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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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Synthetic procedure for α-alkyl histidine [18].
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f16-ijms-12-02853: Synthetic procedure for α-alkyl histidine [18].

Mentions: Two years later DeGraw et al. used the route outlined in Scheme 3 to synthesize α-substituted histidines. 4-Chloromethylimidazole hydrochloride 8 [18], was added to a solution of an appropriate 2-alkyl acetoacetate 9a–d,f or 2-acetylbutyrolactone 9e in ethanol solution containing sodium ethoxide to afford the 2-alkyl 2-(4-imidazolylmethyl)acetoacetate 10. When the keto ester 10 was allowed to react with a slight excess of hydrazoic acid in sulfuric acid solution, the N-acetylhistidine esters 11a–e were obtained in 50–70% yields. Under the acidic conditions employed, the α-allyl-analogue 10f was apparently subjected to additional attack on the vinyl moiety, leading to an unidentified product rather than the anticipated product 11f. Schmidt [19] had qualitatively shown that in β-keto esters the HN3 reagent afforded selective attack on the ketone carbonyl with subsequent rearrangement occurring at the α-carbon. Synthesis of the histidines 12 and 13 were completed by acid hydrolysis of the amide and ester functions. This route seems to have been little used in the synthesis of α-substituted amino acids, but especially valuable in the histidine series.


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)

Synthetic procedure for α-alkyl histidine [18].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f16-ijms-12-02853: Synthetic procedure for α-alkyl histidine [18].
Mentions: Two years later DeGraw et al. used the route outlined in Scheme 3 to synthesize α-substituted histidines. 4-Chloromethylimidazole hydrochloride 8 [18], was added to a solution of an appropriate 2-alkyl acetoacetate 9a–d,f or 2-acetylbutyrolactone 9e in ethanol solution containing sodium ethoxide to afford the 2-alkyl 2-(4-imidazolylmethyl)acetoacetate 10. When the keto ester 10 was allowed to react with a slight excess of hydrazoic acid in sulfuric acid solution, the N-acetylhistidine esters 11a–e were obtained in 50–70% yields. Under the acidic conditions employed, the α-allyl-analogue 10f was apparently subjected to additional attack on the vinyl moiety, leading to an unidentified product rather than the anticipated product 11f. Schmidt [19] had qualitatively shown that in β-keto esters the HN3 reagent afforded selective attack on the ketone carbonyl with subsequent rearrangement occurring at the α-carbon. Synthesis of the histidines 12 and 13 were completed by acid hydrolysis of the amide and ester functions. This route seems to have been little used in the synthesis of α-substituted amino acids, but especially valuable in the histidine series.

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