Torrey Pines Institute for Molecular Studies science image
Torrey Pines Institute for
Molecular Studies
3550 General Atomics Court, 2-129
San Diego, CA 92121-1122
USA
Scientists
Adel Nefzi
Assistant Member
Combinatorial Chemistry

858.455.3803 - phone
858.455.3804 - fax

Solid Phase Synthesis of Acyclic and Heterocyclic Mixture-Based Combinatorial Libraries

Combinatorial chemistry initially involved the synthesis of very large libraries of biological oligomers such as peptides, peptidomimetics and oligonucleotides. Such oligomers, while valuable in their own right, have limitations as pharmaceutical agents and are susceptible to rapid enzymatic degradation. The focus of combinatorial chemistry has shifted in recent years to libraries of small acyclic and heterocyclic molecules having molecular weights of 500 dalton or less, due to their proven utility as therapeutic agents. The goal of our group is the design and synthesis of organic acyclic and heterocyclic compounds on solid supports, and the synthesis of subsequent combinatorial libraries.

Using amino acids and peptides, we have developed strategies for the parallel solid-phase synthesis of a wide range of different acyclic and heterocyclic compounds, such as: polyureas, polyamines, diazepines, hydantoins, thiohydantoins, cyclic ureas, cyclic thioureas, thiomorpholinones, diketopiperazines, piperazines, benzothiazepines and other molecules (Figure 1). The general nature of our approaches permits not only large numbers of individual compounds to be prepared, but also combinatorial libraries. The majority of our heterocyclic combinatorial libraries have been prepared in the positional scanning format.

At TPIMS, we have the chance to interact with a multidisciplinary team that includes biologists, microbiologists and immunologists. Thus, our combinatorial libraries are screened in a variety of different assays, and many highly active compounds have been identified.

Synthesis of tetrasubstituted tetraazacyclotetradecanes

The promise of radiolabeled macrocyclic antibody conjugates for radioimmunotherapy has led to the synthesis and evaluation of several series of tetraazamacrocycle chelating ligands. Tetraazacyclotetradecane has been shown to be an effective reagent for linking copper to proteins. We are developing an approach for the synthesis of tetrafunctional tetraazamacrocycles from resin-bound cyclic tetrapeptides. Starting from resin-bound glutamic acid, cyclic tetrapeptides will be prepared via intra-molecular amide formation of the resin-bound intermediate. The complete reduction of amide bonds will afford the tetraazamacrocycle library.

Synthesis of glycopeptide libraries

Despite the recognized biological significance of cell-surface oligosaccharides as targets for bacterial, toxin, and viral attachment, and in mammalian cell-cell adhesion, approaches for the chemical assembly of sugar-containing libraries have not been extensively explored. Starting from resin-bound polyamides, the generated secondary amines will be treated with the commercially available 2,3,4,6-tetra-O-acetyl-ß-D-glucopyranosyl isothiocyanate to afford the corresponding polyaminoglycoside following cleavage of the solid support. Using different amino acids and different carboxylic acids, different polyaminoglycoside libraries are being prepared in the positional scanning format.

Key References. 1-6

  1. Nefzi, A., et al. The current status of heterocyclic combinatorial libraries. Chemical Reviews 97:449-472, 1997.
  2. Nefzi, A., et al. Combinatorial chemistry: From peptides and peptidomimetics to small organic and heterocyclic compounds.  Bioorg. Med. Chem. Lett. 8:2273-2278, 1998.
  3. Nefzi, A., et al. Efficient solid phase synthesis of 3,5-disubstituted hydantoins. Tetrahedron Lett. 39:8199-8202, 1998.
  4. Nefzi, A., et al. Solid phase synthesis of 1,4-benzothiazepin-5-one derivatives. Tetrahedron Lett. 40:4939-4942, 1999.
  5. Nefzi, A., et al. Solid phase synthesis of trisubstituted 2-imidazlidones and 2-imidazolidinethiones.  J. Comb. Chem. 1:195-198, 1999.
  6. Houghten, R.A., et al. Mixture-based synthetic combinatorial libraries. J. Med. Chem. 42:3743-3778, 1999.

