Preparation of potential inhibitors of the mur-pathway enzymes on solid support using an acetal linker

Bioorganic and Medicinal Chemistry Letters

Volumn 13, Issue 6, 2003, Pages 1125-1128

  Maletic, Milana ^a   Antonic, Jelena ^a   Leeman, Aaron ^a   Santorelli, Gina ^a   Waddell, Sherman ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIINFECTIVE AGENT; BENZYLIDENE DERIVATIVE; ENZYME INHIBITOR; GLYCOPEPTIDE; SUGAR;

ARTICLE; COMBINATORIAL CHEMISTRY; DRUG EFFECT; DRUG SYNTHESIS; ENZYME INHIBITION; IMMOBILIZATION; INHIBITION KINETICS; PEPTIDE SYNTHESIS; SOLID;

EID: 0037463751     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(03)00043-X     Document Type: Article

References (30)

1. Park J.T., Strominger J.L. Science. 125:1957;99.
2. (a) Gegnas L.D., Waddell S.T., Chabin R.M., Reddy S., Wong K.K. Bioorg. Med. Chem. Lett. 8:1998;1643.
3. (b) Tanner M.E., Vaganay S., van Heijenoort J., Blanot D. J. Org. Chem. 61:1996;1756
4. (c) Victor, F.; Tebbe, M. J.; Birch, G. B.; Smith, M. C.; Letourneau, D. L.; Wu, C. E. Abstract 1276, 39th ICAAC (Interscience Conference on Antimicrobial Agents and Chemotherapy), San Francisco, CA, Sept 26-29, 1999; p 330.
5. (d) Gobec S., Urleb U., Auger G., Blanot D. Pharmazie. 56:2001;295.
6. Bugg T., Walsh C.T. Nat. Prod. Rep. 9:1992;199.
7. Wong K.K., Kuo D.W., Chabin R.M., Fournier C., Gegnas L.D., Waddell S.T., Marsilio F., Leiting B., Pompliano D.L. J. Am. Chem. Soc. 120:1998;13527.
8. (a) Gallop M.A., Barrett R.W., Dower W.P., Fodor S.P.A., Gordon E.M. J. Med. Chem. 37:1994;1233.
9. (b) Gordon E.M., Barrett R.W., Dower W.P., Fodor S.P.A., Gallop M.A. J. Med. Chem. 37:1994;1385.
10. (c) Terret N.K., Gardner M., Gordon D.W., Kobylecki R.J., Steele J. Tetrahedron. 51:1995;8135.
11. (d) Ellman J.A. Acc. Chem. Res. 29:1996;132.
12. (e) Lam K.S., Lebl M., Krchnak M.L.V. Chem. Rev. 97:1997;411.
13. (f) Nefzi A., Ostresh J.M., Houghten R.A. Chem. Rev. 97:1997;449.
14. (a) Furka A., Sebestyen F., Asgedom M., Dibo G. Int. J. Pept. Protein Res. 37:1991;487.
15. (b) Sebestyen F., Dibo G., Kovacs A., Furka A. Bioorg. Med. Chem. Lett. 3:1993;413.
16. (c) Lam K.S., Salmon S.E., Hersh E.M., Hruby V.J., Kazmierski W.M., Knapp R.J. Nature. 354:1991;82.
17. (d) Ohlmeyer M.H.J., Swanson R.N., Dillard L.W., Reader J.C., Asouline G., Kobayashi R., Wigler M., Still W.C. Proc. Natl. Acad. Sci. U.S.A. 90:1993;10922.
18. An H., Cook D.P. Chem. Rev. 100:2000;3311. and references therein.
19. Schullek J.R., Butler J.H., Ni Z.-J., Chen D., Yuan Z. Analytical Biochem. 246:1997;20.
20. Hanessian S., Ogawa T., Guindon Y., Kamennof J., Roy R. Carbohydr. Res. 38:1974;C15.
21. (a) For recent use of benzylidene acetal linkers see: Hanessian S., Huynh H.K. Synlett. 1999;102.
22. (b) Lampe T.F.J., Weitz-Schmidt G., Wong C.-H. Angew. Chem. Int. Ed. Engl. 37:1998;1707
23. (c) Hamachi I., Kiyonaka S., Shinkai S. Tetrahedron Lett. 42:2001;6142.
24. Our solid support was: LCC Engineering aminomethyl polystyrene, uniform beads, with 1.1 mmol/g (4.4 nmol/bead) loading.
25. (a) Kaiser E., Colescott R.L., Bossinger C.D., Cook P.I. Anal. Biochem. 34:1970;595.
26. (b) Sarin V.K., Kent S.B.H., Tam J.P., Merrifield R.B. Anal. Biochem. 117:1981;147.
27. The library was characterized by single bead cleavage of compounds followed by LC/MS analysis. Beads were picked, suspended in 50 μL of cleavage cocktail for 15 min, then dried under a nitrogen stream, resuspended in 15 μL of acetonitrile and analyzed by LC/MS. Individual cleavage of 20 beads resulted in finding all of the nine desired compounds. The HPLC trace of each compound confirmed the high purity (>90%) or each analogue.
28. Forty milligrams of resin were treated with 15%TFA in methylene chloride for 10 min. The resin was filtered off and washed with three washes of methylene chloride and acetonitrile. The filtrates were combined and solvent was removed under reduced pressure to yield 9 mg of oily residue (53% yield).
29. While this conversion could be followed by IR (observing the disappearance of the carbonyl stretch) on the Wang aldehyde resin, it could not be followed by the same method on the methyl amino resin due to the presence of the amide bond. Instead, the optimized conditions for the Wang aldehyde resin were applied to the aminomethyl polystyrene resin.
30. Loading was assessed gravimetrically, by weighing the cleaved product from the known amount of resin (assuming 1.1 mmol/g loading) and also by comparison of cleavage product HPLC trace with the cleavage product of resin 8.