Abstract

Novel nucleoside analogous will be prepared and studied as potential antitumor and antiviral agents. These compounds will include: (i) """"""""Hydroxycarbocyclic"""""""" analogous of cytidine, 3- deazaadenosine, vidarabine and cytarabine, (ii) unsaturated carbocyclic nucleoside analogues related to neplanocin A including L-homocysteinylneplanocin A, (iii) phosphonate derivatives of open- chain unsaturated nucleoside analogues and (iv) analogues of adenosine deaminase inhibitor EHNA. All compounds will be obtained by chemical synthesis. Analogues (i) and (ii) will be obtained either in racemic form or optically pure by a new chemico-enzymatic approach. Antitumor activity and mechanism of action of the active analogues will be studied in vitro and in vivo in murine leukemia L 1210, 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 obtained analogues will also be investigated. Suitable analogues will be studied as substrates (inhibitors) of adenosine deaminase and adenosine homocysteine hydrolase.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA032779-06
Application #
3170636
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1984-07-01
Project End
1990-12-31
Budget Start
1990-02-25
Budget End
1990-12-31
Support Year
6
Fiscal Year
1990
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