Solid-Phase Synthesis of Phosphorothioate Oligonucleotides
1299
16. Tang, J.Y.; Han, Y.; Tang, J.X.; Zhang, Z. Large-scale synthesis of oligonucleotide phosphorothioates using
3-amino-1,2,4-dithiazole-5-thione as an efficient sulfur-transfer reagent. Org. Process Res. Dev. 2000, 4,
194–198.
17. Rao, M.V.; Macfarlane, K. Solid phase synthesis of phosphorothioateoligonucleotides using benzyltriethy-
lammonium tetrathiomolybdate as a rapid sulfur transfer reagent. Tetrahedron Lett. 1994, 35, 6741–6744.
18. Ju, J.; McKenna, C.E. Synthesis of oligodeoxyribonucleoside phosphorothioates using Lawesson’s reagent for
the sulfur transfer step. Bioorg. Med. Chem. Lett. 2002, 12, 1643–1645.
19. Kamer, P.C.J.; Roelen, H.C.P.F.; van den Elst, H.; van der Marel, G.A.; van Boom, J.H. An efficient approach
toward the synthesis of phosphorothioate diesters via the Scho¨nberg reaction. Tetrahedron Lett. 1989, 30,
6757–6760.
20. Roelen, H.C.P.F.; Kamer, P.C.J.; van den Elst, H.; van der Marel, G.A.; van Boom, J.H. A study on the use of
phenylacetyl disulfide in the solid-phase synthesis of oligodeoxynucleoside phosphorothioates. Recl. Trav.
Chim. Pays-Bas 1991, 110, 325–331.
21. Cheruvallath, Z.S.; Kumar, R.K.; Rentel, C.; Cole, D.L.; Ravikumar, V.T. Solid phase synthesis of
phosphorothioate oligonucleotides utilizing diethyldithiocarbonate disulfide (DDD) as an efficient sulfur
transfer reagent. Nucleosides Nucleotides Nucleic Acids 2003, 22, 461–468.
22. Cheruvallath, Z.S.; Carty, R.L.; Moore, M.N.; Capaldi, D.C.; Krotz, A.H.; Wheeler, P.D.; Turney, B.J.; Craig,
S.R.; Gaus, H.J.; Scozzari, A.N.; Cole, D.L.; Ravikumar, V.T. Synthesis of antisense oligonucleotides:
replacement of 3H-1,2-benzodithiol-3-one 1,1-dioxide (Beaucage reagent) with phenylacetyl disulfide (PADS)
as efficient sulfurization reagent: from bench to bulk manufacture of active pharmaceutical ingredient. Org.
Process Res. Dev. 2000, 4, 199–204.
23. Cheruvallath, Z.S.; Wheeler, P.D.; Cole, D.L.; Ravikumar, V.T. Use of phenylacetyl disulfide (PADS) in the
synthesis of oligodeoxyribonucleotide phosphorothioates. Nucleosides Nucleotides 1999, 18(3), 485–492.
24. Song, Q.; Wang, Z.; Sanghvi, Y.S. A short, novel, and cheaper procedure for oligonucleotide synthesis using
automated solid phase synthesis. Nucleosides Nucleotides Nucleic Acids 2003, 22(5–8), 629–633.
25. Krotz, A.H.; Gorman, D.; Mataruse, P.; Foster, C.; Godbout, J.D.; Coffin, C.C.; Scozzari, A.N.
Phosphorothioate oligonucleotides with low phosphate diester content: greater than 99.9% sulfurization
efficiency with ‘‘aged’’ solutions of phenylacetyl disulfide (PADS). Org. Process Res. Dev. 2004, 8, 852–858.
26. Robert, J.; Anouti, M.; Paris, J. Formation of acyldisulfide ions from the reaction of sulfur with thiocarboxylate
ions, and reactivity towards acyl chlorides in N,N-dimethylformamide. J. Chem. Soc., Perkin Trans. 2 1997,
473–478.
27. Burgers, P.M.J.; Eckstein, F. Synthesis of dinucleoside monophosphorothioates. Tetrahedron Lett. 1978, 40,
3835–3838.
28. Bartlett, P.D.; Cox, E.F.; Davis, R.E. Reactions of elemental sulfur. IV. Catalytic effects in the reaction of sulfur
with triphenylphosphine. J. Am. Chem. Soc. 1961, 83, 103–109.
29. Krebs, H. Die katalytische Aktivierung des Schwefels. H. Silicium, Schwefel, Phosphate, Colloq. Sek. anorg.
Chem. Intern. Union reine u. Angew. Chem. 1954, 107–111.
30. Janz, G.J.; Downey, J.R., Jr.; Roduner, E.; Wasilczyk, G.J.; Coutts, J.W.; Eluard, A. Raman studies of sulfur-
containing anions in inorganic polysulfides. Sodium polysulfides. Inorg. Chem. 1976, 15, 1759–1763.
31. Oei, D.-G. The sodium-sulfur system II. Polysulfides of sodium. Inorg. Chem. 1973, 12, 438–441.
32. Lloyd, J.R.; Lowther, N.; Zsabo, G.; Hall, C.D. J. Chem. Soc., Perkin Trans. 2 1985, 1813–1817.
33. Yu, R.Z.; Su, J.Q.; Grundy, J.S.; Geary, R.S.; Sewell, K.L.; Dorr, A.; Levin, A.A. Prediction of clinical
responses in a simulated phase III trial of Crohn’s patients administered the antisense phosphorothioate
oligonucleotide ISIS 2302: comparison of proposed dosing regimens. Antisense Nucleic Acid Drug Dev.
2003, 13, 57–66.
34. 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. Formation of 4,4’-dimethoxytrityl-C-phosphonate oligonucleo-
tides. Bioorg. Med. Chem. Lett. 2004, 14, 4683–4690.
35. Butler, M.; McKay, R.A.; Popoff, I.J.; Gaarde, W.A.; Witchell, D.; Murray, S.F.; Dean, N.M.; Bhanot, S.;
Monia, B.P. Specific inhibition of PTEN expression reverses hyperglycemia in diabetic mice. Diabetes 2002,
51, 1028–1034.