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 Fmoc-β3hHis(Tr)-OH 104 starting from 100 [80].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f40-ijms-12-02853: Preparation of Fmoc-β3hHis(Tr)-OH 104 starting from 100 [80].

Mentions: The successful preparation of Fmoc-β3hHis(Tr)-OH was accomplished by using the Boc-protected homo-histidine esters 100 as starting materials. As such, Boc deprotection, followed by saponification or hydrogenolysis of the ester groups, gave the completely unprotected β3-homo-histidine, which was then phthaloyl(Phth)-protected and acidified to yield the HCl salt 103 in 67% yield. Subsequent tritylation and N-Phth/N-Fmoc protecting-group exchange afforded the acid 104 in 61% yield over the three steps (Scheme 27).


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 Fmoc-β3hHis(Tr)-OH 104 starting from 100 [80].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f40-ijms-12-02853: Preparation of Fmoc-β3hHis(Tr)-OH 104 starting from 100 [80].
Mentions: The successful preparation of Fmoc-β3hHis(Tr)-OH was accomplished by using the Boc-protected homo-histidine esters 100 as starting materials. As such, Boc deprotection, followed by saponification or hydrogenolysis of the ester groups, gave the completely unprotected β3-homo-histidine, which was then phthaloyl(Phth)-protected and acidified to yield the HCl salt 103 in 67% yield. Subsequent tritylation and N-Phth/N-Fmoc protecting-group exchange afforded the acid 104 in 61% yield over the three steps (Scheme 27).

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