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the hydroxyl group. On the other hand, the 30-hydroxy
analogue of the cis guanine derivative (6a), displayed a
dramatic 100-fold increase in activity compared to 1a.
The fluoro analogues showed an interesting activity
profile; the 30S isomer (14a) was inactive whereas the
30R isomer (17a) displayed a slight enhancement in
activity in comparison. The bis-hydroxylated (20a)
exhibited no antiproliferative activity indicating that
substitution on the 20-position may not be tolerated. By
methylating the 30-position of (as in 10a), one is still able
to retain biological activity. Diaminopurines 23b and
22a also retained activity of guanine analogues 1b and
6a, whereas the N6-cyclopropyldiaminopurine analogues
24a and 25b were inactive. These results suggest that the
N6-cyclopropyldiaminopurines are not converted to the
guanine derivatives.
2. Compton, M. L.; Toole, J. J.; Paborsky, L. R. Biochem.
Pharm. 1999, 58, 709.
3. Nguyen-Ba, P.; Turcotte, N.; Yuen, L.; Bedard, J.; Quim-
pere, M.; Chan, L. Bioorg. Med. Chem. Lett. 1998, 8, 3561.
4. Bedard, J.; May, S.; Lis, M.; Tryphonas, L; Drach, J.;
Huffman, J.; Sidwell, R.; Chan, L.; Bowlin, T.; Rando, R.
Antimicrob. Agents. Chemother. 1999, 43, 557.
5. Leblond, L.; Attardo, G.; Hamelin, B.; Bouffard, D. Y.;
Nguyen-Ba, N.; Goudreau, H. Mol. Cancer Ther. 2002, 1, 737.
6. Krecmerova, M.; Hrebabecky, H.; Masojidkova, M.; Holy,
A. Collect. Czech. Chem. Commun. 1996, 61, 478.
7. All attempts to assign the relative stereochemistry using NOE
experiments failed since adequate separation of the relevant
proton signals of various intermediates could not be achieved.
We assigned the major isomer, 4a, as having the cis configuration
since we believe the approach of the large phosphite would be
opposite to the bulky TBDMS group. Under identical Arbuzov
reaction conditions, no stereochemical bias was observed with
compounds lacking 30-substituants, such as 1a and 1b.
8. Yu, K. L.; Bronson, J. J.; Yang, H.; Patrick, A.; Alam, M.;
Brankovan, V.; Datema, R.; Hitchcock, M. J. M.; Martin,
J. C. J. Med. Chem. 1992, 35, 2958.
We have identified several potent phosphonate nucleo-
tides in vitro. The in vivo efficacy and the mechanism of
action of these compounds are currently being examined
and will be presented in due course.5
9. McKenna, C. E.; Schmidhauser, J. J. Chem. Commun. 1979,
739.
10. Mikhailopulo, I. A.; Sivets, G. G. Synlett 1996, 173.
11. The stereochemistry of 14a and 17a was assigned based on
a comparison of J(C4,F) values of the precursors with those of
structurally similar compounds reported in the literature: (a)
Mikhailopulo, I. A.; Sivets, G. G. Helvetica Chimica Acta
1999, 82, 2052. (b) Fleet, G. W. J.; Son, J. C. Tetrahedron Lett.
1987, 28, 3615.
Acknowledgements
The authors would like to thank Therese Godbout for
her help in the preparation of this manuscript.
12. Sasaki, S.; Nakashima, S.; Nagatsugi, F.; Tanaka, Y.;
Hisatome, M.; Maeda, M. Tetrahedron. Lett. 1995, 36, 9521.
13. Humber, D. C.; Jones, M. F.; Payne, J. J.; Ramsay,
M. V. J.; Zacharie, B.; Jin, H.; Siddiqui, A.; Evans, C. A.; Tse,
A.; Mansour, T. S. Tetrahedron Lett. 1992, 33, 4625.
14. All cell lines were adapted in RPMI culture media. The
cells are treated for 72h at 37 ꢀC and 5% CO2 with the drugs.
Methyl H-thymidine (0.5 mCi) is added for the last 16 h. The
cells were harvested on a fiber glass filter mat and counted on
a Beta counter.
References and Notes
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Otova, B. Anticancer Res. 2001, 21, 2057. (b) Pisarev, V. M.;
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