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¹H NMR conformational study of antiherpetic C5-substituted 2′-deoxyuridines:: Insight into the nature of structure-activity relationships

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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 2000年第1期272卷 64-74页

作者： Poznanski, J Felczak, K Kulikowski, T Remin, M Univ Warsaw Dept Phys Inst Expt Phys Div Biophys PL-02089 Warsaw Poland Polish Acad Sci Inst Biochem & Biophys PL-02106 Warsaw Poland

H-1 NMR study and conformational analysis of a broad series of biologically important CB-substituted 2'-deoxyuridines, including alkyl, halogen, vinyl, hydroxymethyl, and hydroxy derivatives as well as nitro, formyl, trifluoromethyl, and dimethylamino substituents, is presented. A thorough analysis of chemical shifts in correlation with CB-substituent electronegativity as well as calculations by SCF semi-empirical method of the formal charge localized on C6 carbon is discussed in terms of charge distribution for electron attracting and electron donating groups. Conformation of the sugar ring is determined from proton-proton coupling constants and described in terms of pseudorotation between two main puckering domains C2'endo (S) and C3'endo (N). Generally, electron donating groups destabilise the N conformation, simultaneously decreasing the mean pseudorotation amplitude. Absolute assignments of the H5' and H5" methylene protons in H-1 NMR spectra permitted the unequivocal determination of molar fractions of the three classical exocyclic C4'-C5' rotamers gauche(+), trans, and gauche(-), and correlation of them with the sugar ring puckering domains. Conformation about the glycosidic bond is described in terms of equilibrium between two conformational regions, anti and syn. Finally, the role of the CB-substituent in the creation of cytotoxic activity is considered on the basis of a simplified model assuming that compound activity is a function of substituent polar surface, its molecular volume, and its molecule polarity defined at the relative partition of the polar atoms. (C) 2000 Academic Press.

关键词：抗病毒药/化学抗病毒药/药理学细胞存活/药物作用细胞培养的脱氧尿苷/类似物和衍生物脱氧尿苷/化学脱氧尿苷/药理学电化学疱疹病毒科/药物作用磁共振波谱学分子构象立体异构现象构效关系动物兔

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Structure-activity relationships of (E)-5-(2-bromovinyl) uracil and related pyrimidine nucleosides as antiviral agents for herpes viruses

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JOURNAL OF MEDICINAL CHEMISTRY 2000年第13期43卷 2538-2546页

作者： Choi, Y Li, L Grill, S Gullen, E Lee, CS Gumina, G Tsujii, E Cheng, YC Chu, CK Univ Georgia Coll Pharm Dept Pharmaceut & Biomed Sci Athens GA 30602 USA Yale Univ Sch Med Dept Pharmacol New Haven CT 06510 USA

A series of (E)-5-(2-bromovinyl)uracil analogues and related nucleosides was synthesized, and their antiviral activities were evaluated. (E)-5-(2-Bromovinyl)-2'-deoxy-L-uridine (L-BVDU, 2), 1-(beta-L-arabinofuranosyl)-(E)-5-(2-bromovinyl)uracil (L-BVAU, 4), (E)-5-(2-bromovinyl)-1-(2-deoxy-2-fluoro-beta-L-ribofuranosyl)uracil (L-FBVRU, 8) and (E)-5-(2-bromovinyl)-1-(2-deoxy-2-fluoro-beta-L-arabinofuranosyl)uracil (L-FBVAU, 10) were synthesized via appropriate 5-iodouracil analogues from L-arabinose. D- and L-Oxathiolane and -dioxolane derivatives 13, 16, 20, 21, and 29-34 were prepared by glycosylation reaction of the oxathiolane and dioxolane intermediates with silylated uracil analogues using TMSI as the coupling agent. The synthesized compounds were evaluated in cell cultures infected with the following viruses: varicella tester virus (VZV), Epstein Barr virus (EBV), and herpes simplex virus types 1 and 2 (HSV-1 and HSV-8). Among the tested compounds, beta-L-CV-OddU (29), beta-L-BV-OddU (31), and beta-L-IV-OddU (33) exhibited potent in vitro antiviral activity against VZV with EC50 values of 0.15, 0.07, and 0.035 mu M, respectively, and against EBV with EC50 values of 0.49, 0.59, and 3.91 mu M, respectively.

