Synthesis of cyclic peptide hybrids with amino acid and nucleobase side- chains

Tetrahedron Letters

Volumn 41, Issue 21, 2000, Pages 4097-4100

  Planas, Marta ^a,b   Bardají, Eduard ^b   Barany, George ^a  

^a University of Minnesota   (United States)

^b UNIVERSITY OF GIRONA   (Spain)

Author keywords

Cyclization; Peptide nucleic acids; Solid phase synthesis

Indexed keywords

AMINO ACID; CYCLOPEPTIDE; NUCLEIC ACID BASE;

ARTICLE; CHEMICAL REACTION; CHEMICAL STRUCTURE; CYCLIZATION; HYDROGEN BOND; REACTION ANALYSIS; SYNTHESIS;

EID: 0034729187     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(00)00550-5     Document Type: Article

References (25)

1. Our initial experiments were reported at a conference in Minneapolis, MN, June 26 to July 1, 1999. See: Planas, M.; Bardají, E.; Barany, G. In Peptides for the New Millennium: Proceedings of the Sixteenth American Peptide Symposium; Fields, G. B.; Tam, J. P.; Barany, G., Eds.; Kluwer Academic Publishers: Dordrecht, The Netherlands, 2000, pp. 786-787.
2. Abbreviations used are as follows: Acc, 1-aminocyclopropane-1-carboxylic acid; Aib, α-aminoisobutyric acid; Bhoc, benzhydryloxycarbonyl; DIEA, N,N-diisopropylethylamine; DIPCDI, N,N′-diisopropylcarbodiimide; DMAP, N,N-dimethyl-4-aminopyridine; HBTU, N-[1H-(benzotriazol-1-yl) (dimethylamino)methylene]-N-methylmethanaminium hexafluorophosphate N-oxide; HOAc, acetic acid; HOAt, 7-aza-1-hydroxybenzotriazole (3-hydroxy-3H-1,2,3-triazolo-[4,5-b]pyridine); HOBt, 1-hydroxybenzotriazole; NMM, N-methylmorpholine; NMP, N-methyl-2-pyrrolidinone; PAC, p-alkoxybenzyl alcohol handle; PEG-PS, polyethylene glycol-polystyrene (graft resin support); PyAOP, 7-azabenzotriazol-1-yl-N-oxy-tris(pyrrolidino)phosphonium hexafluorophosphate; TFA, trifluoroacetic acid. Amino acid symbols denote the l-configuration. In denoting PNA structures, standard oligopeptide nomenclature is used. A, C, G, and T are the A-acetyl, C-acetyl, G-acetyl, and T-acetyl N-(2-aminoethyl)glycyl units, respectively. We also point out that while technically PNA molecules are neutral rather that acid, workers in the field have retained the term acid in the name to emphasize the analogy to DNA and RNA.3.
3. Nielsen, P. E.; Egholm, M.; Berg, R. H.; Buchardt, O. Science 1991, 254, 1497-1500.
4. For reviews, see: (a) Hyrup, B.; Nielsen, P. E. Bioorg. Biomed. Chem. 1996, 4, 5-23.
5. (b) Eriksson, M.; Nielsen, P. E. Quart. Rev. Biophys. 1996, 29, 369-394.
6. (c) Good, L.; Nielsen, P. E. Antisense and Nucleic Acid Drug Development 1997, 7, 431-437.
7. (d) Knudsen, H.; Nielsen, P. E. Anti-Cancer Drugs 1997, 8, 113-118.
8. (e) Dueholm, K. L.; Nielsen, P. E. New J. Chem. 1997, 21, 19-31.
9. (f) Haaima, G.; Nielsen, P. E. Chem. Soc. Rev. 1997, 73-78.
10. (g) Corey, D. R. TIBTECH 1997, 15, 224-229.
11. (h) Uhlmann, E.; Peyman, A.; Breipohl, G.; Will, D. W. Angew. Chem., Int. Ed. 1998, 37, 2796-2823.
12. (a) Ghadiri, H. R.; Granja, J. R.; Milligan, R. A.; McRee, D. E.; Khazanovich, N. Nature 1993, 366, 324-327.
13. (b) Clark, T. D.; Buehler, L. K.; Ghadiri, M. R. J. Am. Chem. Soc. 1998, 120, 651-656.
14. (c) Vollmer, M. S.; Clark, T. D.; Steinem, C.; Ghadiri, M. R. Angew. Chem., Int. Ed. 1999, 38, 1598-1601.
15. Kates, S. A.; Solé, N. A.; Johnson, C. R.; Hudson, D.; Barany, G.; Albericio, F. Tetrahedron Lett. 1993, 34, 1549-1552.
16. Albericio, F.; Cases, M.; Alsina, J.; Triolo, S. A.; Carpino, L. A.; Kates, S. A. Tetrahedron Lett. 1997, 38, 4853-4856.
17. A typical cyclization experiment was carried out as follows: PNA-peptide-resin (∼250 mg) was suspended in NMP (1 mL), following which PyAOP (5 equiv.), HOAt (5 equiv.), and DIEA (10 equiv.) were added successively. After 3-5 h, ninhydrin tests (Kaiser, E.; Colescott, R. L.; Bossinger, C. D.; Cook, P. I. Anal. Biochem. 1970, 34, 595-598) were negative.
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20. Azobenzotriazole-derived coupling reagents have been reported as being among the most effective for the cyclization of linear peptides. Such cyclizations proceed rapidly and with C-terminal epimerization generally less than 10% (Ehrlich, A.; Heyne, H.-U.; Winter, R.; Beyermann, M.; Haber, H.; Carpino, L. A.; Bienert, M. J. Org. Chem. 1996, 61, 8831-8836). Thus, we consider it unlikely that the observed heterogeneity in our cyclic peptide-PNA hybrids is due entirely to racemization upon activation of the Glu residue.
21. Bertho, J. N.; Loffet, A.; Pinel, C.; Reuther, F.; Senney, G. Tetrahedron Lett. 1991, 32, 1303-1306.
22. 2, 4 h at 25°C. All couplings took place with yields above 90% as demonstrated by spectrophotometric determination of the Fmoc group. Fmoc deprotection was carried out with DBU:piperidine:NMP (1:15:35) (2+15 min).
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24. Cyclization was performed as follows: To a solution of the linear PNA-peptide hybrid in NMP (0.1 mM concentration), PyAOP (5 equiv.), HOAt (5 equiv.), and DIEA (10 equiv.) were added successively. Cyclization was followed by HPLC. For the synthesis of c(A-Aib-T-Aib), linear and cyclic compounds coeluted; therefore, cyclization was confirmed by LC/MS.
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