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DOI: 10.1055/s-2006-926249
Design, Synthesis, and Applications of 3-Aza-6,8-Dioxabicyclo[3.2.1]Octane-Based Scaffolds for Peptidomimetic Chemistry
Publikationsverlauf
Publikationsdatum:
06. Februar 2006 (online)
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Abstract
During the last three decades numerous peptides have been introduced in the treatment of several diseases, though, due to their low bioavailability, non-peptide compounds have been preferred for the generation of new therapeutic agents presenting a peptide as lead candidate. Thus, much effort has been devoted towards the development of isosteres capable to mimic either backbone or side chain structures, in order to improve biological stability and potency, and to reduce the complexity of the lead peptide. Such process has taken advantage of the synthesis of compounds using combinatorial library methodologies, which have achieved a major role in drug discovery, and recently, diversity-oriented synthesis has gained interest from many organic and medicinal chemists. Our group has focused on the development of a new class of bicyclic molecular scaffolds named BTAa (Bicycles from Tartaric acid and Amino acids), having a 3-aza-6,8-dioxa-bicyclo[3.2.1]octane as core structure, and amino acid side chain functionalities on stereodefined positions. These molecules are good templates for peptidomimetic design, and examples varying substituents, stereochemistry and ring-size have been reported using different synthetic strategies. Moreover, scaffolds derived from amino ketones and sugar derivatives (BTKa) have been synthesised on solid phase, thus exploring new methodologies for the generation of focused libraries of peptidomimetics. These compounds have been applied as dipeptide isosteres by the introduction in a cyclic oligopeptide chymotripsin inhibitor, and it has been demonstrated that BTAa scaffolds having the carboxylic group in 7-endo position can be considered as mimetics of β-turns in cyclic and linear peptides. New synthetic methodologies for proline-like bicyclic scaffolds have been developed for the production of different species of reverse-turn inducers, and BTAa scaffolds as γ/δ-amino acids have been used as monomers for the synthesis of oligomeric structures.
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1 Introduction
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2 3-Aza-6,8-dioxabicyclo[3.2.1]octane-Based Scaffolds
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2.1 Formal COOH Shift
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2.2 BTKa and 7-endo-BTKa
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2.3 [4.2.1]- and [5.2.1]-Sized Scaffolds
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2.4 Towards Polycyclic Scaffolds
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2.5 Chemical Stability
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2.6 Structural Features
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3 Bicyclic Scaffolds for Combinatorial Chemistry
