Cyclic β‐Tetra‐ and Pentapeptides: Synthesis through On‐Resin Cyclization and Conformational Studies by X‐Ray, NMR and CD Spectroscopy and Theoretical Calculations

Büttner, Frank; Norgren, Anna S.; Zhang, Suode; Prabpai, Samran; Kongsaeree, Palangpon; Arvidsson, Per I.

doi:10.1002/chem.200500249

Cited by 20 publications

(17 citation statements)

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“…Gly and Thr residues were introduced in the structure to provide flexibility and solubility of the compound. For cyclization of a peptide, a minimum of five amino acids is required . However, four amino acid residues containing cyclic peptides can have cis or trans peptide bonds .…”

Section: Discussionmentioning

confidence: 99%

Structure–activity relationships of peptidomimetics that inhibit PPI of HER2‐HER3

2014

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Human epidermal growth factor receptor-2 (HER2) is a tyrosine kinase family protein receptor that is known to undergo heterodimerization with other members of the family of epidermal growth factor receptors (EGFR) for cell signaling. Overexpression of HER2 and deregulation of signaling has implications in breast, ovarian, and lung cancers. We have designed several peptidomimetics to block the HER2-mediated dimerization, resulting in antiproliferative activity for cancer cells. In the present work we have investigated the structure-activity relationships of peptidomimetic analogs of compound 5. Compound 5 was conformationally constrained by N- and C-terminal modification and cyclization as well as by substitution with D-amino acids at the N-and C-termini. Among the compounds studied in this work, a peptidomimetic compound 21 with D-amino acid substitution and its N- and C-termini capped with acetyl and amide functional groups and a reversed sequence compared to that of compound 5 exhibited better antiproliferative activity in HER2-overexpressed breast, ovarian, and lung cancer cell lines. Compound 21 was further evaluated for its protein-protein interaction (PPI) inhibition ability using enzyme fragment complementation (EFC) assay, proximity ligation assay (PLA), and Western blot analysis. Results suggested that compound 21 is able to block HER2:HER3 interaction and inhibit phosphorylation of the kinase domain of HER2. The mode of binding of compound 21 to HER2 protein was modeled using a docking method. Compound 21 seems to bind to domain IV of HER2 near the PPI site of EGFR:HER2 and HER:HER3 and inhibit PPI.

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Section: Discussionmentioning

confidence: 99%

Structure–activity relationships of peptidomimetics that inhibit PPI of HER2‐HER3

2014

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“…Scheme 3. Cyclopeptide Head-to-Tail Synthesis by the Three-Dimensional Orthogonal Solid-Phase Methodology (Fmoc/Boc, t-Bu/allyl) [31] [46]. After the cyclization step, the cyclopeptide is removed from the resin with simultaneous deprotection of the side-chain functional groups.…”

Section: Receptors Hsst 1-5 Were Determined By Competition With [ 125mentioning

confidence: 99%

New Open‐Chain and Cyclic Tetrapeptides, Consisting of α‐, β²‐, and β³‐Amino‐Acid Residues, as Somatostatin Mimics – A Survey

