26th European Peptide Symposium, Montpellier, France, 2000, P72, Proceedings

17th American Peptide Symposium, San Diego, CA, USA, 2001, L1, Proceedings

Sugar Amino Acids (SAAs) are sugar moieties containing at least one amino as well as at least one carboxyl group. In this work we studied them mainly as structural templates in respect to their ability to induce new, potentially useful structures for peptidomimetic drug design. They can be used as substitutes for conventional amino acids or peptide fragments [1]. Sugar amino acid monomeres 1, 2 were synthesised starting from diacetoneglucose. The amino group was introduced via activation of the hydroxyl group with triflate anhydride, azidolysis (70%), and reduction.
 

Using standard solid phase coupling procedures 1 and 2 were alternatively coupled with b-alanine or GABA to form trimers up to hexamers (3, 4). The solution structure in DMSO and pyridine were investigated by 2-D NMR techniques as well as by CD-spectroscopy.

[1] E. Lohof, F. Burkhart, M. A. Born, E. Planker, H. Kessler, Advances in Amino Acid Mimetics and Peptidomimetics, Vol. 2 (Ed: Abell, A.) JAI Press Inc., Stanford, Connecticut, pp. 263-292.
 
 

Institut für Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching, Germany
 

Introduction

Sugar Amino Acids (SAAs) are sugar moieties containing at least one amino as well as at least one carboxyl group. In this work the new SAAs 1 and 2 as well as their mixed linear and cyclic hexapeptides 3, 4, and 5 are described (Scheme 1). We studied them mainly as structural templates in respect to their ability to induce new, potentially useful structures for peptidomimetic drug design. SAAs can be used as substitutes for conventional amino acids or peptide fragments [1]. b- and g-peptides as well as SAA-oligomers have been shown to form stable secondary structures in solution [2-5]. 
 

Scheme 1: b- and g-SAA 1 and 2, their mixed linear oligomers 3 and 4 as well as cyclic oligomer 5.
 

Results and Discussion

The synthesis of SAAs 1 and 2 is shown in Scheme 2. Both were synthesized via the azides 6 and 7. The crucial step is the azidolysis of the triflate activated diacetoneglucose. Considerable higher yields than given in ref. [6-8] were obtained, by using the cheaper and less hazardous reagents NaN₃ and catalytic amounts of Bu₄NCl. After 3-5 h the azide 6 was obtained by reaction of the triflate activated diacetoneglucose with 2 eq. NaN₃ in DMF at 50 °C, using catalytic amounts of Bu₄NCl, thus suppressing elimination more sufficiently. Azidolysis is followed by quantitative deprotection of the exocyclic hydroxyl groups using acetic acid [9]. In a one-pot reaction the azide was reduced and simultaneously Fmoc-protected yielding about 70 % of the Fmoc-protected amine.

Scheme 2: Synthesis of SAAs 1 and 2.

To prevent decarboxylation during TEMPO oxidation, it is crucial to avoid too basic conditions, and to keep the temperature below 0 °C.
 Using TCP resin and HATU/collidine as coupling reagents 1 and 2 were alternatively coupled with b-alanine or GABA respectively to form hexapeptides 3 and 4. After deprotection 3 was cyclisized using HATU/collidine to afford 5 in quantitative yield.
 2D NMR showed 5 to be C₃ symmetric on the NMR timescale, while for the linear hexapeptides 3 and 4 each residue shows its own, complete, distinguishable set of chemical shifts. 

Figure 1: TOCSY of the amide region of the mixed oligomers 3 and 5.

At present it remains uncertain, whether a single structure or a structural ensemble fit the observed NOE data sets.
 