Publications

  1. Hensler, M.E., Bernstein, G., Nizet, V., Nefzi, A. Pyrrolidine bis-cyclic guanidines with antimicrobial activity against drug-resistant Gram-positive pathogens identified from a mixture-based combinatorial library. Bioorg. Med. Chem. Lett. 16:5073-5078, 2006.
  2. Hoesl, C.E., Ostresh, J.M., Houghten, R.A., Nefzi, A. Solid phase synthesis of 3,4,7-trisubstituted 4,5,8,9-tetrahydro-3H-imidazo[1,2-a][1,3,5]triazepin-2(7H)-thiones and N-alkyl-4,5,7,8-tetrahydro-3H-imidazo[1,2-a][1,3,5]triazepin-2-amines. J. Comb Chem. 8:127-131, 2006.
  3. Nefzi, A., Hoesl, C.E., Pinilla, C., Kauffman, G.B., Maggiora, G.M., Pasquale, E., Houghten, R.A. Synthesis of platinum(II) chiral tetraamine coordination complexes J. Comb. Chem. 8:780-783, 2006.
  4. Nefzi, A., Ostresh, J.M., Appel, J.R., Bidlack, J., Dooley, C.T., Houghten, R.A. Identification of potent and highly selective chiral tri-amine and tetra-amine u opoid receptors ligands. An example of lead optimization using mixture based libraries. Bioorg. Med. Chem. Lett. 16:4331-4338, 2006.
  5. Nefzi, A., Santos, R.T. Efficient approach for the parallel solid phase synthesis of 1,1,3,4-tetrasubstituted-5-oxopiperazin-1-ium compounds. Tetrahedron Lett. 47:3819-3822, 2006.
  6. Nefzi, A., Santos, R.T. A versatile access to new macrocyclic oligohetercycles (MOH). Bioorg. Med. Chem. Lett. 16:3358-3361, 2006.
  7. Carter, B., Gronda, M., Wang, Z., Welsh, K., Pinilla, C., Andreeff, M., Schober, W., Nefzi, A., Pond, G., Mawji, I., Houghten, R., Ostresh, J., Brandwein, J., Minden, M., Schuh, A., Wells, R., Messner, H., Chun, K., Reed, J. Schimmer, A. Small-molecule XIAP inhibitors depress downstream effector caspases and induce apoptosis of acute myeloid leukemia cells. Blood 105:4043-4050, 2005.
  8. Kater, A.P., Dicker, F., Mangiola, M., Welsh, K., Houghten, R., Ostresh, J., Nefzi, A., Reed, J.C., Pinilla, C., Kipps, T.J. Inhibitors of XIAP sensitize CD40-activated chronic lymphocytic leukemia cells to CD95-mediated apoptosis. Blood 106:1742-1748, 2005.
  9. Nefzi, A., Santos, R.T. Efficient approaches toward the solid-phase synthesis of new heterocyclic azoniaspiro ring systems: synthesis of tri- and tetrasubstituted 10-oxo- 3,9-diaza-6-azoniaspiro[5.5]undecanes. J. Org. Chem. 70:9622-9625, 2005.
  10. Hoesl, C.E., Nefzi, A., Houghten, R.A. Halogenoalkyl isocyanates a bifunctional reagents in an Aza-Wittig/heterocyclization reaction on the solid phase: efficient entry into new tetra-cyclic benzimidazole systems J. Comb. Chem. 6:220-223, 2004.
  11. Nefzi, A., Ostresh, J.M., Yu, Y., Houghten, R.A. Combinatorial chemistry: libraries from libraries, the art of the diversity-oriented transformation of resin-bound peptides and chiral polyamides to low molecular weight acyclic and heterocyclic compounds. J. Org. Chem. 69:3603-3609, 2004.
  12. Schimmer, A.D., Welsh, K., Pinilla, C., Wang, Z., Krajewska, M., Bonneau, M.-J., Pedersen, I.M., Kitada, S., Scott, F.L., Bailly-Maitre, B., Glinsky, G., Scudiero, D., Sausville, E., Salvesen, G., Nefzi, A., Ostresh, J.M., Houghten, R.A., Reed, J.C. Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell 5:25-35, 2004.
