Conformationally Constrained Histidines in the Design of Peptidomimetics: Strategies for the χ-Space Control

International Journal of Molecular Sciences

Azzurra Stefanucci¹  Francesco Pinnen¹  Federica Feliciani¹  Ivana Cacciatore¹  Gino Lucente² 

[1] 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

关键词: amino acids;    alkyl substitution;    conformation;    histidine;    stereoselective synthesis;    χ-space;   

DOI  :  10.3390/ijms12052853

来源: mdpi

【 摘 要 】

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 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 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.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.