Design, synthesis, conformational analysis and application of indolizidin-2-one dipeptide mimics

Abstract

Growth in the field of peptide mimicry over the past few decades has resulted in the synthesis of many new compounds and the investigation of novel pharmacological agents. Azabicyclo[X.Y.0]alkanone amino acids are among the attractive classes of constrained mimics, because they can create rigid peptide structures for probing the conformation and roles of natural motifs in recognition events important for biological activity. Herein, we review the last ten years of the synthesis, conformational analysis and activity of analogs of the azabicyclo[4.3.0]alkan-2-one amino acid subclass, so-called indolizidin-2-one amino acids, with particular attention on their employment as inputs for biological applications.

Peptide Coupling Challenges to Aza-Pipecolyl Smac Mimetic

“…Considering the turn conformation adopted by this peptide on receptor binding, constrained analogs such as indolizidinone amino acids have been used to rigidify the Val-Pro dipeptide to enhance potency (e.g., 2) [7][8][9]. Although such bicyclic amino acid analogs represent an important class of Smac mimetics, their multiple step synthesis has restricted analog development.…”

Constrained Dipeptide Surrogates: 5- and 7-Hydroxy Indolizidin-2-one Amino Acid Synthesis from Iodolactonization of Dehydro-2,8-diamino Azelates

“…In peptide science, conformationally constrained dipeptides serve effectively as tools for structure–activity relationship studies to identify biologically active conformers [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Among approaches for creating constrained dipeptides that employ steric [ 2 , 3 ], stereo-electronic [ 4 , 5 ], and covalent constraints [ 1 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ], the use of azabicyclo[X.Y.0]alkanone amino acids offers unique potential for locking the polyamide backbone into specific orientations that may mimic natural secondary structures such as β-turns.…”

X‐ray structure analysis reveals β‐turn mimicry by N‐amino‐imidazolidin‐2‐ones†

“…Diverse strategies employing chemical modifications of the peptide may improve their pharmacological profile. For example, incorporation of constrained peptidomimetics into the peptide backbone may improve pharmacological and chemical properties of endogenous peptides . Moreover, this strategy can furnish insight regarding the bioactive conformation of the native peptide, useful for the rational design of subsequent generations of peptide‐based and small molecule drug candidates for the treatment of human diseases …”

“…Among conformational constraints, the electronic interactions induced by the insertion of a semicarbazide moiety into a peptide to make a so‐called azapeptide may offset the conformational equilibrium of flexible peptides to favour turn conformations (Figure 1) . More rigid constraints such as those imposed by α ‐amino‐ γ ‐lactam (Agl, so‐called Freidinger–Veber lactam) residues may predispose the peptide backbone to mimic a β‐turn secondary structure by covalent restraints of the ψ ‐ and ω ‐dihedral angles . Moreover, introduction of a β‐hydroxyl residue onto an Agl structure in a so‐called Hgl residue, offers means to study relationships of backbone and side chain conformation for the recognition of the alcohol moiety of serine and threonine residues .…”