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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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An ORTEP view of Spi [46].
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f5-ijms-12-02853: An ORTEP view of Spi [46].

Mentions: X-ray studies reported by Andreetti et al. [46], showed that the crystals correspond to the tautomer having the N(3) atom protonated as shown in Figure 5, in which the bond distances are also reported. Thus, the compound corresponds to the amphionic form of the 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid. Condensation of imidazole with tetrahydropyridine removes the π electron delocalisation on the imidazole and produces a double bond localized on C(2)-C(7) [C(2)-C(7) = 1.331(10) Å]. The other bond distances and angles are in agreement with the hybridisation state of the atoms. The imidazole ring and the C(6) and C(3) atoms lie on a plane whereas C(4) and N(1) are out of that plane by 0.208 and −0.568 Å respectively; this as a consequence of the sp3 character of the four atoms of the six-membered ring. The torsional angles around the N(1)-C(3) and C(4)-C(6) are −25.6° and 30.8° respectively. The carboxyl group is equatorial and orientated in such a way that one oxygen points to the NH2+ group to compensate the opposite electrical charge.


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)

An ORTEP view of Spi [46].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f5-ijms-12-02853: An ORTEP view of Spi [46].
Mentions: X-ray studies reported by Andreetti et al. [46], showed that the crystals correspond to the tautomer having the N(3) atom protonated as shown in Figure 5, in which the bond distances are also reported. Thus, the compound corresponds to the amphionic form of the 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid. Condensation of imidazole with tetrahydropyridine removes the π electron delocalisation on the imidazole and produces a double bond localized on C(2)-C(7) [C(2)-C(7) = 1.331(10) Å]. The other bond distances and angles are in agreement with the hybridisation state of the atoms. The imidazole ring and the C(6) and C(3) atoms lie on a plane whereas C(4) and N(1) are out of that plane by 0.208 and −0.568 Å respectively; this as a consequence of the sp3 character of the four atoms of the six-membered ring. The torsional angles around the N(1)-C(3) and C(4)-C(6) are −25.6° and 30.8° respectively. The carboxyl group is equatorial and orientated in such a way that one oxygen points to the NH2+ group to compensate the opposite electrical charge.

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