关键词：抗病毒药/化学合成抗病毒药/化学抗病毒药/药理学细胞分裂/药物作用细胞系二恶茂烷类/化学合成二恶茂烷类/化学二恶茂烷类/药理学疱疹病毒科/药物作用疱疹病毒1型人/药物作用疱疹病毒2型人/药物作用疱疹病毒3型人/药物作用疱疹病毒4型人/药物作用嘧啶核苷类/化学合成嘧啶核苷类/化学嘧啶核苷类/药理学构效关系尿嘧啶/类似物和衍生物尿嘧啶/化学合成尿嘧啶/化学尿嘧啶/药理学乙烯化合物/化学合成乙烯化合物/化学乙烯化合物/药理学人类

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Anti-herpesvirus activity of (1′S,2′R)-9-[[1′,2′-bis(hydroxymethyl)-cycloprop-1′-yl]methyl] x guanine (A-5021) in vitro and in vivo

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ANTIVIRAL RESEARCH 2001年第2期49卷 115-120页

作者： Neyts, J Naesens, L Ying, CX De Bolle, L De Clercq, E Katholieke Univ Leuven Rega Inst Med Res B-3000 Louvain Belgium

The novel nucleoside analog (1S ' ,2R ')-9-[[1 ' ,2 '- bis(hydroxymethyl)cycloprop-1-yl]methyl]guanine (A-5021) was previously shown to be a potent inhibitor of the replication of herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) and varicella tester virus (VZV), both in vitro and in vivo (J. Med. Chem. 41, 1284-1298;Antimicrob. Agents Chemother. 42, 1666-1670). Here we demonstrate that A-5021 is also a potent inhibitor of Epstein-Barr virus (EBV) and human herpes virus 6 (HHV-6A and HHV-6B), but that the compound lacks activity against HHV-8. A-5021, in comparison to acyclovir, was also assessed for protective activity against HSV-l-induced mortality in SCID mice. The compounds were administered at 50 mg/kg per day by subcutaneous injection for four consecutive days and treatment was initiated at either 2 h, 1 or 2 days post infection (p.i.). When administered from day 0 to 4 p.i., A-5021 conferred complete protection against the infection las assessed at 22 days p.i.), whereas acyclovir delayed virus induced mortality by only 5 days. When treatment was begun on day 1 or 2, A-5021 still afforded marked protection against the infection, whereas acyclovir was virtually devoid of any activity under these conditions. Our data underline that A-5021 may offer great promise for the treatment of herpesvirus infections. (C) 2001 Elsevier Science B.V. All rights reserved.

关键词：阿昔洛韦/药理学抗病毒药/药理学抗病毒药/治疗应用细胞系鸟嘌呤/类似物和衍生物鸟嘌呤/药理学鸟嘌呤/治疗应用疱疹单纯/药物疗法疱疹单纯/病毒学疱疹病毒科/药物作用疱疹病毒科感染/病毒学疱疹病毒1型人/药物作用小鼠 SCID 动物人类小鼠

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3′-(N-hydroxyimino)-2′,3-dideoxynucleosides and their derivatives:: Synthesis, broad spectrum antiviral properties and synthetical application for the preparation of other nucleoside analogues

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NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS 1999年第4-5期18卷 633-634页

作者： Fedorov, I Kazmina, E Jasko, M Balzarini, J De Clercq, E Sommadossi, JP Imbach, JL Gosselin, G Moscow Med Sechenov Acad Moscow Russia Katholieke Univ Leuven Rega Inst Med Res B-3000 Louvain Belgium Univ Alabama Dept Pharmacol Birmingham AL 35294 USA Univ Montpellier 2 Chim Bioorgan Lab UMR CNRS USTL 5625 F-34095 Montpellier 5 France

A series of 3'-(N-hydroxyimino)-2',3'-dideoxynucleosides bearing different nucleic bases has been prepared. In vitro antiviral activity studies showed that among these compounds the thymine derivative possesses significant activity against HIV, HSV, EBV and HBV. Conveniently 5'-protected 3'-(N-hydroxyimino)-2',3'-dideoxythymidine was further used as a synthon for the preparation of other nucleoside analogues.