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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.

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Synthesis of dl-α-Amino-1,2,3-triazole-4-propionic acid [84].
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f43-ijms-12-02853: Synthesis of dl-α-Amino-1,2,3-triazole-4-propionic acid [84].

Mentions: Robinson et al. [84] proposed the synthesis of dl-α-Amino-l,2,3-triazole-4-propionic acid 112, prepared by two independent routes. The catalytic hydrogenation of the oximino acid was extremely slow and the yield of the amino acid was small (17%). As an unambiguous method, the synthesis was also accomplished through the azlactone. From 1,2,3-triazole-4-carboxaldehyde 111, the crude azlactone was obtained (52%) as a mixture of a ring-acetylated azlactone and a small amount of the non-acetylated form which was separated through its insolubility in chloroform. The latter compound was readily converted into the former by acetylation. Purified samples of both forms gave α-benzamido-1,2,3-triazole-4-acrylic acid dihydrate on hydrolysis (86–88%). The yield of the acrylic acid dihydrate from the crude mixture of azlactones was 85%. α-Benzamido-l,2,3-triazole-4-propionic acid was obtained in 61% yield by hydrogenation of the acrylic acid in glacial acetic acid using platinum oxide. Hydrolysis of this benzamido acid gave analytically pure dl-amino-l,2,3-triazole-4-propionic acid 112 in 51% yield (Scheme 30).


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)

Synthesis of dl-α-Amino-1,2,3-triazole-4-propionic acid [84].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f43-ijms-12-02853: Synthesis of dl-α-Amino-1,2,3-triazole-4-propionic acid [84].
Mentions: Robinson et al. [84] proposed the synthesis of dl-α-Amino-l,2,3-triazole-4-propionic acid 112, prepared by two independent routes. The catalytic hydrogenation of the oximino acid was extremely slow and the yield of the amino acid was small (17%). As an unambiguous method, the synthesis was also accomplished through the azlactone. From 1,2,3-triazole-4-carboxaldehyde 111, the crude azlactone was obtained (52%) as a mixture of a ring-acetylated azlactone and a small amount of the non-acetylated form which was separated through its insolubility in chloroform. The latter compound was readily converted into the former by acetylation. Purified samples of both forms gave α-benzamido-1,2,3-triazole-4-acrylic acid dihydrate on hydrolysis (86–88%). The yield of the acrylic acid dihydrate from the crude mixture of azlactones was 85%. α-Benzamido-l,2,3-triazole-4-propionic acid was obtained in 61% yield by hydrogenation of the acrylic acid in glacial acetic acid using platinum oxide. Hydrolysis of this benzamido acid gave analytically pure dl-amino-l,2,3-triazole-4-propionic acid 112 in 51% yield (Scheme 30).

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