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3.1 Ketone on Resin
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3.2 Sugar Moiety on Resin
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3.3 Amine on Resin
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3.4 Parallel Synthesis of Amides
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4 Bicyclic Scaffolds in Foldamer Design
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5 Bicyclic Scaffolds as Reverse-Turn Inducers
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5.1 BTAa as Reverse-Turn Mimetics in Cyclic Peptides
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5.2 BTAa as Reverse-Turn Mimetics in Linear Model Peptides
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5.3 Model Peptides for BGS Scaffolds as Proline Mimetics
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6 Concluding Remarks
Key words
peptidomimetics - solid-phase synthesis - peptides - conformational analysis - combinatorial chemistry
- 1
Giannis A.Kolter T. Angew. Chem., Int. Ed. Engl. 1993, 32: 1244 - 2
Gante J. Angew. Chem., Int. Ed. Engl. 1994, 33: 1699 - 3
Adessi C.Soto C. Curr. Med. Chem. 2002, 9: 963 - 4
Liskamp RMJ. Recl. Trav. Chim. Pays-Bas 1994, 113: 1 - 5
Olson GL.Bolin DR.Bonner MP.Bös M.Cook CM.Fry DC.Graves BJ.Hatada M.Hill DE.Kahn M.Madison VS.Rusiecki VK.Sarabu R.Sepinwall J.Vincent GP.Voss ME. J. Med. Chem. 1993, 36: 3039 - 6
Ripka AS.Rich DH. Curr. Opin. Chem. Biol. 1998, 2: 441 - 7
Hirschmann R.Nicolau KC.Pietranico S.Leahy EM.Salvino J.Arison B.Cichy MA.Spoors PG.Shakespeare WC.Sprengeler PA.Hamley P.Smith AB.Reisine T.Raynor K.Maechler L.Donaldson C.Vale W.Freidinger RM.Cascieri MR.Strader CD. J. Am. Chem. Soc. 1993, 115: 12550 - 8
Hirschmann R.Sprengeler PA.Kawasaki T.Leahy JW.Shakespeare WC.Smith AB. J. Am. Chem. Soc. 1992, 114: 9699 - 9
Lam KS.Lebl M.Krchňák V. Chem. Rev. 1997, 97: 411 - 10
Dolle RE. J. Comb. Chem. 2001, 3: 477 - 11
Dolle RE. J. Comb. Chem. 2002, 4: 369 - 12
Dolle RE. J. Comb. Chem. 2003, 5: 693 - 13
Dolle RE. J. Comb. Chem. 2004, 6: 623 - 14
Thompson LA.Ellman JA. Chem. Rev. 1996, 96: 555 - 15
Nefzi A.Ostresh JM.Houghten RA. Chem. Rev. 1997, 97: 449 - 16
Golebiowski A.Klopfenstein SR.Shao X.Chen JJ.Colson A.-O.Grieb AL.Russell AF. Org. Lett. 2000, 2: 2615 - 17
Creighton CJ.Zapf CW.Bu JH.Goodman M. Org. Lett. 1999, 1: 1407 - 18
Kim HO.Nakanishi H.Lee MS.Kahn M. Org. Lett. 2000, 2: 301 - 19
Eguchi M.Lee MS.Nakanishi H.Stasiak M.Lovell S.Kahn M. J. Am. Chem. Soc. 1999, 121: 12204 - 20
Guarna A.Guidi A.Machetti F.Menchi G.Occhiato EG.Scarpi D.Sisi S.Trabocchi A. J. Org. Chem. 1999, 64: 7347 - 21
Cini N.Machetti F.Menchi G.Occhiato EG.Guarna A. Eur. J. Org. Chem. 2002, 873 - 22
Trabocchi A.Menchi G.Rolla M.Machetti F.Bucelli I.Guarna A. Tetrahedron 2003, 59: 5251 - 23
Trabocchi A.Cini N.Menchi G.Guarna A. Tetrahedron Lett. 2003, 44: 3489 - 24
Guarna A.Bucelli I.Machetti F.Menchi G.Occhiato EG.Scarpi D.Trabocchi A. Tetrahedron 2002, 58: 9865 - 25
Guarna A,Menchi G,Machetti F,Occhiato EG, andScarpi D. inventors; WO 01/64686. ; Chem. Abstr. 2001, 135, 211044 - 26
