAU, IEAU-TA) and 2'-Deoxyuridines (TMSEDU, EDU, IEDU) having a variety of substituents at the uracil C-5 position (trimethylsilylethynyl, TMSE; ethynyl, E; or iodoethynyl, IE), and the sugar C-2' position (2'-arabino OH in arabinouridine, AU; or 2'-deoxyribo H in 2'-Deoxyuridine, DU) were prepared to acquire antiviral structure-activity relationships. A broad-spectrum viral panel screen showed that these 5-alkynylarabino/deoxy-uridines exhibit moderate anti-HSV-1 activity, with no difference in potency between arabinouridines and 2'-Deoxyuridines. The 2'-Deoxyuridines TMSEDU, EDU, and IEDU, unlike the arabinouridines, exhibited potent antiviral activity against cytomegalovirus, but they were also highly cytostatic. The abilities of the 5-alkynylarabino/deoxy-uridines to inhibit nontransfected (wild-type or thymidine kinase-deficient, tk-) and viral gene transfected (HSV-1, HSV-2, or VZV thymidine kinase-positive, tk+) FM3A and OST (osteosarcoma) cells were determined. This group of 5-alkynylarabino/deoxy-uridines showed an enhanced ability to inhibit cells transfected with a viral thymidine kinase gene (HSV-1tk+, HSV-2tk+, VZVtk+) relative to wild-type or thymidine kinase-deficient (tk-) cells.
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Synthesis and antiviral activity of 5-thien-2-yl-2'-Deoxyuridine analogues
Journal of medicinal chemistry, 1993Co-Authors: Piet Wigerinck, L. Kerremans, P. Claes, Robert Snoeck, Maudgal P, De Clercq E, Piet HerdewijnAbstract:A number of 5-heteroaromatic-substituted 2'-Deoxyuridines were synthesized from 5-iodo-2'-Deoxyuridine using tetraorganotin reagents and palladium complexes as catalyst. The palladium-catalyzed cross-coupling reaction between 5-iodo-2'-Deoxyuridine and stannylated heteroaromatics was optimized for the synthesis of the 5-thien-3-yl-2'-Deoxyuridine and 5-furan-3-yl-2'-Deoxyuridine. 5-(5-Iodothien-2-yl)-2'-Deoxyuridine was used as starting material for the synthesis of 5-(5-methylthien-2-yl)-2'-Deoxyuridine, 5-(5-vinylthien-2-yl)-2'-Deoxyuridine, and 5-(5-ethynylthien-2-yl)-2'- Deoxyuridine. 5-(5-Nitrothien-2-yl)-2'-Deoxyuridine was synthesized using ceric ammonium nitrate as reagent. 5-(Isoxazol-5-yl)-2'-Deoxyuridine was synthesized from 5-(3-oxopropyn-1-yl)-2'-Deoxyuridine. Finally, 5-(5-chlorothien-2-yl)-beta-D-arabinofuranosyluracil and 5-(5-bromothien-2-yl)-beta-D-arabinofuranosyluracil were obtained by halogenation of 5-thien-2-yl-beta-D-arabinofuranosyluracil. Introduction of an alkyl substituent in the 5-position of the thienyl group of 5-thien-2-yl-2'-Deoxyuridine or substitution of the 2-deoxyribofuranose ring by an arabinofuranose moiety gave decreased activity against HSV-1 and VZV replication when compared with the 5"-halogenated-5-thien-2-yl-2'-Deoxyuridines. 5-(5-Bromothien-2-yl)-2'-Deoxyuridine caused prompt healing of HSV-1 keratitis when administered as eye drops (0.2%) to rabbits.
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Synthesis and anti-herpes activity of 5-trifluorovinyl-2'-Deoxyuridine
Bioorganic & Medicinal Chemistry Letters, 1992Co-Authors: Piet Herdewijn, L. Kerremans, Robert Snoeck, Aerschot Arthur Van, E. Esmans, E. De ClercqAbstract:Abstract 5-Trifluorovinyl-2′-Deoxyuridine was synthesized from protected 5-iodo-2′-Deoxyuridine and tetrakis(perfluorovinyl)tin. The compound demonstrates significant activity against HSV-1 but activity against HSV-2.
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5-(5-Bromothien-2-yl)-2'-Deoxyuridine and 5-(5-chlorothien-2-yl)-2'-Deoxyuridine are equipotent to (E)-5-(2-bromovinyl)-2'-Deoxyuridine in the inhibition of herpes simplex virus type I replication.
