Acyloxyaryl prodrugs of oligonucleoside phosphorothioates

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 16, 1996, Pages 1917-1922

  Iyer, Radhakrishnan P ^a   Yu, Dong ^a   Devlin, Theresa ^a   Ho, Nan Hui ^a   Agrawal, Sudhir ^a  

^a HYBRIDON INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

OLIGODEOXYNUCLEOTIDE PHOSPHOROTHIOATE; PRODRUG;

ARTICLE; DRUG DESIGN; DRUG STABILITY; DRUG SYNTHESIS; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; REACTION ANALYSIS; TECHNIQUE;

EID: 0030594979     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00332-0     Document Type: Article

References (21)

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2. (b) Balant, L. P.; Doelker, E. In Burger's Medicinal Chemistry and Drug Discovery, Wolff, M. E., Ed.; John Wiley & Sons: New York, NY., 1995; Vol. 1, pp 949-982;
3. (c) For recent examples see: (i) Manouilov, K. K.; Fedorov, I. I.; Boudinot, F. D.; White, C. A.; Kotra, L. P.; Schinazi, R. F.; Hong, C.; Chu, C. K. Antiviral Chem. Chemother. 1995,6, 230;
4. (ii) Mitchell, A. G.; Thomson, W.; Nicholls, D.; Irwin, W. J.; Freeman, S. J. Chem. Soc. Perkin Trans. 1 1992, 2345.
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6. (b) Iyer, R. P.; Boal, J.; Phillips, L. R.; Thakker, D. R.; Egan, W. J. Pharm. Sci. 1994, 83, 1269.
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8. (b) Barber, I.; Rayner, B.; Imbach, J.-L. Bioorg. Med. Chem. Lett. 1995, 5, 563.
9. 4. For reviews see: (a) Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 544;
10. (b) Agrawal, S.; Iyer, R. P. Curr. Op. Biotech. 1995, 6, 12.
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12. (b) Iyer, R. P.; Yu, D.; Ho, N.-H.; Agrawal, S. Synth. Commun. 1995, 25, 2739;
13. 5a
14. 6. For a discussion on phosphate ester hydrolysis see: (a) Cox, Jr., J. R.; Ramsay, O. B. Chem. Rev. 1964, 64, 317;
15. (b) Dugas, H.; Penney, C. Bioorganic Chemistry: A Chemical Approach to Enzyme Action; Springer-Verlag: New York, 1981; pp 93-135.
16. 8a was first advanced to explain the product distribution during the hydrolysis of dimethyl phosphoacetoin, see: Frank, D. S.; Usher, D. A. J. Am. Chem. Soc. 1967, 89, 6360.
17. 8. (a) The concept of pseudorotation (along with the associated "preference rules") is well known, and is used to explain the observed rate enhancement, as well as, the unusual product profiles observed during the hydrolysis of five-membered cyclic phosphates, phosphinates and phostonates, compared to their acyclic counterparts. For excellent reviews on this subject, see: (i) Westheimer, F. H. Acc. Chem. Res. 1968, 1, 70;
18. (ii) Singleton Jr., R. J. Chem. Ed. 1973, 50, 538;
19. (b) In the case of the prodrugs 1a-c, although the suggested hydrolytic pathway involves the formation of six-membered ring intermediates, the concept of pseudorotation is being invoked only to account for the observed dichotomy in product distribution during their hydrolysis under enzymatic and non-enzymatic conditions.
20. 9. Mitchell et al., have used the acyloxyaryl moiety for prodrug derivatization of phosphonoacetic acid; see ref 1ce (ii).
21. 10. Manuscript in preparation.