Trabocchi A.Mancini F.Menchi G.Guarna A. Mol. Diversity 2003, 6: 245 - 27
Scarpi D.Stranges D.Cecchi L.Guarna A. Tetrahedron 2004, 60: 2583 - 28
Danieli E.Trabocchi A.Menchi G.Guarna A. Eur. J. Org. Chem. 2005, 4372 - 29
Trabocchi A.Rolla M.Menchi G.Guarna A. Tetrahedron Lett. 2005, 46: 7813 - 31 The use of anhydride followed by SOCl2 treatment was reported for the preparation of BTG. See:
Dienes Z.Vogel P. J. Org. Chem. 1996, 61: 6958 - 32
Reymond J.-L.Vogel P. J. Chem. Soc., Chem. Commun. 1990, 1070 - 33
Reymond J.-L.Vogel P. Tetrahedron: Asymmetry 1990, 1: 729 - 35
Hanessian S.Xie F. Tetrahedron Lett. 1998, 39: 733 - 36
Christensen T. Acta Chem. Scand., Ser. B 1979, 33: 763 - 37 The Bromophenol Blue test is not specific, as it reveals the presence of primary to quaternary amines. See:
Krchnák V.Vágner J.Safár P.Lebl M. Collect. Czech. Chem. Commun. 1988, 53: 2542 - 38
Furman B.Thürmer R.Kaluża Z.Lysek R.Voelter W.Chmielewski M. Angew. Chem. Int. Ed. 1999, 38: 1121 - 39
Purandare AV.Poss MA. Tetrahedron Lett. 1998, 39: 935 - 40
Caputo R.Cassano E.Longobardo L.Palumbo G. Tetrahedron 1995, 51: 12337 - 41
Yan LZ.Mayer JP. J. Org. Chem. 2003, 68: 1161 - 42
Abdel-Magid AF.Carson KG.Harris BD.Maryanoff CA.Shah RD. J. Org. Chem. 1996, 61: 3849 - 43 This compound was obtained by oxidative cleavage of d-1,2:5,6-di-O-isopropylidene-mannitol with NaIO4 as reported. See:
Earle MJ.Abdur-Rashid A.Priestley ND. J. Org. Chem. 1996, 61: 5697 - 44
Machetti F.Bucelli I.Indiani G.Guarna A. C. R. Chimie 2003, 6: 631 - 45
Gellman SH. Acc. Chem. Res. 1998, 31: 173 - 46
Hill DJ.Mio MJ.Prince RB.Hughes TS.Moore JS. Chem. Rev. 2001, 101: 3893 - 47
Machetti F.Ferrali A.Menchi G.Occhiato EG.Guarna A. Org. Lett. 2000, 2: 3987 - 48
Chou PY.Fasman GD. J. Mol. Biol. 1977, 115: 135 - 49
Rose GD.Gierasch LM.Smith JA. Adv. Protein Chem. 1985, 37: 1 - 50
Stanfield RL.Fieser TM.Lerner RA.Wilson IA. Science 1990, 248: 712 - 51
Müller G.Hessler G.Decornez HY. Angew. Chem. Int. Ed. 2000, 39: 894 - 52
Richardson JS. Adv. Protein Chem. 1981, 34: 167 - 53
Müller G. Angew. Chem., Int. Ed. Engl. 1996, 35: 2767 - 54
Belvisi L.Gennari C.Mielgo A.Potenza D.Scolastico C. Eur. J. Org. Chem. 1999, 389 - 55
Halab L.Lubell WD. J. Org. Chem. 1999, 64: 3312 - 56
Halab L.Lubell WD. J. Am. Chem. Soc. 2002, 124: 2474 - 57
Dumas J.-P.Germanas JP. Tetrahedron Lett. 1994, 35: 1495 - 58
Kim K.Germanas JP. J. Org. Chem. 1997, 62: 2847 - 59
Cumberbatch S.North M.Zagotto G. Tetrahedron 1993, 49: 9049 - 60
An SSA.Lester CC.Peng J.-L.Li Y.-J.Rothwarf DM.Welker E.Thannhauser TW.Zhang LS.Tam JP.Scheraga HA. J. Am. Chem. Soc. 1999, 121: 11558 - 61
Keller M.Sager C.Dumy P.Schutkowsky M.Fischer GS.Mutter M. J. Am. Chem. Soc. 1998, 120: 2714 - 62
Brady SF.Paleveda WJ.Arison BH.Saperstein R.Brady EJ.Raynor K.Reisine T.Veber DF.Freidinger RM. Tetrahedron 1993, 49: 3449 - 63
Sukumaran DK.Prorok M.Lawrence DS. J. Am. Chem. Soc. 1991, 113: 706 - 64
Zabrocki J.Smith GD.Dunbar JB.Marshall GR. J. Am. Chem. Soc. 1988, 110: 5875 - 65
Souers AJ.Virgilio AA.Schürer SS.Ellman JA.Kogan TP.West HE.Ankener W.Vanderslice P. Bioorg. Med. Chem. Lett. 1998, 8: 2297 - 66
