339079-54-8

Upstream product

• 100-39-0 benzyl bromide 
• 156122-25-7 ethyl 2-benzyl-3-phenyl-2-nitropropionate 
• 93949-90-7 ethyl 2-amino-2-benzyl-3-phenylpropanoate 
• 28920-43-6 (fluorenylmethoxy)carbonyl chloride 
• 6278-96-2 2-amino-2-benzyl-3-phenylpropanoic acid 

Relevant academic research and scientific papers

Constraining the Side Chain of C-Terminal Amino Acids in Apelin-13 Greatly Increases Affinity, Modulates Signaling, and Improves the Pharmacokinetic Profile

Side-chain-constrained amino acids are useful tools to modulate the biological properties of peptides. In this study, we applied side-chain constraints to apelin-13 (Ape13) by substituting the Pro12 and Phe13 positions, affecting the binding affinity and signaling profile on the apelin receptor (APJ). The residues 1Nal, Trp, and Aia were found to be beneficial substitutions for Pro12, and the resulting analogues displayed high affinity for APJ (Ki 0.08-0.18 nM vs Ape13 Ki 0.7 nM). Besides, constrained (d-Tic) or α,α-disubstituted residues (Dbzg; d-α-Me-Tyr(OBn)) were favorable for the Phe13 position. Compounds 47 (Pro12-Phe13 replaced by Aia-Phe, Ki 0.08 nM) and 53 (Pro12-Phe13 replaced by 1Nal-Dbzg, Ki 0.08 nM) are the most potent Ape13 analogues activating the Gα12 pathways (53, EC50 Gα12 2.8 nM vs Ape13, EC50 43 nM) known to date, displaying high affinity, resistance to ACE2 cleavage as well as improved pharmacokinetics in vitro (t1/2 5.8-7.3 h in rat plasma) and in vivo.

Sterically hindered Cα,α-disubstituted α-amino acids: Synthesis from α-nitroacetate and incorporation into peptides

The preparation of sterically hindered and polyfunctional Cα,α-disubstituted α-amino acids (ααAAs) via alkylation of ethyl nitroacetate and transformation into derivatives ready for incorporation into peptides are described. Treatment of ethyl nitroacetate with N,N-diisopropylethylamine (DIEA) in the presence of a catalytic amount of tetraalkylammonium salt, followed by the addition of an activated alkyl halide or Michael acceptor, gives the doubly C-alkylated product in good to excellent yields. Selective nitro reduction with Zn in acetic acid or hydrogen over Raney Ni gives the corresponding amino ester that, upon saponification, can be protected with the fluorenylmethyloxycarbonyl (Fmoc) group. The first synthesis of an orthogonally protected, tetrafunctional Cα,α-disubstituted analogue of aspartic acid, 2,2-bis(tert-butylcarboxymethyl)glycine (Bcmg), is described. Also, the sterically demanding Cα,α-dibenzylglycine (Dbg) has been incorporated into a peptide using solid-phase synthesis. It was found that once sterically congested Dbg is at the peptide N-terminus, further chain extension becomes very difficult using uronium or phosphonium salts (PyAOP, PYAOP/HOAt, HATU). However, preformed amino acid symmetrical anhydride couples to N-terminal Dbg in almost quantitative yield in nonpolar solvent (dichloroethane-DMF, 9:1).

Zinc promoted rapid and efficient synthesis of Fmoc- and Z-α,α-dialkylamino acids under neutral conditions

The introduction of Nα-9-fluorenylmethyloxycarbonyl (Fmoc) and benzyloxycarbonyl (Z) groups into α,α-dialkylamino acids is described at neutral pH using Fmoc-Cl or Z-Cl as an acylating agent respectively in the presence of activated zing powder. The reaction is simple, fast and clean. It also permits the scale up with high yields. It is completely free from protected oligomer formation, which is a known side-reaction when Schotten-Baumann procedure is followed. All the Fmoc- and Z-amino acids prepared have been fully characterized.