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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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Preparation of the β3-homo-histidine derivative 102 by Arndt-Eistert homologation of Boc-His(Ts)-OH, followed by Tr-protection and saponification of the methyl ester group in 101 [80].
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f39-ijms-12-02853: Preparation of the β3-homo-histidine derivative 102 by Arndt-Eistert homologation of Boc-His(Ts)-OH, followed by Tr-protection and saponification of the methyl ester group in 101 [80].

Mentions: First attempts at synthesizing the homo-histidine derivatives by Seeback et al. [80] using the Arndt-Eistert homologation from Fmoc-His(τ-BOM)-OH, Fmoc-His(τ-Tr)-OH, Boc-His(τ-Bn)-OH, Boc-His(π-Bn)-OH, and Boc-His(τ-BOM)-OH were unsuccessful. Only Ts-protected histidines reacted with CH2N2 to form the corresponding diazo ketones, probably due to the strong electron-withdrawing effect of the tosylate, which renders the 1H-imidazolyl-N-atom less nucleophilic. Thus, commercially available Fmoc-His(Ts)-OH and Boc-His(Ts)-OH were converted via their mixed anhydrides (NMM/ClCO2Et or NEt3/ClCO2iBu) to the diazo ketones 99a and 99b in 56 and 86% yields respectively (Scheme 26). Attempts at converting diazo ketone 99a to a β3-homo-histidine derivative were shown to be ineffective, due to its insolubility in most solvents suitable for the Wolff rearrangement (e.g., BnOH, H2O, THF, dioxane, etc.). On the other hand, decomposition of diazo ketone 99b in the presence of the corresponding alcohol (MeOH, BnOH), by reaction with catalytic amounts of Ag+ (CF3CO2Ag dissolved in Et3N) gave the Boc-protected methyl or benzyl ester 100 as a mixture of three products in a 1:1:1 ratio. It was found that the Ag+ ion interacts with the 1H-imidazole ring inducing the partial displacement of the Ts protecting group from the τ-N to the π-N, as well as the complete removal of this protecting group. With this result at hand, they decided to use Boc-His(πTs)-OH as starting material for conversion to the β3-amino acid derivative Fmoc-β3hHis(πTr)-OH. Since the use of histidine derivatives with unprotected 1H-imidazolyl side chains for peptide couplings in solution or on solid support are known to cause side reactions, Tr-protected 1H-imidazolyl group of the ester 100 was used: treatment with TrCl and Et3N afforded compound 101 in quantitative yield. Hydrolysis of the methyl ester with LiOH in MeOH/H2O gave the acid 102 as a single product (Scheme 26). The Boc-β3hHis(Tr)-OH 102 was thus prepared from α-Boc-His(Ts)-OH in ca. 75% yield over four steps.


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 the β3-homo-histidine derivative 102 by Arndt-Eistert homologation of Boc-His(Ts)-OH, followed by Tr-protection and saponification of the methyl ester group in 101 [80].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f39-ijms-12-02853: Preparation of the β3-homo-histidine derivative 102 by Arndt-Eistert homologation of Boc-His(Ts)-OH, followed by Tr-protection and saponification of the methyl ester group in 101 [80].
Mentions: First attempts at synthesizing the homo-histidine derivatives by Seeback et al. [80] using the Arndt-Eistert homologation from Fmoc-His(τ-BOM)-OH, Fmoc-His(τ-Tr)-OH, Boc-His(τ-Bn)-OH, Boc-His(π-Bn)-OH, and Boc-His(τ-BOM)-OH were unsuccessful. Only Ts-protected histidines reacted with CH2N2 to form the corresponding diazo ketones, probably due to the strong electron-withdrawing effect of the tosylate, which renders the 1H-imidazolyl-N-atom less nucleophilic. Thus, commercially available Fmoc-His(Ts)-OH and Boc-His(Ts)-OH were converted via their mixed anhydrides (NMM/ClCO2Et or NEt3/ClCO2iBu) to the diazo ketones 99a and 99b in 56 and 86% yields respectively (Scheme 26). Attempts at converting diazo ketone 99a to a β3-homo-histidine derivative were shown to be ineffective, due to its insolubility in most solvents suitable for the Wolff rearrangement (e.g., BnOH, H2O, THF, dioxane, etc.). On the other hand, decomposition of diazo ketone 99b in the presence of the corresponding alcohol (MeOH, BnOH), by reaction with catalytic amounts of Ag+ (CF3CO2Ag dissolved in Et3N) gave the Boc-protected methyl or benzyl ester 100 as a mixture of three products in a 1:1:1 ratio. It was found that the Ag+ ion interacts with the 1H-imidazole ring inducing the partial displacement of the Ts protecting group from the τ-N to the π-N, as well as the complete removal of this protecting group. With this result at hand, they decided to use Boc-His(πTs)-OH as starting material for conversion to the β3-amino acid derivative Fmoc-β3hHis(πTr)-OH. Since the use of histidine derivatives with unprotected 1H-imidazolyl side chains for peptide couplings in solution or on solid support are known to cause side reactions, Tr-protected 1H-imidazolyl group of the ester 100 was used: treatment with TrCl and Et3N afforded compound 101 in quantitative yield. Hydrolysis of the methyl ester with LiOH in MeOH/H2O gave the acid 102 as a single product (Scheme 26). The Boc-β3hHis(Tr)-OH 102 was thus prepared from α-Boc-His(Ts)-OH in ca. 75% yield over four steps.

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