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Mathad

et al. 2008

Helvetica Chimica Acta

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Dedicated to Prof. Elias J. Corey on the occasion of his 80th birthday Cyclo-b-tetrapeptides are known to adopt a conformation with an intramolecular transannular hydrogen bond in solution. Analysis of this structure reveals that incorporation of a b 2 -amino-acid residue should lead to mimics of a-peptidic b-turns (cf. A, B, C). It is also known that short-chain mixed b/a-peptides with appropriate side chains can be used to mimic interactions between a-peptidic hairpin turns and G protein-coupled receptors. Based on these facts, we have now prepared a number of cyclic and open-chain tetrapeptides, 7 -20, consisting of a-, b 2 -, and b 3 -amino-acid residues, which bear the side chains of Trp and Lys, and possess backbone configurations such that they should be capable of mimicking somatostatin in its affinity for the human SRIF receptors (hsst 1-5 ). All peptides were prepared by solid-phase coupling by the Fmoc strategy. For the cyclic peptides, the three-dimensional orthogonal methodology (Scheme 3) was employed with best success. The new compounds were characterized by high-resolution mass spectrometry, NMR and CD spectroscopy, and, in five cases, by a full NMRsolution-structure determination (in MeOH or H 2 O; Fig. 4). The affinities of the new compounds for the Fig. 1. Molecular formulae of somatostatin (SRIF-14) and Sandostatin , and X-ray crystal structure of Sandostatin [11] 16 ) One of the first to recognize the quasi-high-dilution effect with polymer-bound reagents and intermediates was Patchornik [39]. 17 ) Cf. the use of a simple thioester linkage [45]. 18 ) For some representative examples, see [31] [46]. 19 ) Besides the somatostatin-mimicking cyclopeptides described herein, we have also synthesized RGD-mimicking cyclopeptides, and, in all cases, the yields obtained with the safety catch method were disappointingly low. Scheme 2. Cyclopeptide Head-to-Tail Synthesis by the Kenner -Ellman Safety Catch Methodology [43].The 4-sulfamoyl-butyryl AM resin is commercially available. For activation of the acyl-sulfonamide group, the sulfamoyl N-atom is alkylated (R' ¼ Me, CH 2 CN). In the cyclization step, the peptide is removed from the resin, with the side-chain functional-group protection still in place [44]. This method was applied to the synthesis of the cyclo-b-tetrapeptide 7.Helvetica Chimica Acta -Vol. 91 (2008) 20 ) In the spectrum of 18, this second Cotton effect is at 220 nm! Fig. 2. Normalized CD spectra of cyclic tetrapeptides 10 -14 recorded in MeOH (0.2 mm). The CD spectra of compounds 7 -9 have not been recorded. Fig. 4. NMR Solution structures of the cyclic tetrapeptides 7, 9, and 14 , and of the open-chain tetrapeptides 16 and 17. Low-energy structures derived from SA annealing calculations are shown.

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“…Compound 6 could be readily synthesized from a sugar amino alkyne 10 by coupling with Boc protected D-alanine using a standard protocol (employing EDC$HCl, HOBt and DIEA). Compound 7, obtained from diacetone glucose following a well established protocol, 11 was then coupled with 6 to yield the intermediate 8.…”

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confidence: 99%

Design and synthesis of conformationally homogeneous pseudo cyclic peptides through amino acid insertion: investigations on their self assembly

et al. 2015

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Macrocyclic C 2 symmetric peptides, containing bis furanoid triazole amino acids as di-b-peptides linked to a D-a-amino acid or a b-amino acid in each half, have been designed and synthesized. The D-a-amino acid derived product undergoes parallel homo-stacking in solution via amide NH and amide carbonyl oxygen H-bonding; such macrocycles may be used as model systems for artificial ion channels as their unidirectional assembly pattern attributes them with large dipole moments. In contrast, the b-amino acid based compound forms only a conformationally homogeneous cyclic peptide without undergoing self assembly.

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Cyclic β‐Tetra‐ and Pentapeptides: Synthesis through On‐Resin Cyclization and Conformational Studies by X‐Ray, NMR and CD Spectroscopy and Theoretical Calculations

Cited by 20 publications

References 57 publications

Structure–activity relationships of peptidomimetics that inhibit PPI of HER2‐HER3

Structure–activity relationships of peptidomimetics that inhibit PPI of HER2‐HER3

New Open‐Chain and Cyclic Tetrapeptides, Consisting of α‐, β²‐, and β³‐Amino‐Acid Residues, as Somatostatin Mimics – A Survey

Design and synthesis of conformationally homogeneous pseudo cyclic peptides through amino acid insertion: investigations on their self assembly

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Cyclic β‐Tetra‐ and Pentapeptides: Synthesis through On‐Resin Cyclization and Conformational Studies by X‐Ray, NMR and CD Spectroscopy and Theoretical Calculations

Cited by 20 publications

References 57 publications

Structure–activity relationships of peptidomimetics that inhibit PPI of HER2‐HER3

Structure–activity relationships of peptidomimetics that inhibit PPI of HER2‐HER3

New Open‐Chain and Cyclic Tetrapeptides, Consisting of α‐, β2‐, and β3‐Amino‐Acid Residues, as Somatostatin Mimics – A Survey

Design and synthesis of conformationally homogeneous pseudo cyclic peptides through amino acid insertion: investigations on their self assembly

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New Open‐Chain and Cyclic Tetrapeptides, Consisting of α‐, β²‐, and β³‐Amino‐Acid Residues, as Somatostatin Mimics – A Survey