1,2,3-Triazoles as Biomimetics in Peptide Science

Abstract

Natural peptides are an important class of chemical mediators, essential for most vital processes. What limits the potential of the use of peptides as drugs is their low bioavailability and enzymatic degradation in vivo. To overcome this limitation, the development of new molecules mimicking peptides is of great importance for the development of new biologically active molecules. Therefore, replacing the amide bond in a peptide with a heterocyclic bioisostere, such as the 1,2,3-triazole ring, can be considered an effective solution for the synthesis of biologically relevant peptidomimetics. These 1,2,3-triazoles may have an interesting biological activity, because they behave as rigid link units, which can mimic the electronic properties of amide bonds and show bioisosteric effects. Additionally, triazole can be used as a linker moiety to link peptides to other functional groups.

Keywords: 1,2,3-triazole; CuAAC; amide bond; bioisostere; click chemistry; peptidomimetic.

Figure 1

Topological and electronic mimicry of amide units by 1,2,3-triazoles.

Scheme 1

Preparation of triazole: (reaction 1) uncatalyzed Huisgen cycloaddition leading to 1,4₋ and 1,5₋regioisomer; (reaction 2) copper₋catalyzed azide₋alkyne cycloaddition (CuAAC) leading to 1,4₋regioisomer.

Figure 2

Structure of the peptidotriazole library.

Figure 3

Structure of BP100 peptide sequence analogues.

Figure 4

Sequence of cystatin A (1) and structure of the related triazole containing peptidomimetic (2).

Figure 5

Substitution of the cis-prolyl peptide bond with 1,4- and 1,5-disubstituted triazole rings.

Scheme 2

Synthesis of the triazole Pro-Gly dipeptide.

Figure 6

Peptidomimetics of the cis-amide bond.

Scheme 3

Synthesis of 4,5-substituted triazole peptidomimetics.

Figure 7

Formation of turns by cycloaddition using “click” chemistry.

Scheme 4

Convergent synthesis of peptide mimetics adopting a β-helix conformation.

Figure 8

Predominant zig-zag conformation of the triazolamer revealed by the ROESY experiments. The solid and dashed lines indicate strong and weak NOE correlations, respectively. Atom colors: light blue for carbon, dark blue for nitrogen, and red for oxygen.

Scheme 5

Solid phase synthesis of triazolamers.

Figure 9

The possible anti-conformations and syn-conformations adopted by the triazole dimer.

Figure 10

(a) Exchange of the dipeptide fragment with the triazole dipeptide mimetic; (b) replacement of the native amino acids, pLI-GCN4 K₈L₉ (21), K₁₅L₁₆ (22), and E₂₂L₂₃ (23), with the peptidomimetic 20.

Scheme 6

Synthesis of phosphorylated histidine analogues by CuAAC and RuAAC.

Figure 11

Two selective AMPA receptor ligands exhibiting competitive binding.

Figure 12

l-tryptophane and its triazole analogue.

Figure 13

Substitution of the amide bond in the natural product 30 with 1,4-triazole.

Figure 14

Structure of the Smac dimer 32 and its two derivatives, 33 and 34.

Figure 15

Cyclic peptide mimetic compound 35 containing a triazole.

Figure 16

Example of peptidomimetic synthesis using the diversity-oriented synthesis (DOS) strategy.

Figure 17

Structures of the migrastatin analogue 37 and triazole-migrastatine 38.

Figure 18

Stapled peptide targeting the β-catenin/BCL9 interaction. * indicates l-amino acid, and # indicates d-amino acid.

Figure 19

General structure of the stapled bis-triazolyl peptide product, SP1–SP5 (46–50).

Figure 20

Comparison of AFGP 51 and its triazole-based tetramer mimetic 52.

Figure 21

Triazole glycopeptide mimetics.

Scheme 7

Cycloaddition between pseudopeptides 55 and 56 and conjugated biotin and fluorescein.

Scheme 8

Synthesis of a peptide with substituted proline.

Figure 22

Triazole peptide derivatives with conjugated 2-alkoxy-8-hydroxyadenine.

Figure 23

Strategy for the synthesis of peptide dendrimers using click chemistry. (a): CuAAC of an alkyne anchored in one dendron and an azide in another dendron; (b): CuAAC of a dialkyne nucleus and dendrons functionalized with azide units; (c): CuAAC of a diazide nucleus and dendrons functionalized with alkyne units.

Figure 24

Metal complexes 66 and 67 obtained from the triazole peptide derivative 68.

Figure 25

Cyclam metal complex derivatives.

Scheme 9

Synthesis of conjugated peptide 72 by CuAAC.

Scheme 10

Example of synthesis of 1,4-triazolopeptoid in solid phase.

Figure 26

Structure of the compounds WC 10 and WC 44, and their triazole analogues.

Figure 27

Different ways of mimicking amide bonds.