  13. Yu, Y., Nefzi, A., Ostresh, J.M., Houghten, R.A. Parallel solid phase synthesis, mixture based combinatorial libraries & libraries from libraries: The versatility of chiral polyamines. In: Innovation and Perspectives in Solid Phase Synthesis & Combinatorial Libraries 2004 (Epton, R., Ed.), Mayflower Worldwide, Kingswinford, UK, pp. 1-4, 2004.
  14. Giulianotti, M., Nefzi, A. Efficient approach for the diversity-oriented synthesis of macro-heterocycles on solid-support Tetrahedron Letters 44:5307–5309, 2003.
  15. Hoesl, C.E., Nefzi, A., Houghten, R.A. Parallel solid-phase synthesis of 2-imino-4-oxo-1,3,5-triazino[1,2-a]benzimidazoles via tandem aza-Wittig/heterocumulene-mediated annulation reaction. J. Comb. Chem. 5:155-160, 2003.
  16. Hoesl, C.E., Nefzi, A., Houghten, R.A. Abnormal aza-Wittig reaction on the solid phase: chemoselectivity studies towards the parallel synthesis of 3-aryl-2,4-dioxo-1,3,5-triazino[1,2-a]benzimidazoles Tetrahedron Lett. 44:3705-3708, 2003.
  17. Hoesl, C.E., Nefzi, A., Ostresh, J.M., Yu, Y., Houghten, R.A. Mixture-based combinatorial libraries: From peptides and peptidomimetics to small molecule acyclic and heterocyclic compounds. Methods Enzymol. 369:496-517, 2003.
  18. Klein, G., Ostresh, J.M., Nefzi, A. Solid-phase synthesis of new fused tetra, penta and hexacyclic â-carboline derivatives Tetrahedron Lett. 4:2211-2215, 2003.
  19. Nefzi, A., Ostresh, J.M., Houghten, R.A. Combinatorial chemistry: Mixture-based combinatorial libraries of acyclic and heterocyclic compounds from amino acids and short peptides. In: Modern Methods of Drug Discovery (Hillisch, A., Hilgenfeld, R., Eds.) Birkhäuser Verlag, Basel, pp. 109-123, 2003.
  20. Nefzi, A., Vidal, A., Rinnova, M., Houghten, R.A. N-Substituted benzotriazole: Useful template for the solid-phase synthesis of diverse small molecule compounds. In: Innovation and Perspectives in Solid Phase Synthesis & Combinatorial Libraries 2002 (Epton, R., Ed.), Mayflower Worldwide, Kingswinford, UK, pp. 185-188, 2003.
  21. Nefzi, A., Giulianotti, M., Truong, L., Rattan, S., Ostresh, J.M., Houghten, R.A. Solid phase synthesis of linear ureas tethered to hydantoins and thiohydantoins. J. Comb. Chem. 4:175-178, 2002.
  22. Nefzi, A., Mimna, R.A., Houghten, R.A. Parallel solid-phase synthesis of 1,6-piperazine-2-ones J. Comb. Chem. 4:542-545, 2002.
  23. Rinnova, M., Nefzi, A., Houghten, R.A. An expedient method for solid-phase synthesis of α-aminoalkyl phosphopeptides. Tetrahedron Lett. 43:4103-4106, 2002
  24. Rinnova, M., Nefzi, A., Houghten, R.A. An efficient approach for solid-phase synthesis of peptidomimetics based on 4-imidazolidinones. Tetrahedron Lett. 43:2343-2346, 2002.
  25. Rinnova, M., Nefzi, A., Houghten, R.A. Opioid activity of 4-imidazolidinone positional analogues of Leu-Enkephalin Bioorg. Med. Chem. Lett. 12: 3175-3178, 2002.
  26. Rinnova, M., Vidal, A., Nefzi, A., Houghten, R.A. Solid-phase synthesis of 1,2,5-trisubstituted 4-imidazolidinones. J. Comb. Chem. 4:209-213, 2002.
