Abstract

Selected 6-amino- and 2-amino-6-substituted purine Z- methylenecyclopropane nucleoside analogues (mostly S-enantiomers) will be prepared for biological evaluation as potential drugs against human cytomegalovirus (HCMV). New 2,6-disubstituted purine methylenecyclopropanes will be synthesized for studies of structure- activity relationships. Several types of prodrugs of enantiomeric Z- methylenecyclopropane analogues will also be prepared for a detailed in vitro and in vivo evaluation. The major aim of the project is to provide multigram quantities of analogues in enantiopure form (lipophilic phosphate prodrugs as two diastereoisomers each) to permit (i) their evaluation in vitro against wild type and mutated forms of cytomegalovirus (CMV), (ii) in vivo studies in animals infected with CMV, (iii) investigation of cross-resistance with current drugs and (iv) studies of mechanism of action of these analogues. These studies are relevant for preclinical development of methylenecyclopropane analogues of nucleosides as anti-HCMV drugs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI046390-02
Application #
6344679
Study Section
Special Emphasis Panel (ZAI1)
Project Start
2000-09-30
Project End
2001-09-29
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
$187,308
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Type
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

Chien, Tun-Cheng; Drach, John C; Townsend, Leroy B (2008) Design and synthesis of 1-(beta-D-ribofuranosyl)imidazo[4,5-c]pyrazoles as 5:5 bicyclic analogs of purine nucleosides. Nucleic Acids Symp Ser (Oxf) :593-4
Zhou, Shaoman; Zemlicka, Jiri; Kern, Earl R et al. (2007) Fluoroanalogues of anti-cytomegalovirus agent cyclopropavir: synthesis and antiviral activity of (E)- and (Z)-9-{[2,2-bis(hydroxymethyl)-3-fluorocyclopropylidene]methyl}-adenines and guanines. Nucleosides Nucleotides Nucleic Acids 26:231-43
Qin, Xinrong; Chen, Xinchao; Wang, Kun et al. (2006) Synthesis, antiviral, and antitumor activity of 2-substituted purine methylenecyclopropane analogues of nucleosides. Bioorg Med Chem 14:1247-54
Zhou, Shaoman; Kern, Earl R; Gullen, Elizabeth et al. (2006) 9-{[3-fluoro-2-(hydroxymethyl)cyclopropylidene]methyl}adenines and -guanines. Synthesis and antiviral activity of all stereoisomers1. J Med Chem 49:6120-8
Lorenzi, Philip L; Landowski, Christopher P; Brancale, Andrea et al. (2006) N-methylpurine DNA glycosylase and 8-oxoguanine dna glycosylase metabolize the antiviral nucleoside 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole. Drug Metab Dispos 34:1070-7
Ambrose, Amalraj; Zemlicka, Jiri; Kern, Earl R et al. (2005) Phosphoralaninate pronucleotides of pyrimidine methylenecyclopropane analogues of nucleosides: synthesis and antiviral activity. Nucleosides Nucleotides Nucleic Acids 24:1763-74
Yan, Zhaohua; Kern, Earl R; Gullen, Elizabeth et al. (2005) Nucleotides and pronucleotides of 2,2-bis(hydroxymethyl)methylenecyclopropane analogues of purine nucleosides: synthesis and antiviral activity. J Med Chem 48:91-9
Kern, Earl R; Kushner, Nicole L; Hartline, Caroll B et al. (2005) In vitro activity and mechanism of action of methylenecyclopropane analogs of nucleosides against herpesvirus replication. Antimicrob Agents Chemother 49:1039-45
Chien, Tun-Cheng; Berry, David A; Drach, John C et al. (2005) Synthesis of 3-aminoimidazo[4,5-c]pyrazole nucleoside via the N-N bond formation strategy as a [5:5] fused analog of adenosine. Nucleosides Nucleotides Nucleic Acids 24:1971-96
Lorenzi, Philip L; Landowski, Christopher P; Song, Xueqin et al. (2005) Amino acid ester prodrugs of 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole enhance metabolic stability in vitro and in vivo. J Pharmacol Exp Ther 314:883-90

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