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Synthesis, Cytotoxicity and Metabolism of the 2′,2′-Difluoro-Analogs of Deoxyadenosine (dFdA)and Deoxyguanosine (dFdG)

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Pages 951-955 | Published online: 24 Oct 2006

References

  • Hertel , L. W. , Kroin , J. S. , Misner , J. W. and Tustin , J. M. 1988 . J. of Org. Chem. , 53 : 2406
  • Szarek , W. A. , Depew , C. , Jarrell , H. C. and Jones , J. K. N. 1975 . J. C. S. Chem. Comm. , : 648 For review of Mitsunobu chemistry see: Mltsunobu O., Synthesis. 1981,1
  • dFdA: 1H NMR (CD3OD, 300mHz)<, α3.80–4.10 (m, 4H, H-3′,4′, & 5′), 6.33 (dd. 1, H-1′1, 8.22 (s. 1. H-2), 8.40 (s, 1, H-8). MS m/z 287. UU .max,nm[10%MeOH/H2O], 259
  • Montgomery , J. A. , Shortnacy , A. T. , Carson , D. A. and Secrist , J. A. III . 1986 . J. Med. Chem. , 29 : 2389
  • dFdG: 1H NMR (Me2SO-d6,300mHz) α 3.65 (m, 2, 5′-CH2), 3.85 (m, 1, H- 4′), 4.39 (m, 1, H-3′1, 5.19 (apparent t, 1, 5′-OH), 5.98 (dd, 1. H-1′), 6.28 (d, 1, 3′-OH), 6.55 (bs, 2, 2-NH2), 7.90 (s, 1, H-8). MS, m/z 303. UU max, nm(EX 10–3)[pH 7] 273 (sh), 252 (8.36)
  • Secrist , J. A. III , Montgomery , J. A. , Shealy , Y. F. , O'Dell , C. R. and Clayton , S. J. 1987 . J. Med. Chem. , 30 : 746 Resolution of racemic carbocylic nucleosldes
  • Determined by 3H-thymidine/uridine Incorporation studies
  • CEM were maintained in exponential growth in RPMI-1640 medium supplemented with 5% heat inactivated fetal bouine serum. To inhibit adenosine deaminase activity, cells were incubated with deohycoformycin (1 μM) for 30 min prior to the addition of dFdR. After a 2-hr incubation with the indicated concentrations of dFdR, cells were either prepared for clonogenicity assays or nucleotide pools were analyzed. For cloning studies, cells were washed twice and diluted in pre-warmed fresh medium, and portions of the cell suspension estimated to contain between 50 to 200 colony forming units were plated in medium containing 0.26% agar. After 7 to 10 days, colonies of greater than 50 cells were counted with the aid of a dissecting microscope. A separate portion of the culture incubated with dFdR was washed and cellular nucleotides were extracted with HC104. Following neutralization, dFdRTP was quantitated after separation from normal nucleotides by anion-exchange HPLC.

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