  27. Acharya, A.N., Nefzi, A., Ostresh, J.M., Houghten, R.A. Tethered libraries: Solid-phase synthesis of substituted urea-linked bicyclic guanidines. J. Comb. Chem. 3:189-195, 2001.
  28. Acharya, A.N., Ostresh, J.M., Nefzi, A., Houghten, R.A. Solid-phase synthesis of substituted dihydroimidazoles and their bis analogs. In: Peptides: The Wave of the Future: Proceedings of the 2nd International/17th American Peptide Symposiium (Lebl, M. and Houghten, R.A., Eds.), Kluwer Academic Publishers, Dordrecht, The Netherlands, pp. 255-256, 2001.
  29. Blondelle, S.E., Nefzi, A., Boggiano, C. Inhibition of HIV-1 fusion by diethylenetriamines. In: Peptides 2000: Proceedings of the 26th European Peptide Symposium, (Martinez, J., Fehrentz, J.A., Eds.) Editions EDK, Paris, France, pp. 955-956, 2001.
  30. Nefzi, A., Giulianotti, M.A., Houghten, R.A. Solid-phase synthesis of bis-heterocyclic compounds from resin-bound orthogonally protected lysine. J. Comb. Chem. 3:68-70, 2001.
  31. Nefzi, A., Giulianotti, M.A., Ong, N.A., Ostresh, J.M., Dooley, C.T., Blondelle, S.E., Houghten, R.A. Solid phase synthesis of acyclic and heterocyclic combinatorial libraries from resin-bound triamines. In: Innovation and Perspectives in Solid Phase Synthesis & Combinatorial Libraries 2000 (Epton, R., Ed.), Mayflower Worldwide, Birmingham, UK, pp. 119-122, 2001.
  32. Nefzi, A., Houghten, R.A. Polyamines as intermediates for the synthesis of heterocyclic compounds and oligomeric heterocyclic compounds from resin-bound polyamides. In: Peptides: The Wave of the Future. Proceedings of the 2nd International/17th American Peptide Symposium. (Houghten, R.A., Lebl, M., Eds.), Kluwer Academic Publishers, Dordrecht, pp. 252-254, 2001.
  33. Nefzi, A., Ong, N.A, Houghten, R.A. Parallel synthesis of 4,5-dihydro-1H-1,4-benzodiazepine-2,3-diones. Tetrahedron Lett. 42:5141-5143, 2001.
  34. Nefzi, A., Ostresh, J.M., Houghten, R.A. Solid phase synthesis of mixture-based acyclic and heterocyclic small molecule combinatorial libraries from resin-bound polyamides. Biopolymers (Peptide Science) 60:212-219, 2001.
  35. Rinnova, M., Vidal, A., Nefzi, A., Houghten, R.A. Solid phase synthesis of 1,2,5-substituted derivatives of 4-imidazolidinone. In: Peptides: The Wave of the Future. Proceedings of the 2nd International/17th American Peptide Symposium. (Houghten, R.A., Lebl, M., Eds.), Kluwer Academic Publishers, Dordrecht, pp. 257-258, 2001.
  36. Vidal, A., Nefzi, A., Houghten, R.A. Solid-phase synthesis of α,α-difluoro-β-amino acids via the Reformatsky reaction. J. Org. Chem. 66:8268-8272, 2001.
  37. Vidal, A., Nefzi, A., Houghten, R.A. Solid-phase synthesis of α-difluoro-β-amino acids by a Reformatsky reaction. In: Peptides: The Wave of the Future. Proceedings of the 2nd International/17th American Peptide Symposium. (Houghten, R.A., Lebl, M., Eds.), Kluwer Academic Publishers, Dordrecht, pp. 261-262, 2001.
  38. Alvarez-Gutierrez, J.M., Nefzi, A., Houghten, R.A. Solid phase synthesis of 1,3-disubstituted succinimides. Tetrahedron Lett. 41:609-612, 2000.
  39. Alvarez-Gutierrez, J.M., Nefzi, A., Houghten, R.A. Solid phase synthesis of 1-substituted pyroglutamates. Tetrahedron Lett. 41:851-854, 2000.
