Abstract

New nucleoside and nucleotide analogues will be prepared and studied as antiviral and antitumor agents. These compounds will include (i) enantiomeric triphosphates and non-hydrolyzable triphosphates of methylenecyclopropanes, (ii) ethynyl methylenecyclopropanes, (iii) fluorinated analogues of gem-bis (hydroxymethyl)methylenecyclopropanes, (iv) tris-(hydroxymethy)methylenecyclopropanes and (v) cyclopropavir phosphonates, acyclic and cyclic. Antiviral activity will be investigated in the following viral assays: Human immunodeficiency virus (HIV), human and murine cytomegalovirus (HCMV and MCMV), herpes simplex virus type 1 and 2 (HSV-1 and HSV-2), human herpes virus 6 and 8 (HHV-6 and HHV-8) and hepatitis B virus (HBV). In vivo activity and mechanism of action of active analogues will also be studied. Selected compounds will also be tested for antitumor activity

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA032779-24
Application #
7227496
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Lees, Robert G
Project Start
1984-07-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
24
Fiscal Year
2007
Total Cost
$193,288
Indirect Cost

  Institution

Name
Wayne State University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202

  Publications

Chen, Han; Li, Chengwei; Zemlicka, Jiri et al. (2016) Potency and Stereoselectivity of Cyclopropavir Triphosphate Action on Human Cytomegalovirus DNA Polymerase. Antimicrob Agents Chemother 60:4176-82
Gentry, Brian G; Vollmer, Laura E; Hall, Ellie D et al. (2013) Resistance of human cytomegalovirus to cyclopropavir maps to a base pair deletion in the open reading frame of UL97. Antimicrob Agents Chemother 57:4343-8
Gentry, Brian G; Gentry, Sara N; Jackson, Trachette L et al. (2011) Phosphorylation of antiviral and endogenous nucleotides to di- and triphosphates by guanosine monophosphate kinase. Biochem Pharmacol 81:43-9
Gentry, Brian G; Kamil, Jeremy P; Coen, Donald M et al. (2010) Stereoselective phosphorylation of cyclopropavir by pUL97 and competitive inhibition by maribavir. Antimicrob Agents Chemother 54:3093-8
Li, Chengwei; Gentry, Brian G; Drach, John C et al. (2009) Synthesis and enantioselectivity of cyclopropavir phosphates for cellular GMP kinase. Nucleosides Nucleotides Nucleic Acids 28:795-808
Zhou, Shaoman; Drach, John C; Prichard, Mark N et al. (2009) (Z)- and (E)-2-(1,2-dihydroxyethyl)methylenecyclopropane analogues of 2'-deoxyadenosine and 2'-deoxyguanosine. Synthesis of all stereoisomers, absolute configuration, and antiviral activity. J Med Chem 52:3397-407
Wu, Zhimeng; Drach, John C; Prichard, Mark N et al. (2009) L-valine ester of cyclopropavir: a new antiviral prodrug. Antivir Chem Chemother 20:37-46
Mhaske, Santosh B; Ksebati, Bashar; Prichard, Mark N et al. (2009) Phosphonate analogues of cyclopropavir phosphates and their E-isomers. Synthesis and antiviral activity. Bioorg Med Chem 17:3892-9
Wu, Zhimeng; Zhou, Shaoman; Zemlicka, Jiri (2009) Stereoselective approach to the Z-isomers of methylenecyclopropane analogues of nucleosides: a new synthesis of antiviral synguanol. Nucleosides Nucleotides Nucleic Acids 28:165-74
Li, Chengwei; Prichard, Mark N; Korba, Brent E et al. (2008) Fluorinated methylenecyclopropane analogues of nucleosides. Synthesis and antiviral activity of (Z)- and (E)-9-{[(2-fluoromethyl-2-hydroxymethyl)-cyclopropylidene]methyl}adenine and -guanine. Bioorg Med Chem 16:2148-55

Showing the most recent 10 out of 55 publications