Journal of medicinal chemistry, 1991Co-Authors: Piet Wigerinck, Robert Snoeck, E. De Clercq, Christophe Pannecouque, Paul Claes, Piet HerdewijnAbstract:2'-Deoxyuridines with a five-membered heterocyclic substituent in the 5-position were synthesized by palladium-catalyzed coupling reactions of 5-iodo-2'-Deoxyuridine with the activated heteroaromatics. Further modification of the compound with the 5-thien-2-yl substituent gave 5-(5-bromothien-2-yl)-2'-Deoxyuridine and 5-(5-chlorothienyl-2-yl)-2'-Deoxyuridine. Both compounds show potent and selective activity against herpes simplex virus type 1 and varicella-zoster virus.
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Synthesis and antiviral activity of 5-heteroaryl-substituted 2'-Deoxyuridines.
Journal of medicinal chemistry, 1991Co-Authors: Piet Wigerinck, Robert Snoeck, E. De Clercq, Paul Claes, Piet HerdewijnAbstract:The synthesis of 5-heteroaryl-substituted 2'-Deoxyuridines is described. The heteroaromatics were obtained from three different 5-substituted 2'-Deoxyuridines. Cycloaddition reaction of nitrile oxides on the 5-ethynyl derivative 1 gave the isoxazoles 4a-e. The thiazole derivatives 14a-c were obtained from the 5-thiocarboxamide 11, while 5-pyrrol-1-yl-2'-Deoxyuridine (17) could be synthesized directly from 5-amino-2'-Deoxyuridine. The compounds were evaluated for antiviral activity. Selective activity against herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) was noted for 5-(3-bromoisoxazol-5-yl)-2'-Deoxyuridine (4c). The compound was inactive against herpes simplex virus type 2, cytomegalovirus, and thymidine kinase (TK)-deficient mutants of HSV-1 and VZV, which indicates that, most likely, its antiviral activity depends on phosphorylation by the virus-specified TK.
Piet Wigerinck - One of the best experts on this subject based on the ideXlab platform.
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2′-Deoxyuridines with a 5-Heteroaromatic Substituent: Synthesis and Biological Evaluation
Antiviral Chemistry and Chemotherapy, 1995Co-Authors: Ingrid Luyten, Leonard I. Wiebe, Piet Wigerinck, Christophe Pannecouque, L. Jie, A. Van Aerschot, J. Rozenski, C. Hendrix, C. Wang, Jan BalzariniAbstract:A series of novel 2′-Deoxyuridines with a thienyl substituent in the 5-position were synthesized as potential anti-HSV-1 agents. The brominated derivatives (1d, 1e and 3b) were obtained via halogenation reactions of the protected 5-(thien-2-yl)-2′-Deoxyuridine and 5-(thien-3-yl)-2′-Deoxyuridine, respectively. The palladium-catalysed cross-coupling reaction with stannylated thiophene was used for the synthesis of (E)-5-(2-thienylvinyl)-2′-Deoxyuridine and 5-(5,2′-dithien-2-yl)-2′-Deoxyuridine. These compounds show moderate to good activity against herpes simplex virus type 1 (HSV-1) in the order of decreasing activity 1d>4>1e>3b∼5. Finally, two substituted 5-isoxazol derivatives of 2′-Deoxyuridine (6a and 6b) were obtained via a 1,3-dipolar cycloaddition of the protected 5-ethynyl-2′-Deoxyuridine. These new compounds demonstrated poor affinity for the virus-specific enzyme thymidine kinase.
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Synthesis and antiviral activity of 5-thien-2-yl-2'-Deoxyuridine analogues
Journal of medicinal chemistry, 1993Co-Authors: Piet Wigerinck, L. Kerremans, P. Claes, Robert Snoeck, Maudgal P, De Clercq E, Piet HerdewijnAbstract:A number of 5-heteroaromatic-substituted 2'-Deoxyuridines were synthesized from 5-iodo-2'-Deoxyuridine using tetraorganotin reagents and palladium complexes as catalyst. The palladium-catalyzed cross-coupling reaction between 5-iodo-2'-Deoxyuridine and stannylated heteroaromatics was optimized for the synthesis of the 5-thien-3-yl-2'-Deoxyuridine and 5-furan-3-yl-2'-Deoxyuridine. 5-(5-Iodothien-2-yl)-2'-Deoxyuridine was used as starting material for the synthesis of 5-(5-methylthien-2-yl)-2'-Deoxyuridine, 5-(5-vinylthien-2-yl)-2'-Deoxyuridine, and 5-(5-ethynylthien-2-yl)-2'- Deoxyuridine. 5-(5-Nitrothien-2-yl)-2'-Deoxyuridine was synthesized using ceric ammonium nitrate as reagent. 5-(Isoxazol-5-yl)-2'-Deoxyuridine was synthesized from 5-(3-oxopropyn-1-yl)-2'-Deoxyuridine. Finally, 5-(5-chlorothien-2-yl)-beta-D-arabinofuranosyluracil and 5-(5-bromothien-2-yl)-beta-D-arabinofuranosyluracil were obtained by halogenation of 5-thien-2-yl-beta-D-arabinofuranosyluracil. Introduction of an alkyl substituent in the 5-position of the thienyl group of 5-thien-2-yl-2'-Deoxyuridine or substitution of the 2-deoxyribofuranose ring by an arabinofuranose moiety gave decreased activity against HSV-1 and VZV replication when compared with the 5"-halogenated-5-thien-2-yl-2'-Deoxyuridines. 5-(5-Bromothien-2-yl)-2'-Deoxyuridine caused prompt healing of HSV-1 keratitis when administered as eye drops (0.2%) to rabbits.
