title: Conformationally constrained histidines in the design of peptidomimetics: strategies for the χ-space control.
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 χ(1) and χ(2) 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 C(α)-C(β) cyclopropane insertion (ACC derivatives). Attention is also dedicated to the relevant field of β-aminoacid chemistry by describing the synthesis of β(2)- and β(3)-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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Chieti-Pescara "G. d'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.
authors.forename: Azzurra
authors.initials: A
authors.lastname: Stefanucci
authors.forename: Francesco
authors.initials: F
authors.lastname: Pinnen
authors.forename: Federica
authors.initials: F
authors.lastname: Feliciani
authors.forename: Ivana
authors.initials: I
authors.lastname: Cacciatore
authors.forename: Gino
authors.initials: G
authors.lastname: Lucente
authors.forename: Adriano
authors.initials: A
authors.lastname: Mollica
mesh_terms: D003521:Cyclopropanes / Q000737:chemistry; D006639:Histidine / Q000737:chemistry*; D008958:Models, Molecular; D057786:Peptidomimetics / Q000737:chemistry*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D003521:Cyclopropanes; D057786:Peptidomimetics; D006639:Histidine; C030797:cyclopropane