Limits...
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.

Show MeSH
Preparation of the acyloxazolidinone (R)-92 starting from urocanic acid [80].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f36-ijms-12-02853: Preparation of the acyloxazolidinone (R)-92 starting from urocanic acid [80].

Mentions: Initial attempts of diastereoselective alkylation (cf. A in Scheme 22) of homo-glycine derived acyloxazolidinones III (PG = Phth; PG = Ph2C) with (1H-imidazol-4-yl)methyl derivatives II (PG’ = Trt, X = Cl; PG’ = Ts, X = MsO) were ineffective due to the low reactivity. In a second approach (cf. B in Scheme 22), the aldol addition of the oxazolidinone derivatives III with aldehydes IV (PG’ = Tr; PG’ = Ts), followed by deoxygenation under Barton-McCombie conditions, resulted in the isolation of degradation products caused by retro-aldol reactions, occurring during the oxygenation step. Thus, the amidomethylation reaction via Ti-enolates was attempted (cf. C in Scheme 22): treatment of the acyloxazolidinone V (PG’ = Tr) with the electrophile VI resulted in a complex mixture of inseparable products; although the desired compounds had been formed, long reaction times were required for good conversion, causing the partial cleavage of the trityl protecting group. Seebach et al. envisaged the use of a more reactive electrophile, for instance, 1,3,5-trioxane (cf. D in Scheme 22), with subsequent OH/NH2 replacement. This route led eventually to the synthesis of the desired β2-homo-histidine derivatives for solid phase syntheses. For the preparation of the acyloxazolidinone 92, 1H-imidazole-4-acrylic acid (urocanic acid) was selected as the starting material. Hydrogenation of the urocanic acid, followed by esterification under acid conditions, gave the methyl ester 89, which was trityl protected to give crude 90. Product 90 was saponified to afford the acid 91 in 73% yield over four steps (Scheme 23).


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 acyloxazolidinone (R)-92 starting from urocanic acid [80].
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f36-ijms-12-02853: Preparation of the acyloxazolidinone (R)-92 starting from urocanic acid [80].
Mentions: Initial attempts of diastereoselective alkylation (cf. A in Scheme 22) of homo-glycine derived acyloxazolidinones III (PG = Phth; PG = Ph2C) with (1H-imidazol-4-yl)methyl derivatives II (PG’ = Trt, X = Cl; PG’ = Ts, X = MsO) were ineffective due to the low reactivity. In a second approach (cf. B in Scheme 22), the aldol addition of the oxazolidinone derivatives III with aldehydes IV (PG’ = Tr; PG’ = Ts), followed by deoxygenation under Barton-McCombie conditions, resulted in the isolation of degradation products caused by retro-aldol reactions, occurring during the oxygenation step. Thus, the amidomethylation reaction via Ti-enolates was attempted (cf. C in Scheme 22): treatment of the acyloxazolidinone V (PG’ = Tr) with the electrophile VI resulted in a complex mixture of inseparable products; although the desired compounds had been formed, long reaction times were required for good conversion, causing the partial cleavage of the trityl protecting group. Seebach et al. envisaged the use of a more reactive electrophile, for instance, 1,3,5-trioxane (cf. D in Scheme 22), with subsequent OH/NH2 replacement. This route led eventually to the synthesis of the desired β2-homo-histidine derivatives for solid phase syntheses. For the preparation of the acyloxazolidinone 92, 1H-imidazole-4-acrylic acid (urocanic acid) was selected as the starting material. Hydrogenation of the urocanic acid, followed by esterification under acid conditions, gave the methyl ester 89, which was trityl protected to give crude 90. Product 90 was saponified to afford the acid 91 in 73% yield over four steps (Scheme 23).

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