Abstract

Novel nucleoside analogs will be prepared and studied as potential antitumor and antiviral agents. These compounds will include: (i) """"""""Hydroxycarbocyclic"""""""" analogs of adenosine and cytidine, (ii) Hydroxycarbocyclic analogs of antitumor and antiviral agents araC [Cytarabine, 1-(Beta-D-arabinofuranosyl)cytosine] and araA [Vidarabine, 9-(Beta-D-arabinofuranosyl)-adenine] related to the neplanocin group of antitumor nucleoside antibiotics, and (iii) neplanocin A (NPC-A) and the corresponding cytidine analog. All compounds will be obtained by chemical synthesis using anti-7-tert-butoxy-5-norbornene-exo-cis-2,3-diol as a key common intermediate. Antitumor activity and mechanism of action of NPC-A and synthetic analogs will be studied in vitro and in vivo in murine leukemia L1210, P388, and sixteen solid tumor systems. Particular attention will be paid to (i) inhibition of macromolecular synthesis, (ii) reversal studies with specific metabolites, (iii) alterations in nucleotide pool sizes, and (iv) effects on RNA maturation. Antiviral activity of the nucleoside analogs will also be investigated.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA032779-03
Application #
3170634
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1984-07-01
Project End
1987-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
3
Fiscal Year
1986
Total Cost
Indirect Cost

  Institution

Name
Barbara Ann Karmanos Cancer Institute
Department
Type
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48201

  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