Aminomethylation of chiral silyl enol ethers: access to β2-homotryptophane and β2-homolysine derivatives

Kisspeptin analogues with improved metabolic stability may represent important ligands in the study of the kisspeptin/KISS1R system and have therapeutic potential. In this paper we assess the activity of known and novel kisspeptin analogues utilising a dual luciferase reporter assay in KISS1R-transfected HEK293T cells. In general terms the results reflect the outcomes of other assay formats and a number of potent agonists were identified among the analogues, including β(2) -hTyr-modified and fluorescently labelled forms. We also showed, by assaying kisspeptin in the presence of protease inhibitors, that proteolysis of kisspeptin activity within the reporter assay itself may diminish the agonist outputs. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.

show abstract

“…From IIIb (0.321 mg, 1.24 mmol) Pale yellow oil (0.301 g, 99%). 1 Boc-(±)-β 2 -homotryptophan (IVd) [40]. From IIId (0.856 mg, 2.57 mmol).…”

Section: General Procedures For the Ester Hydrolysismentioning

confidence: 99%

Beta amino acid‐modified and fluorescently labelled kisspeptin analogues with potent KISS1R activity

Camerino

Liu

Moriya

et al. 2016

Journal of Peptide Science

View full text Add to dashboard Cite

show abstract

“…For the synthesis of β2-homotryptophan, we used the diastereoselective methodology based on aminomethylation of chiral silyl enol ether recently described by Moumné et al. (Scheme ) . This method allows the preparation of enantiomerically pure functionalized β2-amino acids.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Evaluation of Analogues of N-Phthaloyl-l-tryptophan (RG108) as Inhibitors of DNA Methyltransferase 1

et al. 2014

Self Cite

View full text Add to dashboard Cite

DNA methyltransferases (DNMT) are promising drug targets in cancer provided that new, more specific, and chemically stable inhibitors are discovered. Among the non-nucleoside DNMT inhibitors, N-phthaloyl-l-tryptophan 1 (RG108) was first identified as inhibitor of DNMT1. Here, 1 analogues were synthesized to understand its interaction with DNMT. The indole, carboxylate, and phthalimide moieties were modified. Homologated and conformationally constrained analogues were prepared. The latter were synthesized from prolinohomotryptophan derivatives through a methodology based amino-zinc-ene-enolate cyclization. All compounds were tested for their ability to inhibit DNMT1 in vitro. Among them, constrained compounds 16-18 and NPys derivatives 10-11 were found to be at least 10-fold more potent than the reference compound. The cytotoxicity on the tumor DU145 cell line of the most potent inhibitors was correlated to their inhibitory potency. Finally, docking studies were conducted in order to understand their binding mode. This study provides insights for the design of the next-generation of DNMT inhibitors.

show abstract

“…Solvents and reagents were used as commercially available without further purification. (S)-α-Azido-Lys(Boc)-OH [32], Boc-(S)β 3 -hArg(Z) 2 -OH [33] and Boc-(R)-β 2 -hTrp-OH [34] were prepared in the laboratory. All peptides were synthesized by SPPS for compounds (1)(2)(3)(4) and (6) α-p-methylbenzylhydrylamine (MBHA resin, Merck Chemicals Ltd.), for compound (5) Boc-Trp(For)-PAM resin (Applied Biosystems, Foster City, CA, USA) and for compound (7) Rink amide MBHA resin (Merck Chemicals Ltd.).…”

Section: Peptide Synthesis and Purificationmentioning

confidence: 99%

β‐Amino acids containing peptides and click‐cyclized peptide as β‐turn mimics: a comparative study with ‘conventional’ lactam‐ and disulfide‐bridged hexapeptides

Larregola

Lequin

Karoyan

et al. 2011

Journal of Peptide Science

Self Cite

View full text Add to dashboard Cite

The increasing interest in click chemistry and its use to stabilize turn structures led us to compare the propensity for β-turn stabilization of different analogs designed as mimics of the β-turn structure found in tendamistat. The β-turn conformation of linear β-amino acid-containing peptides and triazole-cyclized analogs were compared to 'conventional' lactam- and disulfide-bridged hexapeptide analogs. Their 3D structures and their propensity to fold in β-turns in solution, and for those not structured in solution in the presence of α-amylase, were analyzed by NMR spectroscopy and by restrained molecular dynamics with energy minimization. The linear tetrapeptide Ac-Ser-Trp-Arg-Tyr-NH(2) and both the amide bond-cyclized, c[Pro-Ser-Trp-Arg-Tyr-D-Ala] and the disulfide-bridged, Ac-c[Cys-Ser-Trp-Arg-Tyr-Cys]-NH(2) hexapeptides adopt dominantly in solution a β-turn conformation closely related to the one observed in tendamistat. On the contrary, the β-amino acid-containing peptides such as Ac-(R)-β(3) -hSer-(S)-Trp-(S)-β(3) -hArg-(S)-β(3) -hTyr-NH(2) , and the triazole cyclic peptide, c[Lys-Ser-Trp-Arg-Tyr-βtA]-NH(2) , both specifically designed to mimic this β-turn, do not adopt stable structures in solution and do not show any characteristics of β-turn conformation. However, these unstructured peptides specifically interact in the active site of α-amylase, as shown by TrNOESY and saturation transfer difference NMR experiments performed in the presence of the enzyme, and are displaced by acarbose, a specific α-amylase inhibitor. Thus, in contrast to amide-cyclized or disulfide-bridged hexapeptides, β-amino acid-containing peptides and click-cyclized peptides may not be regarded as β-turn stabilizers, but can be considered as potential β-turn inducers.

show abstract

Aminomethylation of chiral silyl enol ethers: access to β2-homotryptophane and β2-homolysine derivatives

Cited by 10 publications

References 37 publications

Beta amino acid‐modified and fluorescently labelled kisspeptin analogues with potent KISS1R activity

Beta amino acid‐modified and fluorescently labelled kisspeptin analogues with potent KISS1R activity

Synthesis and Evaluation of Analogues of N-Phthaloyl-l-tryptophan (RG108) as Inhibitors of DNA Methyltransferase 1

β‐Amino acids containing peptides and click‐cyclized peptide as β‐turn mimics: a comparative study with ‘conventional’ lactam‐ and disulfide‐bridged hexapeptides

Contact Info

Product

Resources

About