Collect. Czech. Chem. Commun. 2006, 71, 1063-1087

Synthesis and Biological Evaluation of Some 4'-C-(Hydroxymethyl)-α- and -β-D-Arabinofuranosyl Pyrimidine and Adenine Nucleosides

Jean-François Griffona, Sue C. Shaddixa, William B. Parkera, Ashraf S. Al-Madhounb, Staffan Erikssonc, John A. Montgomerya and John A. Secrist IIIa,*

a Southern Research Institute, P.O. Box 55305, Birmingham, AL 35255-5305, U.S.A.
b Department of Biochemistry, Microbiology and Immunology, University of Ottawa, 451 Smyth Street, Ottawa, Ontario, Canada
c Department of Molecular Biosciences, Swedish University of Agricultural Sciences, The Biomedical Centre, SE 753 24 Uppsala, Sweden


A series of 4'-C-(hydroxymethyl) analogs of pyrimidine and purine nucleosides have been prepared utilizing standard methodologies, and the α and β anomers were separated. These analogs are part of our continuing efforts to identify new anticancer drugs as well as to explore the substrate specificities of these analogs with the initial activating enzymes in the metabolic pathway leading to nucleoside triphosphates. Although not cytotoxic to CCRF-CEM cells (an acute lymphoblastic leukemia of T-cell origin), many of these compounds were utilized as substrates for the various human nucleoside kinases, including deoxycytidine kinase, thymidine kinase 1, and thymidine kinase 2. Because the 4'-C-(hydroxymethyl) analog of arabinofuranosyl cytosine was identified as a good substrate with deoxycytidine kinase, its metabolism in CEM cells was evaluated. These results indicated that nucleosides with this modification could be activated in human cells without cytotoxicity, which suggested that they should be examined for antiviral activity.

Keywords: 4'-C-(Hydroxymethyl)nucleosides; 4'-C-Branched nucleosides; Deoxycytidine kinase; Cytotoxicity; Phosphorylation; Glycosidation; Pyrimidines; Purines.

References: 43 live references.