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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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Removal of the auxiliary with BnOLi followed by Mitsunobu Reaction and functional group modifications for the preparation of Fmoc-(S)-β2hHis(Tr)-OH 98 [80].
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f38-ijms-12-02853: Removal of the auxiliary with BnOLi followed by Mitsunobu Reaction and functional group modifications for the preparation of Fmoc-(S)-β2hHis(Tr)-OH 98 [80].

Mentions: The next step required the replacement of the OH group of 93 by a N-substituent by means of a Mitsunobu reaction. Thus, treatment of (R,S)-93 with Ph3P, DIAD and either DPPA or hydrazoic acid afforded the azide derivative (R,S)-94 in moderate to good yields (55 and 89% resp.). However attempts to cleave the auxiliary were not successful. Indeed, removal of the oxazolidinone group by BnOH/BuLi afforded the elimination product 95 (Scheme 24). To circumvent this problem, the hydroxymethyl derivative 93 was first treated with BnOH/BuLi to form the corresponding benzyl ester (S)-96, which was subsequently transformed to the azide (S)-97 under the Mitsunobu conditions in good yield (Scheme 25).


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)

Removal of the auxiliary with BnOLi followed by Mitsunobu Reaction and functional group modifications for the preparation of Fmoc-(S)-β2hHis(Tr)-OH 98 [80].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f38-ijms-12-02853: Removal of the auxiliary with BnOLi followed by Mitsunobu Reaction and functional group modifications for the preparation of Fmoc-(S)-β2hHis(Tr)-OH 98 [80].
Mentions: The next step required the replacement of the OH group of 93 by a N-substituent by means of a Mitsunobu reaction. Thus, treatment of (R,S)-93 with Ph3P, DIAD and either DPPA or hydrazoic acid afforded the azide derivative (R,S)-94 in moderate to good yields (55 and 89% resp.). However attempts to cleave the auxiliary were not successful. Indeed, removal of the oxazolidinone group by BnOH/BuLi afforded the elimination product 95 (Scheme 24). To circumvent this problem, the hydroxymethyl derivative 93 was first treated with BnOH/BuLi to form the corresponding benzyl ester (S)-96, which was subsequently transformed to the azide (S)-97 under the Mitsunobu conditions in good yield (Scheme 25).

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