Synthesis of β-Lactam Scaffolds for Ditopic Peptidomimetics

Palomo, Claudio; Aizpurua, J. M.; Balentová, Eva; Jiménez, Azucena; Oyarbide, Joseba; Fratila, Raluca M.; Miranda, José I.

doi:10.1021/ol0626241

Cited by 49 publications

(33 citation statements)

References 17 publications

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“…Despite this limitation, the β-LASD design method provides a simple steric model that opens up the route for a better understanding of the steric interactions driving the shallow β-/γ-transition in larger peptides. General Procedure for the Preparation of 1-Carboxyalkyl-3-methyl-3-(2-nitrobenzene sulfonylamino)azetidin-2-ones 8b-f: 18 To a solution of (R) methyl 2-methyl-serinate 10 (1.90 mmol, 0.32 g) and 2-nitrobenzenesulfonyl chloride (NsCl, 4.18 mmol, 0.935 g) in acetonitrile (30 mL) was added KHCO 3 (9.50 mmol, 0.951 g) and the suspension was stirred at reflux for 16 hours. Then, saturated aqueous NaHCO 3 (15 mL) was added and the mixture was extracted with EtOAc (3 x 15 mL).…”

Section: Discussionmentioning

confidence: 99%

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Chirality-Driven Folding of Short β-Lactam Pseudopeptides

et al. 2012

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Novel enantiopure pseudopeptide models containing a central -(-lactam)-(Aa)-scaffold characterized by the combined presence of an -alkyl--amino--lactam (i+1) residue and a -substituted (i + 2) amino acid have been readily synthesized from -alkyl serines. The conformational analysis of such -lactam pseudopeptides conducted in CDCl3 and DMSO-d6 solutions using 1D-and 2D-NMR techniques revealed an equilibrium between -II turn and -turn conformers, which was ultimately modulated by the relative configuration of the -(-lactam)-(Aa)-residues. Long-range chiral effects on the -lactam pseudopeptide conformers were also found when two (i) and (i + 3) chiral residues were attached to the termini of a central -(-lactam)-(Aib)-segment. In such mimetics, heterochiral (i) and (i + 3) residues reinforced a -II turn conformer, whereas homochiral corner residues stabilized an overlapped -II/ -I double turn motif. No -hairpin nucleation was observed in any instance. In good agreement with the conformers found in solution, -turned and open structures were also characterized by X-ray crystallography. Relative stabilities of the different conformers were estimated computationally at a B3LYP/6-31++G** calculation level, and finally, a conformation equilibrium model based on steric inter-residual interactions around the -(-lactam)-(i + 2)-segment was proposed to account for the observed chiral effects. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 substituted (i+2) amino acid have been readily synthesized from α-alkyl serines. The conformational analysis of such β-lactam pseudopeptides conducted in CDCl 3 and DMSO d6 solutions using 1D and 2D-NMR techniques revealed an equilibrium between β-II turn and γ-turn conformers, which was ultimately modulated by the relative configuration of the -(β-lactam)-(Aa)-residues. Long range chiral effects on the α-lactam pseudopeptide conformers were also found when two (i) and (i+3) chiral residues were attached to the termini of a central -(β-lactam)-(Aib)-segment. In such mimetics, heterochiral (i) and (i+3) residues reinforced a β-II turn conformer, whereas homochiral corner residues stabilized an overlapped β-II/ β-I double turn motif. No β-hairpin nucleation was observed in any instance. In good agreement with the conformers found in solution, β-turned and open structures were also characterized by X-ray crystallography. Relative stabilities of the different conformers were estimated computationally at a B3LYP/6-31++G** calculation level and, finally, a conformation equilibrium model based on steric inter-residual interactions around the -(β-lactam)-(i+2)-segment was proposed to account for the observed chiral effects.

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Section: Discussionmentioning

confidence: 99%

“…18 Tables 1 and 2 collect the details of the transformation of the dipeptide scaffolds 8, 9 and 14 into the target β-lactam pseudopeptide models.…”

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confidence: 99%

Chirality-Driven Folding of Short β-Lactam Pseudopeptides

et al. 2012

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“…[34][35][36][37][38][39][40]. As a consequence, a large number of procedures for the synthesis of the azetidin-2-one ring have been developed [41][42][43][44][45][46][47][48].…”

Section: Introductionmentioning

confidence: 99%

An electrochemical alternative strategy to the synthesis of β-lactams

Sotgiu

Chiarotto

Feroci

et al. 2008

Electrochimica Acta

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“…Turns have been found critical in a range of macromolecular recognition motifs, such as integrin or interferon-c binding in biological systems ranging from cell adhesion [3] to antiviral agents [4], respectively. There has, therefore, been considerable effort to mimic reverse turns which has been accomplished by short linear peptides [5,6], cyclic peptides [7][8][9][10][11], and small molecules [7][8][9][10][11][12][13][14][15][16][17][18][19] such as benzodiazepines [9,[12][13][14][15][16], b-turn dipeptides (BTD) [20], indolizinoindole b-turn mimetic (IBTM) [20], and c and b-lactams [19]. The use of proline has long been known to help a peptide adopt a reverse-turn conformation [8].…”

Section: Introductionmentioning

confidence: 99%

A virtual library of constrained cyclic tetrapeptides that mimics all four side-chain orientations for over half the reverse turns in the protein data bank

Arbor

Marshall

2008

J Comput Aided Mol Des

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Reverse turns are often recognition sites for protein/protein interactions and, therefore, valuable potential targets for determining recognition motifs in development of potential therapeutics. A virtual combinatorial library of cyclic tetrapeptides (CTPs) was generated and the bonds in the low-energy structures were overlapped with canonical reverse-turn Calpha-Cbeta bonds (Tran et al., J Comput Aided Mol Des 19(8):551-566, 2005) to determine the utility of CTPs as reverse-turn peptidomimetics. All reverse turns in the Protein Data Bank (PDB) with a crystal structures resolution < or = 3.0 A were classified into the same known canonical reverse-turn Calpha-Cbeta bond clusters (Tran et al., J Comput Aided Mol Des 19(8):551-566, 2005). CTP reverse-turn mimics were compiled that mimicked both the relative orientations of three of the four as well as all four Calpha-Cbeta bonds in the reverse turns of the PDB. 54% of reverse turns represented in the PDB had eight or more CTPs structures that mimicked the orientation of all four of the Calpha-Cbeta bonds in the reverse turn.

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Synthesis of β-Lactam Scaffolds for Ditopic Peptidomimetics

Cited by 49 publications

References 17 publications

Chirality-Driven Folding of Short β-Lactam Pseudopeptides

Chirality-Driven Folding of Short β-Lactam Pseudopeptides

An electrochemical alternative strategy to the synthesis of β-lactams

A virtual library of constrained cyclic tetrapeptides that mimics all four side-chain orientations for over half the reverse turns in the protein data bank

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