614
C. Kurata et al. / Bioorg. Med. Chem. Lett. 16 (2006) 607–614
6. Cheruvallath, Z. S.; Carty, R. L.; Moore, M. N.; Capaldi,
D. C.; Krotz, A. H.; Cole, D. L.; Ravikumar, V. T. Org.
Process Res. Dev. 2000, 4, 199.
7. Capaldi, D. C.; Scozzari, A. N.; Cole, D. C.; Ravikumar,
V. T. Org. Process Res. Dev. 1999, 3, 485.
8. Krotz, A. H.; Cole, D. L.; Ravikumar, V. T. Bioorg. Med.
Chem. 1999, 7, 435.
9. Andrade, M.; Scozzari, A. N.; Cole, D. L.; Ravikumar, V.
T. Nucleosides Nucleotides 1997, 16, 1617.
10. Capaldi, D. C.; Gaus, H.; Krotz, A. H.; Arnold, J.; Carty,
R. L.; Moore, M. N.; Scozzari, A. N.; Lowery, K.; Cole,
D. L.; Ravikumar, V. T. Org. Process Res. Dev. 2003, 7,
832.
11. Krotz, A. H.; McElroy, B.; Scozzari, A. N.; Cole, D. L.;
Ravikumar, V. T. Org. Process Res. Dev. 2003, 7, 47.
12. Krotz, A. H.; Cole, D. L.; Ravikumar, V. T. Nucleosides
Nucleotides Nucleic Acids 2003, 22, 129.
20. Of the depurinated products of ISIS 3521, the 30-terminally-
located lesion is likely the most abundant because (a) the 30-
terminal 20-deoxyadenosine residue is exposed to the
detritylation conditions for every cycle of the synthesis
and (b) a 30-terminal lesion is more stable toward ammo-
nium hydroxide treatment than an internal lesion.
21. See Supplementary data for the synthesis of PS-d(CA),
supports 3 and 4, and trimers 5 and 6.
22. 1H NMR [(CD3)2SO containing D2O] d 8.68 and 8.64 (1H
total, s), 8.39 (1H, s), 7.87 and 7.75 (2H, m) 6.46–6.42 (1H,
m), 6.20–6.15 (2H, m), 5.82–5.76 (2H, m), 5.12–4.99 (1H,
m), 4.87–4.74 (1H, m), 4.55–4.45 (1H, m), 4.19–3.83 (5H,
m), ca. 3.67–3.43 (m, partially obscured by HOD), 2.82–
2.68 (1H, m), 2.47–2.19 (3H, m), 2.09–1.86 (2H, m) 31P
NMR [(CD3)2SO] d 53.86, 53.37, 43.88, 43.58 HRMS
[MH]+ Calcd for C28H37N11O13P2S2: 862.1562. Found:
862.1562.
13. ISIS 3521 is an antisense inhibitor of PKC-a, a protein
important for the growth of human cancers.
23. See Supplementary data for the synthesis of oligonucleo-
tide 1.
14. See Supplementary data for HPLC–UV and MS
conditions.
24. The reaction of phosphoramidites with the exocyclic
amino groups of adenine and cytosine residues has been
described previously. For example, (a) Gryaznov, S. M.;
Letsinger, R. L. J. Am. Chem. Soc. 1991, 113, 5876; (b)
Wada, T.; Moriguchi, T.; Sekine, M. J. Am. Chem. Soc.
1994, 116, 9901; (c) Hayakawa, Y.; Katoaka, M. J. Am.
Chem. Soc. 1998, 120, 12395; (d) Sekine, M.; Akihiro, O.;
Kohji, S. J. Org. Chem. 2003, 68, 5478.
15. (a) Capaldi, D. C.; Gaus, H. J.; Carty, R. L.; Moore, M.
N.; Turney, B. J.; Decottignies, S. D.; McArdle, J. V.;
Scozzari, A. N.; Ravikumar, V. T.; Krotz, A. H. Bioorg.
Med. Chem. Lett. 2004, 14, 4683; (b) Gaus, H.; Olsen, P.;
Van Sooy, K.; Rentel, C.; Turney, B.; Walker, K.;
McArdle, J. V.; Capaldi, D. C. Bioorg. Med. Chem. Lett.
2005, 15, 4118; (c) Rentel, C.; Wang, X.; Batt, M.; Kurata,
C.; Oliver, J.; Gaus, H.; Krotz, A. H.; McArdle, J. V.;
Capaldi, D. C. J. Org. Chem. 2005, 70, 7841.
16. Most abundant masses were calculated using the Peptide
Tools option located within AgilentÕs ChemStationꢀ
software package (Agilent Technologies, 1990–2001).
17. (a) McLuckey, S. A.; Habibi-Goudarzi, S. J. Am. Chem.
Soc. 1993, 115, 12085; (b) Gut, I. V. Int. J. Mass Spectrom.
Ion Processes 1997, 313.
18. (a) Freese, E.; Cashel, M. Biochim. Biophys. Acta 1964, 91,
67; (b) Burnotte, J.; Verly, W. G. Biochim. Biophys. Acta
1972, 262, 449; (c) Goffin, C.; Bricteux-Gregoire, S.; Verly,
W. G. Biochim. Biophys. Acta 1984, 783, 1; (d) Prakash, A.
S.; Gibson, N. W. Carcinogenesis 1992, 13, 425.
19. Sugiyama, H.; Fujiwara, T.; Ura, A.; Tashiro, T.;
Yamamoto, K.; Kawanishi, S.; Saito, I. Chem. Res.
Toxicol. 1994, 7, 673.
25. Scozzari, A., N. Presented at TIDESꢁ, Boston, MA, May
2005.
26. ISIS 113715 is a chimeric, 20-deoxy and 20-(2-methoxy-
ethyl)ribose, second-generation antisense inhibitor of
protein tyrosine phosphatase 1-B (PTB-1B) that is being
evaluated for the treatment of type 2 diabetes mellitus
Zinker, B. A.; Rondinone, C. M.; Trevillyan, J. M.; Gum,
R. J.; Clampit, J. E.; Waring, J. F.; Xie, N.; Wilcox, D.;
Jacobson, P.; Frost, L.; Kroeger, P. E.; Reilly, R. M.;
Koterski, S.; Opgenorth, T. J.; Ulrich, R. G.; Crosby, S.;
Butler, M.; Murray, S. F.; McKay, R. A.; Bhanot, S.;
Monia, B. P.; Jirousek, M. R. PNAS 2002, 99, 11357.
27. t1/2s in concentrated ammonium hydroxide at 20 ꢂC for
N6-benzoyl-20-deoxyadenosine and N4-benzoyl-20-deoxy-
cytidine are reported to be 8 and 2 h, respectively,
Schulhof, J. C.; Molko, D.; Teoule, R. Nucleic Acids
Res. 1987, 15, 397.