  40. Nefzi, A., Giulianotti, M.A., Houghten, R.A. Solid-phase synthesis of substituted 2,3-diketopiperazines from reduced polyamides. Tetrahedron 56:3319-3326, 2000.
  41. Nefzi, A., Giulianotti, M.A., Houghten, R.A. Solid-phase synthesis of branched thiohydantoin benzimidazolinethiones and branched thiohydantoin tetrahydroquinoxalinediones. Tetrahedron Lett. 41:2283-2287, 2000.
  42. Nefzi, A., Giulianotti, M.A., Ong, N.A., Houghten, R.A. Solid-phase synthesis of bis-2-imidazolidines from resin-bound tripeptides. Org. Letters 2:3349-3350, 2000.
  43. Nefzi, A., Giulianotti, M.A., Ong, N.A., Houghten, R.A. Combinatorial chemistry: Solid-phase synthesis of heterocyclic compounds from Cα-functionalized amino acids. In: Peptides for the New Millenium, Proceedings of the 16th American Peptide Symposium (Fields, G.B., Tam, J.P., Barany, G., Eds.), Kluwer Academic Publishers, Dordrecht, The Netherlands, pp. 189-190, 2000.
  44. Nefzi, A., Ong, N.A., Houghten, R.A. An efficient two-step synthesis of mono-, di- and triureas from resin-bound amides. Tetrahedron Lett. 41:5441-5446, 2000.
  45. Nefzi, A., Ostresh, J.M., Houghten, R.A. Solid-phase synthesis of heterocyclic compounds from amino acids and linear peptides. In: Solid-Phase Synthesis: A Practical Guide (Kates, S.A. and Albericio, A., Eds.), Marcel Dekker, Inc., New York, pp. 617-647, 2000.
  46. Ostresh, J.M., Schoner, C.C., Hamashin, V.T., Giulianotti, M.A., Nefzi, A., Kurth, M.J., Houghten, R.A. Solid phase synthesis of heterocyclic combinatorial libraries derived from peptides. In: Peptides, Biology and Chemistry, Proceedings of the 1998 Chinese Peptide Symposium (Hu, Y.J., Wang, R., and Tam, J.P., Eds.), Kluwer Academic Publishers, Dordrecht, The Netherlands, pp. 192-197, 2000.
  47. Pinilla, C., Appel, J.R., Blondelle, S.E., Dooley, C.T., Eichler, J., Nefzi, A., Ostresh, J.M., Martin, R., Wilson, D.B., Houghten, R.A. Synthesis and screening of positional scanning synthetic combinatorial libraries. In: Combinatorial Chemistry: A Practical Approach (Fenniri, H., Ed.), Oxford University Press, Oxford, pp. 51-74, 2000.
  48. Houghten, R.A., Dooley, C.T., Giulianotti, M.A., Hamashin, V.T., Schoner, C., Ostresh, J.M., Nefzi, A. Solid phase synthesis of heterocyclic positional scanning combinatorial libraries. In: Innovation and Perspectives in Solid Phase Synthesis and Combinatorial Libraries 1998 (Epton, R., Ed.), Mayflower Worldwide Ltd., Birmingham,UK, pp. 11-14, 1999.
  49. Houghten, R.A., Pinilla, C., Appel, J.R., Blondelle, S.E., Dooley, C.T., Eichler, J., Nefzi, A., Ostresh, J.M. Mixture-based synthetic combinatorial libraries. J. Med. Chem. 42:3743-3778, 1999.
  50. Meyer, J.-P., Ostresh, J.M., Nefzi, A., Hamashin, V.T., Schoner, C.C., Giulianotti, M.A., Hannah, A.L., Houghten, R.A. Peptides as precursors in the synthesis of heterocyclic positional scanning combinatorial libraries. In: Peptides, Frontiers of Peptide Science, Proceedings of the 15th American Peptide Symposium (Tam, J.P. and Kaumaya, P.T.P., Eds.), Kluwer, Dordrecht, The Netherlands, pp. 25-27, 1999.