Cho N.Harada M.Imaeda T.Imada T.Matsumoto H.Hayase Y.Sasaki S.Furuya S.Suzuki N.Okubo S.Ogi S.Endo S.Onda H.Fujino M. J. Med. Chem. 1998, 41: 4190 - 67
Souers AJ.Virgilio AA.Rosenquist Ĺ.Fenuik W.Ellman JA. J. Am. Chem. Soc. 1999, 121: 1817 - 68
Virgilio AA.Ellman JA. J. Am. Chem. Soc. 1994, 116: 11580 - 69
Virgilio AA.Schürer SC.Ellman JA. Tetrahedron Lett. 1996, 37: 6961 - 70
Virgilio AA.Bray AA.Zhang W.Trinh L.Snyder M.Morissey M.Ellman JA. Tetrahedron 1997, 53: 6635 - 71
Feng Y.Wang Z.Jin S.Burgess K. J. Am. Chem. Soc. 1998, 120: 10768 - 72
Eguchi M.Lee MS.Nakanishi H.Stasiak M.Lovell S.Kahn M. J. Am. Chem. Soc. 1999, 121: 12204 - 73
Nagai U.Sato K. Tetrahedron Lett. 1985, 26: 647 - 74
Feigel M. J. Am. Chem. Soc. 1986, 108: 181 - 75
Diaz H.Espina JR.Kelly JW. J. Am. Chem. Soc. 1992, 114: 8316 - 76
Genin MJ.Johnson RL. J. Am. Chem. Soc. 1992, 114: 8778 - 77
Jones IG.Jones W.North M. J. Org. Chem. 1998, 63: 1505 - 78
Holmes DL.Smith EM.Nowick JS. J. Am. Chem. Soc. 1997, 119: 7655 - 79
Smith EM.Holmes DL.Shaka AJ.Nowick JS. J. Org. Chem. 1997, 62: 7906 - 80
Nesloney CL.Kelly JW. J. Am. Chem. Soc. 1996, 118: 5836 - 81
Gardner RR.Liang G.-B.Gellman SH. J. Am. Chem. Soc. 1995, 117: 3280 - 82
Schneider JP.Kelly JW. J. Am. Chem. Soc. 1995, 117: 2533 - 83
Kemp DS.Li ZQ. Tetrahedron Lett. 1995, 36: 4179 - 84
Gardner B.Nanashi H.Khan M. Tetrahedron 1993, 49: 3433 - 85
Brandmeier V.Feigel M. Angew. Chem., Int. Ed. Engl. 1989, 28: 486 ; Angew. Chem. 1989, 102, 466 - 86
Nowick S.Smith EM.Noronha G. J. Org. Chem. 1995, 60: 7386 - 87
Nagai U.Sato K.Nakamura R.Kato R. Tetrahedron 1993, 49: 3577 - 88
Kemp DS.Sites WE. Tetrahedron Lett. 1988, 29: 5057 - 89
Haque TS.Gellman SH. J. Am. Chem. Soc. 1997, 119: 2303 - 90
Krauthäuser S.Christianson LA.Powell DR.Gellman SH. J. Am. Chem. Soc. 1997, 119: 11719 - 91
Hanessian S.Yang H. Tetrahedron Lett. 1997, 38: 3155 - 92
Fink BE.Kym PR.Katzenellenbogen JA. J. Am. Chem. Soc. 1998, 120: 4334 - 93
Hanessian S.McNaughton-Smith G.Lombart H.-G.Lubell WD. Tetrahedron 1997, 53: 12789 - 94
Wishart DS.Sykes BD.Richards FM. J. Mol. Biol. 1991, 222: 311 - 95
Chang G.Guida WC.Still WC. J. Comput. Chem. 1994, 15: 1302 - 96
Ball JB.Hughes RA.Alewood PF.Andrews PR. Tetrahedron 1993, 49: 3467 - 97
Scarpi D.Occhiato EG.Trabocchi A.Leatherbarrow RJ.Brauer ABE.Nievo M.Guarna A. Bioorg. Med. Chem. 2001, 9: 1625 - 98
Trabocchi A.Occhiato EG.Potenza D.Guarna A. J. Org. Chem. 2002, 67: 7483 - 99
Trabocchi A.Potenza D.Guarna A. Eur. J. Org. Chem. 2004, 4621 - 100
Fisk JD.Powell DR.Gellman SH. J. Am. Chem. Soc. 2000, 122: 5443
References and Notes
TBDMS-protected 3-amino-1,2-propanediol was obtained in high purity and yield after a two-step process involving reaction of benzylamine with TBDMS-protected glycidol in the presence of LiNTf2, and subsequent hydrogenation of the benzylic group.
34Crystallographic data (excluding structure factors) for the structure 110 in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 286087. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].