Limits...
Conformationally constrained histidines in the design of peptidomimetics: strategies for the χ-space control.

Stefanucci A, Pinnen F, Feliciani F, Cacciatore I, Lucente G, Mollica A - Int J Mol Sci (2011)

Bottom Line: A successful design of peptidomimetics must come to terms with χ-space control.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Chieti-Pescara "G. d'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.

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.

Show MeSH
Preparation of Boc-β3hHis(Boc)-OH 110 via Kolbe reaction [81].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC3116161&req=5

f41-ijms-12-02853: Preparation of Boc-β3hHis(Boc)-OH 110 via Kolbe reaction [81].

Mentions: Recently, Wyatt and co-workers [81] accomplished the synthesis of Boc-β3hHis-(Boc)-OH 110 via the Kolbe reaction, i.e., (Scheme 28), by reducing α-Mts-His(Mts)-OMe 105 to the corresponding amino alcohol 106 in 58% yield, the OH group of which was then activated as its methanesulfonate 107 (81%) and replaced by CN, to give compound 109; treatment of the methanesulfonate 107 with NaCN (1 equiv.) in DMF at room temperature gave mainly the aziridine 108, which could be ring-opened by excess cyanide to give the desired nitrile 109; by using two or more equivalents of NaCN in DMF at room temperature the methanesulfonate 107 could be converted into the nitrile 109 (63%) in a single step. The CN group was, in turn, hydrolyzed to the MeNH group, which was Boc-protected to give the final product 110 in 7% yield over five steps. The authors state that this derivative is suitable for direct use in the synthesis of peptides, but so far no applications are known.


Conformationally constrained histidines in the design of peptidomimetics: strategies for the χ-space control.

Stefanucci A, Pinnen F, Feliciani F, Cacciatore I, Lucente G, Mollica A - Int J Mol Sci (2011)

Preparation of Boc-β3hHis(Boc)-OH 110 via Kolbe reaction [81].
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3116161&req=5

f41-ijms-12-02853: Preparation of Boc-β3hHis(Boc)-OH 110 via Kolbe reaction [81].
Mentions: Recently, Wyatt and co-workers [81] accomplished the synthesis of Boc-β3hHis-(Boc)-OH 110 via the Kolbe reaction, i.e., (Scheme 28), by reducing α-Mts-His(Mts)-OMe 105 to the corresponding amino alcohol 106 in 58% yield, the OH group of which was then activated as its methanesulfonate 107 (81%) and replaced by CN, to give compound 109; treatment of the methanesulfonate 107 with NaCN (1 equiv.) in DMF at room temperature gave mainly the aziridine 108, which could be ring-opened by excess cyanide to give the desired nitrile 109; by using two or more equivalents of NaCN in DMF at room temperature the methanesulfonate 107 could be converted into the nitrile 109 (63%) in a single step. The CN group was, in turn, hydrolyzed to the MeNH group, which was Boc-protected to give the final product 110 in 7% yield over five steps. The authors state that this derivative is suitable for direct use in the synthesis of peptides, but so far no applications are known.

Bottom Line: A successful design of peptidomimetics must come to terms with χ-space control.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Sciences, University of Chieti-Pescara "G. d'Annunzio", Via dei Vestini 31, 66100 Chieti, Italy.

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.

Show MeSH