  51. Nefzi, A., Giulianotti, M.A., Houghten, R.A. Solid phase synthesis of 1,6-disubstituted 2,3-diketopiperazines and 1,2-disubstituted piperazines from N-acylated amino acids. Tetrahedron Lett. 40:8539-8542, 1999.
  52. Nefzi, A., Ong, N.A., Giulianotti, M.A., Ostresh, J.M., Houghten, R.A. Solid phase synthesis of 1,4-benzothiazepin-5-one derivatives. Tetrahedron Lett. 40:4939-4942, 1999.
  53. Nefzi, A., Ostresh, J.M., Giulianotti, M.A., Houghten, R.A. Solid-phase synthesis of trisubstituted 2-imidazolidones and 2-imidazolidinethiones. J. Comb. Chem. 1:195-198, 1999.
  54. Nefzi, A., Ostresh, J.M., Houghten, R.A. Parallel solid phase synthesis of tetrasubstituted diethylenetriamines via selective amide alkylation and exhaustive reduction of N-acylated dipeptides. Tetrahedron 55:335-344, 1999.
  55. Blondelle, S.E., Nefzi, A., Ostresh, J.M., Houghten, R.A. Novel antifungal compounds derived from heterocyclic positional scanning combinatorial libraries. Pure Appl. Chem. 70:2141-2141, 1998.
  56. Houghten, R.A., Blondelle, S.E., Dooley, C.T., Meyer, J.-P., Ostresh, J.M., Nefzi, A. Preparation of heterocyclic positional scanning combinatorial libraries from peptides. In: Peptide Science - Present and Future (Shimonishi, Y., Ed.), Kluwer Academic Publishers, The Netherlands, pp. 125-129, 1998.
  57. Meyer, J.-P., Nefzi, A., Dörner, B., Ostresh, J.M., Hannah, A.L., Houghten, R.A. Design and solid phase synthesis of linear and heterocyclic combinatorial libraries using peptide libraries as starting materials. In: Peptides 1996, Proceedings of the Twenty-Fourth European Peptide Symposium (Ramage, R. and Epton, R., Eds.), MPG Books, Cornwall, England, pp. 643-644, 1998.
  58. Nefzi, A., Dooley, C.T., Ostresh, J.M., Houghten, R.A. Combinatorial chemistry: from peptides and peptidomimetics to small organic and heterocyclic compounds. Bioorg. Med. Chem. Lett. 8:2273-2278, 1998.
  59. Nefzi, A., Giulianotti, M., Houghten, R.A. Solid phase synthesis of 2,4,5-trisubstituted thiomorpholin-3-ones. Tetrahedron Lett. 39:3671-3674, 1998.
  60. Nefzi, A., Giulianotti, M.A., Brehm, E., Schoner, C.C., Hamashin, V.T., Houghten, R.A. Synthesis of cyclic ureas and cyclic thioureas from acyl dipeptides. In: Peptides: Frontiers of Peptide Science, Proceedings of the Fifteenth American Peptide Symposium (Tam, J. P., Kaumaya, P. T. P., Eds.) Kluwer Academic Publishers, Dordrecht, The Netherlands, pp. 265-266, 1998.
  61. Nefzi, A., Ostresh, J.M., Giulianotti, M.A., Houghten, R.A. Efficient solid phase synthesis of 3,5-disubstituted hydantoins. Tetrahedron Lett. 39:8199-8202, 1998.
  62. Ostresh, J.M., Schoner, C.C., Hamashin, V.T., Nefzi, A., Meyer, J.-P., Houghten, R.A. Solid phase synthesis of trisubstituted bicyclic guanidines via cyclicization of reduced N-acylated dipeptides. J. Org. Chem. 63:8622-8623, 1998.
  63. Nefzi, A., Ostresh, J.M., Houghten, R.A. Solid phase synthesis of 1,3,4,7-tetrasubstituted perhydro-1,4-diazepine-2,5-diones. Tetrahedron Lett. 38:4943-4946, 1997.
  64. Nefzi, A., Ostresh, J.M., Houghten, R.A. The current status of heterocyclic combinatorial libraries. Chem. Rev. 97:449-472, 1997.
