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Conformationally Constrained Histidines in the Design of Peptidomimetics: Strategies for the χ-Space Control
Department of Pharmaceutical Sciences, University of Chieti-Pescara “G. d’Annunzio”, Via dei Vestini 31, 66100 Chieti, Italy
Institute of Biomolecular Chemistry (CNR), c/o Department of Chemistry and Pharmaceutical Technologies, “Sapienza”, University of Rome, P.le A. Moro, 00185 Rome, Italy
* Author to whom correspondence should be addressed.
Received: 31 March 2011; in revised form: 18 April 2011 / Accepted: 20 April 2011 / Published: 3 May 2011
Abstract: A successful design of peptidomimetics must come to terms with χ-space control. The incorporation of χ-space constrained amino acids into bioactive peptides renders the χ1 and χ2 torsional angles of pharmacophore amino acids critical for activity and selectivity as with other relevant structural features of the template. This review describes histidine analogues characterized by replacement of native α and/or β-hydrogen atoms with alkyl substituents as well as analogues with α, β-didehydro unsaturation or Cα-Cβ cyclopropane insertion (ACC derivatives). Attention is also dedicated to the relevant field of β-aminoacid chemistry by describing the synthesis of β2- and β3-models (β-hHis). Structural modifications leading to cyclic imino derivatives such as spinacine, aza-histidine and analogues with shortening or elongation of the native side chain (nor-histidine and homo-histidine, respectively) are also described. Examples of the use of the described analogues to replace native histidine in bioactive peptides are also given.
Keywords: amino acids; alkyl substitution; conformation; histidine; stereoselective synthesis; χ-space
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Stefanucci, A.; Pinnen, F.; Feliciani, F.; Cacciatore, I.; Lucente, G.; Mollica, A. Conformationally Constrained Histidines in the Design of Peptidomimetics: Strategies for the χ-Space Control. Int. J. Mol. Sci. 2011, 12, 2853-2890.
Stefanucci A, Pinnen F, Feliciani F, Cacciatore I, Lucente G, Mollica A. Conformationally Constrained Histidines in the Design of Peptidomimetics: Strategies for the χ-Space Control. International Journal of Molecular Sciences. 2011; 12(5):2853-2890.
Stefanucci, Azzurra; Pinnen, Francesco; Feliciani, Federica; Cacciatore, Ivana; Lucente, Gino; Mollica, Adriano. 2011. "Conformationally Constrained Histidines in the Design of Peptidomimetics: Strategies for the χ-Space Control." Int. J. Mol. Sci. 12, no. 5: 2853-2890.