Cyclopropane Pipecolic Acids as Templates for Linear and Cyclic Peptidomimetics: Application in the Synthesis of an Arg‐Gly‐Asp (RGD)‐Containing Peptide as an α_vβ₃ Integrin Ligand

Abstract

The synthesis and evaluation of substituted cyclopropane pipecolic acids (CPA) as conformationally restricted templates for linear and cyclic peptidomimetics is reported. A variety of differently substituted (poly)hydroxy- and amino-2-azabicyclo[4.1.0]heptane-1-carboxylic acids were prepared by means of the Pd-catalyzed methoxycarbonylation of suitably functionalized lactam-derived enol phosphates, followed by OH-directed cyclopropanation. CPAs were successfully introduced into a linear peptide sequence to assess the cis/trans isomerism about the pipecolic acid peptide bond, and in a cyclic peptidomimetic that bore the Arg-Gly-Asp (RGD) sequence, which displayed nanomolar activity as antagonist of the αvβ3 integrin in M21 human melanoma cells. Thus, CPAs appear to be suitable for the generation of novel peptidomimetics for drug discovery.

Cyclopropane‐Based Peptidomimetics Mimicking Wide‐Ranging Secondary Structures of Peptides: Conformational Analysis and Their Use in Rational Ligand Optimization

“…Cyclopropanee ffectively restricts the conformation of am olecule in the cis (folded)-or trans (extended)-form as shown in Figure 1a.T his structuralp roperty, cis/trans-restriction, is widely used in medicinal chemistry, [9] including the field of peptidomimetics. [10] Additionally,c yclopropane has two other characteristic features.F irst, cyclopropanes directly connected to an sp 2 carbone xist preferentially in the bisected conformation, as shown in Figure 1b,o wing to the p-donating stereoelectronic effect of the cyclopropanering. [11] Second, cis-configured substituents on ac yclopropane ring mutually exert marked steric repulsion, because they are fixed in the eclipsed form, referred to as cyclopropylic strain.…”

Stereodivergent synthesis of 5-aminopipecolic acids and application in the preparation of a cyclic RGD peptidomimetic as a nanomolar αVβ3 integrin ligand

“…The synthesis of cyclopeptide 22 was carried out in solution (Scheme 4) as reported for 4-aminoproline derivatives 24 and 4amino-substituted cyclopropane pipecolic acids. 32 Carboxylic acid 10 was coupled to dipeptide H-Arg(Mtr)-Gly-OBn by using DEPBT [3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)one] as the coupling reagent in THF at 35 °C which provided, after four days, tripeptide 18 in 98% yield after chromatography. Deprotection of the 5-amino group in 18 by Et 2 NH provided compound 19 quantitatively, which was then coupled to N-Z,O-tBu-protected aspartic acid as above to give tetrapeptide 20 in 50% yield after chromatography.…”

“…The RGD-containing peptidomimetic 22 was tested for its capacity to compete with vitronectin for the binding to α V β 3 integrin expressed in high level by M21 human melanoma cells as reported, 30,32 in comparison to the reference RGD ligand cyclo[RGDf(N-Me)V] (Cilengitide) 45 (Table 1). 47 The comparatively lower inhibition activity of 22 measured on M21 cell line could be due to the presence of other integrins which are inhibited by Cilengitide.…”

“…To date, a few low-nanomolar-affinity α V β 3 receptor binders which present the RGD system installed on rigid hetero-and carbacyclic scaffolds have been reported. For example, bicyclic lactams, [19][20][21] γ-aminocyclopentanecarboxylic acids, 22 cis-β-aminocyclopropanecarboxylic acids, 23 4-aminoprolines, 24,25 bifunctional diketopiperazines, 26 morpholine derivatives, 27,28 7-aminoazocinone-2-carboxylate derivatives, 29 and both aminoand hydroxy-substituted 2,3-methanopipecolic acids (or CPA, cyclopropane pipecolic acid), the latter recently reported by us, [30][31][32] have all been used to generate potent…”

“…Because of our interest in the synthesis [33][34][35][36] and biomedical applications [30][31][32] of pipecolic acid derivatives, in order to further expand the array of available scaffolds which can be grafted into the key α V β 3 -recognizing peptide sequence, we decided to synthesize and evaluate 5-aminopipecolic acid, the homologue of 4-aminoproline, 24,25 as a δ-amino acid on which to install the RGD peptide sequence, thus generating new cyclic α V β 3 integrin ligands. Pipecolic acid derivatives bearing an amino group at position 3, 4 and 5 ( Figure 1) are examples of endocyclic-N α /exocyclic-N β , -N γ , and -N δ constrained basic amino acids with a considerable potential in medicinal cases as an intermediate in the synthesis of (±)-Slaframine.…”