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5-(5-Bromothien-2-yl)-2'-Deoxyuridine and 5-(5-chlorothien-2-yl)-2'-Deoxyuridine are equipotent to (E)-5-(2-bromovinyl)-2'-Deoxyuridine in the inhibition of herpes simplex virus type I replication.
Journal of medicinal chemistry, 1991Co-Authors: Piet Wigerinck, Robert Snoeck, E. De Clercq, Christophe Pannecouque, Paul Claes, Piet HerdewijnAbstract:2'-Deoxyuridines with a five-membered heterocyclic substituent in the 5-position were synthesized by palladium-catalyzed coupling reactions of 5-iodo-2'-Deoxyuridine with the activated heteroaromatics. Further modification of the compound with the 5-thien-2-yl substituent gave 5-(5-bromothien-2-yl)-2'-Deoxyuridine and 5-(5-chlorothienyl-2-yl)-2'-Deoxyuridine. Both compounds show potent and selective activity against herpes simplex virus type 1 and varicella-zoster virus.
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Synthesis and antiviral activity of 5-heteroaryl-substituted 2'-Deoxyuridines.
Journal of medicinal chemistry, 1991Co-Authors: Piet Wigerinck, Robert Snoeck, E. De Clercq, Paul Claes, Piet HerdewijnAbstract:The synthesis of 5-heteroaryl-substituted 2'-Deoxyuridines is described. The heteroaromatics were obtained from three different 5-substituted 2'-Deoxyuridines. Cycloaddition reaction of nitrile oxides on the 5-ethynyl derivative 1 gave the isoxazoles 4a-e. The thiazole derivatives 14a-c were obtained from the 5-thiocarboxamide 11, while 5-pyrrol-1-yl-2'-Deoxyuridine (17) could be synthesized directly from 5-amino-2'-Deoxyuridine. The compounds were evaluated for antiviral activity. Selective activity against herpes simplex virus type 1 (HSV-1) and varicella zoster virus (VZV) was noted for 5-(3-bromoisoxazol-5-yl)-2'-Deoxyuridine (4c). The compound was inactive against herpes simplex virus type 2, cytomegalovirus, and thymidine kinase (TK)-deficient mutants of HSV-1 and VZV, which indicates that, most likely, its antiviral activity depends on phosphorylation by the virus-specified TK.
Guillaume Sartori - One of the best experts on this subject based on the ideXlab platform.
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improved microwave assisted ligand free suzuki miyaura cross coupling of 5 iodo 2 Deoxyuridine in pure water
New Journal of Chemistry, 2013Co-Authors: Shawn Gallagherduval, Guillaume Sartori, G Herve, Gerald Enderlin, Christophe LenAbstract:A facile and efficient methodology for direct synthesis of 5-aryl-2′-Deoxyuridines was developed through ligand-free Suzuki–Miyaura cross-coupling reactions starting from totally deprotected 5-iodo-2′-Deoxyuridine and various boronic acids. Reactions were performed, in pure water, in the presence of very low loading of palladium either by classical thermal heating or with the assistance of microwave irradiation yielding 5-arylated uridine derivatives in moderate to good yields within short reaction times.
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new efficient approach for the ligand free suzuki miyaura reaction of 5 iodo 2 Deoxyuridine in water
Synthesis, 2013Co-Authors: Guillaume Sartori, G Herve, Gerald Enderlin, Christophe LenAbstract:A series of 5-aryl-2′-Deoxyuridines was prepared, using ligandless Suzuki–Miyaura cross-coupling reactions in neat water, starting from 5-iodo-2′-Deoxyuridine as totally deprotected starting material. This ligand-free process gave good to high isolated yields within short reaction times and with low loadings of palladium.