New hetero-oligomeric peptide nucleic acids with improved binding properties to complementary DNA

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 6, 1997, Pages 687-690

  Jordan, Stephan ^a   Schwemler, Christoph ^a   Kosch, Winfried ^a,b   Kretschmer, Axel ^a   Stropp, Udo ^a   Schwenner, Eckhardt ^a   Mielke, Burkhard ^a  

^a BAYER AG   (Germany)

^b BIOTEST AG   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; OLIGOMER; PEPTIDE NUCLEIC ACID;

ARTICLE; CHEMICAL MODIFICATION; CHEMICAL REACTION; DRUG SYNTHESIS; OLIGOMERIZATION;

EID: 0031576885     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00085-1     Document Type: Article

References (26)

1. 1 Uhlmann, E.; Peyman, A. Chem. Rev. 1990, 90, 543.
2. 2 Zamecnik, P. C.; Stephenson, M. L. Proc. Natl. Acad. Sci. U.S.A. 1978, 75, 280; Crooke, S. T. in Burger's Medicinal Chemistry and Drug Discovery, vol. 1 (ed. Manfred E. Wolff), John Wiley & Sons, Inc. 1995, 863.
3. Zamecnik, P. C.; Stephenson, M. L. Proc. Natl. Acad. Sci. U.S.A. 1978, 75, 280; Crooke, S. T. in Burger's Medicinal Chemistry and Drug Discovery, vol. 1 (ed. Manfred E. Wolff), John Wiley & Sons, Inc. 1995, 863.
4. 3 Dagle, J. M.; Weeks, D. L.; Walder, J. A. Antisense Res. Dev. 1991, 1, 11.
5. 4 for reviews see: Szymkowski, D.E. Drug Discovery Today, 1996, 1, 415 and Altmann, K.-H.; Dean, N.M.; Fabbro, D.; Freier, S.M.; Geiger, T.; Häner, R.; Hüsken, D.; Martin, P.; Monia, B.P.; Müller, M.; Natt, F.; Nicklin, P.; Phillips, J.; Pieles, U.; Sasmor, H.; Moser, H.E. Chimica, 1996, 50, 168.
6. for reviews see: Szymkowski, D.E. Drug Discovery Today, 1996, 1, 415 and Altmann, K.-H.; Dean, N.M.; Fabbro, D.; Freier, S.M.; Geiger, T.; Häner, R.; Hüsken, D.; Martin, P.; Monia, B.P.; Müller, M.; Natt, F.; Nicklin, P.; Phillips, J.; Pieles, U.; Sasmor, H.; Moser, H.E. Chimica, 1996, 50, 168.
7. 5 Egholm, M.; Buchardt, O.; Nielsen, P. E.; Berg, R. H. J. Am Chem. Soc. 1992, 114, 1895; Egholm, M.; Nielsen, P. E.; Buchardt, O.; Berg, R. H. ibid 1992, 114, 9677; Nielsen, P. E.; Egholm, M.; Berg, R. H; Buchardt, O. Science 1991, 254, 1497; Dueholm, K. L.; Egholm, M.; Behrens, C.; Christensen, L.; Hansen, H. F.; Vulpius, T.; Petersen, K. H.; Berg, R. H.; Nielsen, P.E.; Buchardt, O. J. Org. Chem. 1994, 59, 5767; Stetsenko, D. A.; Lubyako, E. N.; Potapov, V. K.; Azhikina, T. L.; Syerdlov, E. D. Tetrahedron Lett. 1996, 37, 3571.
8. Egholm, M.; Buchardt, O.; Nielsen, P. E.; Berg, R. H. J. Am Chem. Soc. 1992, 114, 1895; Egholm, M.; Nielsen, P. E.; Buchardt, O.; Berg, R. H. ibid 1992, 114, 9677; Nielsen, P. E.; Egholm, M.; Berg, R. H; Buchardt, O. Science 1991, 254, 1497; Dueholm, K. L.; Egholm, M.; Behrens, C.; Christensen, L.; Hansen, H. F.; Vulpius, T.; Petersen, K. H.; Berg, R. H.; Nielsen, P.E.; Buchardt, O. J. Org. Chem. 1994, 59, 5767; Stetsenko, D. A.; Lubyako, E. N.; Potapov, V. K.; Azhikina, T. L.; Syerdlov, E. D. Tetrahedron Lett. 1996, 37, 3571.
9. Egholm, M.; Buchardt, O.; Nielsen, P. E.; Berg, R. H. J. Am Chem. Soc. 1992, 114, 1895; Egholm, M.; Nielsen, P. E.; Buchardt, O.; Berg, R. H. ibid 1992, 114, 9677; Nielsen, P. E.; Egholm, M.; Berg, R. H; Buchardt, O. Science 1991, 254, 1497; Dueholm, K. L.; Egholm, M.; Behrens, C.; Christensen, L.; Hansen, H. F.; Vulpius, T.; Petersen, K. H.; Berg, R. H.; Nielsen, P.E.; Buchardt, O. J. Org. Chem. 1994, 59, 5767; Stetsenko, D. A.; Lubyako, E. N.; Potapov, V. K.; Azhikina, T. L.; Syerdlov, E. D. Tetrahedron Lett. 1996, 37, 3571.
10. Egholm, M.; Buchardt, O.; Nielsen, P. E.; Berg, R. H. J. Am Chem. Soc. 1992, 114, 1895; Egholm, M.; Nielsen, P. E.; Buchardt, O.; Berg, R. H. ibid 1992, 114, 9677; Nielsen, P. E.; Egholm, M.; Berg, R. H; Buchardt, O. Science 1991, 254, 1497; Dueholm, K. L.; Egholm, M.; Behrens, C.; Christensen, L.; Hansen, H. F.; Vulpius, T.; Petersen, K. H.; Berg, R. H.; Nielsen, P.E.; Buchardt, O. J. Org. Chem. 1994, 59, 5767; Stetsenko, D. A.; Lubyako, E. N.; Potapov, V. K.; Azhikina, T. L.; Syerdlov, E. D. Tetrahedron Lett. 1996, 37, 3571.