  65. Nefzi, A., Ostresh, J.M., Meyer, J.-P., Houghten, R.A. Solid phase synthesis of heterocyclic compounds from linear peptides: Cyclic ureas and thioureas. Tetrahedron Lett. 38:931-934, 1997.
  66. Wöhr, T., Wahl, F., Nefzi, A., Rohwedder, B., Sato, T., Sun, X., Mutter, M. Pseudo-prolines as a solubilizing, structure-disrupting protection technique in peptide synthesis. J. Am. Chem. Soc., 118:9218-9227, 1996.
  67. Mutter, M., Nefzi, A., Sato, T., Sun, X., Wahl., Wöhr, T. Pseudo-prolines for accessing 'inaccessible' peptides. Peptide Res. 8:145-153, 1995.
  68. Tuchscherer, G., Nyanguile, O., Mathieu, M., Nefzi, A., Dumy, P., Kapron, J., Razaname, A., Mutter, M. Chemoselective ligation methods in TASP design. In: Peptides 1994, Proceedings of the 23rd European Peptide Symposium (Maia, H.L.S, Ed.) ESCOM, Leiden, pp 30-31, 1995.
  69. Wöhr, T., Nefzi, A., Sun, X.; Ryan, D., Mutter, M. Pseudo-prolines in peptide chemistry. In: Peptides 1994, Proceedings of the 23rd European Peptide Symposium (Maia, H. L. S, Ed.) ESCOM, Leiden, pp 252-253, 1995.
  70. Haack, T., Nefzi, A., Dhanapal, B., Mutter, M. Pseudo-prolines in peptide synthesis. II. Oxaproline and thiaproline derivatives and their use in SPPS. In: Innovation and Perspectives in Solid Phase Synthesis: Peptides, Proteins and Nucleic Acids (Epton, R., Ed.) Mayflower Scientific Limited, Birmingham, pp 521-524, 1994.
  71. Nefzi, A., Haack, T., Dhanapal, B., Kapron, J., Mutter, M. Oxazolidines and thiazolidines as secondary structure disrupting, solubilizing protection techniques for serine and cysteine. In: Peptides:  Chemistry, Structure and Biology, Proceedings of the 13th American Peptide Symposium (Hodges, R.S., Smith, J.A., Eds.) ESCOM, Leiden, pp. 37-39, 1994.
  72. Nefzi, A., Schenk, K., Mutter, M. Pseudo-prolines: Temporary insertion of a cis-amide bond into peptide backbone. Protein and Peptide Letters 1:66-69, 1994.
  73. Nefzi, A., Sun, X., Mutter, M. Chemoselective ligation of multifunctional peptides to topological templates via thioether formation for TASP synthesis. Tetrahedron Lett. 36:229-230, 1994.
  74. Haack, T., Nefzi, A., Zier, A., Mutter, M. New methodologies in convergent strategies: Ser(Ox) and Cys(Th) as solubilizing building blocks in peptide synthesis. In: Peptides 1992, Proceedings of the 22nd European Peptide Symposium (Schneider, C. H., Eberle, A. N., Eds) ESCOM, Leiden, pp.595-596, 1993.

Patents

  1. Diketoazacyclic compounds, diazacyclic compounds, and combinatorial libraries thereof. U.S. Patent No. 6,809,202. Issued October 26, 2004.  Inventors:  Nefzi, A., Ostresh, J.M., Houghten, R.A.
  2. Diketoazacyclic compounds, diazacyclic compounds, and combinatorial libraries thereof. U.S. Patent No. 6,441,172. Issued August 27, 2002.  Inventors:  Nefzi, A., Ostresh, J.M., Houghten, R.A.
  3. Combinatorial libraries of cyclic urea and cyclic thiourea derivatives and compounds therein. U.S. Patent No. 5,786,448. Issued July 28, 1998.  Inventors:  Nefzi, A., Ostresh, J.M., Houghten, R.A.
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