References

1. Lohof, E., Burkhart, F., Born, M. A., Planker, E., Kessler, H. In Abell, A. (Ed.), Advances in Amino Acid Mimetics and Peptidomimetics, JAI Press Inc.: Stanford, Connecticut, USA, 1999, Vol. 2, p 263.
2. Seebach, D., Overhand, M., Kühnle, F. N. M., Martinoni, B., Oberer, L., Hommel, U., Widmer, H. Helv. Chim. Acta 79, (1996), 913.
3. Appella, D. H., Christianson, L. A., Karle, I. L., Powell, D. R., Gellman, S. H. J. Am.Chem. Soc., 118, (1996), 13071.
4. Appella, D. H., Christianson, L. A., Klein, D. A., Powell, D. R., Huang, X., Barchi Jr, J. J., Gellman, S. H. Nature, 38, (1997), 381.
5. Long, D. D., Smith, M. D., Marquess, D., Claridge, T. D. W., Fleet, G. W. J. Tetrahedorn Lett., 39, (1998), 9293.
6. Daley, L., Monneret, C., Gautier, C., Roger, P. Tetrahedron Lett., 33, (1992), 3749.
7. Fernández, J. M. G., Mellet, C. O., Blanco, J. L. J., Fuentes, J. J. Org. Chem., 59, (1994), 5565.
8. Baer, H. H., Gan, Y. Carbohydrate Research, 210, (1991), 233.
9. Kulinkovich, L. N., Timoshchuk, V. A. J. Gen. Chem. USSR (Engl. Transl.), 53, (1983), 1917.
 

Sibylle Gruner,1 Horst Kessler,1 Gyorgy Kéri,2 and Aniko Venetianer3 
 1 Novaspin Biotech GmbH, 85748 Garching, Germany; 2 Department of Medicinal Chemistry, Semmelweis Medicinal University, H-1444. Budapest 8; and 3 Inst. of Genetics, Biological Research Center, Hungarian Academy of Sciences, 6726 Szeged Temesvari krt. 62, Hungary

Introduction

Sugar Amino Acids (SAAs) are sugar moieties containing at least one amino as well as at least one carboxyl group[1]. Their oligomers represent chimeras between the two big classes of biopolymers, the carbohydrates and proteins. They therefore have been used as both, carbohydrate and peptidomimetics [2]. SAAs have been used in our laboratory mainly as turnmimics. We also applied SAAs to improve bioavailability and selectivity by functionalizing the carbohydrate skeleton.

Results and Discussion

In this work we present the development of new, SAA?containing somatostatin analogues.[3] A library of compounds containing different furanoid and pyranoid SAAs have been synthesized (Fig. 1). Hereby the skeleton and the functional groups of the SAAs as well as the amino acids of the peptide backbone have been optimized. 

Fig. 1. SAA containing somatostatin analogous. R, R’,R’’ = H, Bn, or ketal groups

Some SAA containing somatostatin analogues induce apoptosis most effectively. Remarkably analogues containing D- and L-tryptophane are both active.

The simple and straight forward synthesis of SAAs 1 and 2, which serve as structure inducing templates in our compounds, is shown in Scheme 1. Both were synthesized via the azides 6 and 7. The crucial step is the azidolysis of the triflate activated diacetoneglucose. Considerable higher yields than given in ref. [4-6] were obtained, by using the cheaper and less hazardous reagents NaN3 and catalytic amounts of Bu4NCl. Azidolysis is followed by quantitative deprotection of the exocyclic hydroxyl groups using acetic acid [7]. In a one-pot reaction the azide was reduced and simultaneously Fmoc-protected yielding about 70 % of the Fmoc-protected amine.

Scheme 1: Synthesis of structure inducing furanoid SAAs 1 and 2.

To prevent decarboxylation during TEMPO oxidation, it is crucial to avoid too basic conditions, and to keep the temperature below 0 °C.

References

1. Lohof, E., Burkhart, F., Born, M. A., Planker, E., Kessler, H., Advances in Amino Acid Mimetics and Peptidomimetics, Vol. 2 (Ed.: Abell, A), JAI Press Inc., Stanford, Connecticut, 1999, p. 263.
2. Gruner, S., Locardi, E., Lohof, E., Kessler, H., Chem. Rev., april, (2002).
3. Gruner, S., Locardi, E., Lohof, E., Born, M., Mang, C., Kéri, G., Venetianer, A., Kessler, H., J. Med. Chem., in preparation.
4. Daley, L., Monneret, C., Gautier, C., Roger, P., Tetrahedron Lett., 33, 3749, (1992).
5. Fernández, J. M. G., Mellet, C. O., Blanco, J. L. J., Fuentes, J., J. Org. Chem., 59, 5565, (1994).
6. Baer, H. H., Gan, Y., Carbohydr. Res., 210, 233, (1991).
7. Kulinkovich, L. N., Timoshchuk, V. A., J. Gen. Chem. USSR (Engl. Transl.), 53, 1917, (1983).