11. Egholm, M.; Buchardt, O.; Nielsen, P. E.; Berg, R. H. J. Am Chem. Soc. 1992, 114, 1895; Egholm, M.; Nielsen, P. E.; Buchardt, O.; Berg, R. H. ibid 1992, 114, 9677; Nielsen, P. E.; Egholm, M.; Berg, R. H; Buchardt, O. Science 1991, 254, 1497; Dueholm, K. L.; Egholm, M.; Behrens, C.; Christensen, L.; Hansen, H. F.; Vulpius, T.; Petersen, K. H.; Berg, R. H.; Nielsen, P.E.; Buchardt, O. J. Org. Chem. 1994, 59, 5767; Stetsenko, D. A.; Lubyako, E. N.; Potapov, V. K.; Azhikina, T. L.; Syerdlov, E. D. Tetrahedron Lett. 1996, 37, 3571.
12. 6 Sarmieto, U. M.; Perez, J. R.; Becker, J. M.; Narayanan, R. Antisense Res. Dev. 1994, 4, 99.
13. 7 Abbreviations used: aeg, N-(2-aminoethyl) glycine; Boc, tert.-butoxycarbonyl; Z, benzyloxycarbonyl; TFA, trifluoroacetic acid; NMP, N-methyl-pyrrolidone.
14. 8 Almarsson, Ö.; Bruice, T. C. Proc. Natl. Acad. Sci. U.S.A 1993, 90, 9542.
15. 9 Jordan, S.; Schwemler, C.; Kosch, W., Kretschmer, A., Stropp, U., Schwenner, E.; Mielke, B., submitted. See also Löbberding, A.; Mielke, B.; Schwemler, C.; Schwenner, E.; Stropp, U.; Springer, W.; Kretschmer, A.; Pötter, T. Europian Patent EP 0646595 A1 1995 and EP 0646596 A1 1995.
16. 9 Jordan, S.; Schwemler, C.; Kosch, W., Kretschmer, A., Stropp, U., Schwenner, E.; Mielke, B., submitted. See also Löbberding, A.; Mielke, B.; Schwemler, C.; Schwenner, E.; Stropp, U.; Springer, W.; Kretschmer, A.; Pötter, T. Europian Patent EP 0646595 A1 1995 and EP 0646596 A1 1995.
17. 10 Merrifield, R. B. J. Am. Chem. Soc., 1963 85, 2149; Barany, G.; Kneib-Cordonier, N.; Mullen, D. G. Int. J. Pept. Protein Res. 1990, 30, 705.
18. Merrifield, R. B. J. Am. Chem. Soc., 1963 85, 2149; Barany, G.; Kneib-Cordonier, N.; Mullen, D. G. Int. J. Pept. Protein Res. 1990, 30, 705.
19. 182 columm using a gradient of water (0.1% TFA, buffer A) and water/acetonitrile 7:3 (v/v) (0.1% TFA, buffer B); 0 min: 95% A, 30 min: 40% A; 40 min: 20% A; 45 min: 20% A; 50 min: 95% A.
20. m-values were determined.
21. 13 Agarose gel electrophoretic analysis of compound 2 mediated strand displacement in double stranded plasmid DNA. Specific plasmid DNA fragmentation by S1 nuclease digestion of single strand DNA cleavage is detected in samples 6 - 8. Composition of samples in lanes 1 - 8 is as follows. 1: molecular weight marker; 2: 1 μg plasmid DNA; 3: 1 μg plasmid DNA plus 10 U S1 nuclease; lanes 4 - 8 as for lane 3 with increasing amounts of 2 containing 0.0001 μg, 0.001 μg, 0.01 μg, 0.1 μg, and 1.0 μg respectively.
22. 2, pH 4.4) and 10 U S1-nuclease (Aspergillus niger, Boehringer Mannheim, Germany) were added to the samples and incubated for 15 min at 30°C. The reaction was stopped by cooling on ice and by adding 1 μ1 0.5 M EDTA and 3 μ1 of sample buffer (50% glycerol, 0.25% bromophenol blue in 40 mM tris-HCl, 20 mM sodium acetate, 1 mM EDTA, pH 7.2). The reaction mixture was loaded onto an agarose gel (1.2 %) for electrophoresis and subsequent staining by ethidium bromide. Molecular weight markers for DNA fragments were used from Gibco-BRL, Gaithersburg, Maryland, USA.
23. 8 to compound 2, the hybridisationproduct remains relatively constant, but more and more free DNA is detected.
24. m-value (>80°C) of this compound).
25. 17 This point is some what controversial, see: Chen, S.-M.; Mohan, V.; Kiely, J. S.; Griffith, M. C.; Griffey, R. H. Tetrahedron Lett. 1994, 35, 5105 and Torres, R. A.; Bruice, T. C. Proc. Natl. Acad. Sci. U.S.A 1996, 93, 649.
26. This point is some what controversial, see: Chen, S.-M.; Mohan, V.; Kiely, J. S.; Griffith, M. C.; Griffey, R. H. Tetrahedron Lett. 1994, 35, 5105 and Torres, R. A.; Bruice, T. C. Proc. Natl. Acad. Sci. U.S.A 1996, 93, 649.