Stereodivergent synthesis of 5-aminopipecolic acids and application in the preparation of a cyclic RGD peptidomimetic as a nanomolar α_Vβ₃ integrin ligand

Abstract

A stereodivergent strategy was devised to obtain enantiopure cis and trans 5-aminopipecolic acids (5-APAs) in suitably protected forms to be employed in peptide synthesis as conformationally constrained α- and δ-amino acids. The cis isomer was used as a δ-amino acid to construct a cyclic RGD-containing peptidomimetic, the ability of which to compete with biotinylated vitronectin for binding with the isolated αVβ3 integrin was measured (IC50 = 4.2 ± 0.9 nM). A complete 1H NMR and computational conformational analysis was performed to elucidate the reasons for the high affinity of this cyclic peptidomimetic in comparison with cilengitide.

Enantioselective Synthesis of cis and trans 4‐Aminopipecolic Acids as γ‐Amino Acids for the Construction of Cyclic RGD‐Containing Peptidomimetics Antagonists of αVβ3 Integrin

“…[7] Therefore, RGD-containing peptides and peptidomimetics [8] as well as RGD mimetics [5a] are currently evaluated as antagonists to suppress the events mediated by this integrin and as possible shuttles for the targeted delivery of drugs and diagnostics. [7b, 9] In line with this, we have recently reported that pipecolic acid derivatives such 4-and 5aminocyclopropane pipecolic acids, [10] 4-hydroxycyclopropane pipecolic acids, [11] and 5-aminopipecolic acids [12] are all suitable, rigid amino acids on which to build the RGD sequence to obtain highly active αVβ3 integrin receptor antagonists (Figure 1, b). These aminopipecolic acid derivatives are homologous of 4aminoproline (Figure 1), a derivative of 4-hydroxyproline which has been extensively exploited in the last decade for the generation of αVβ3 integrin ligands and drug conjugates.…”

“…The conformational analysis of compound 34 was also done in silico by temperature replica exchange molecular dynamics (T-REMD), [18] using a protocol that previously proved to be successful for similar questions. [11][12]19] Thus, 12 replica of 400 ns were performed with temperatures ranging from 300 to 860 K, without applying any restraint derived from the experimental NOEs. This resulted in three structures (c0, c1 and c2) with significant populations (49%, 33%, and 13%, respectively) (Figure 3) in each of which atomic distances are such to justify only part of the observed NOEs.…”

“…[11, 12, 19a] The protocol was applied as described previously. [12] To evaluate convergence, the 300 K trajectories were subjected to a cluster analysis every 100 ns. Convergence was considered achieved after 300 ns of simulation, when the population of the three principal clusters in consecutive 100 ns batches differed by no more than 10%.…”

“…These aminopipecolic acid derivatives are homologous of 4aminoproline (Figure 1), a derivative of 4-hydroxyproline which has been extensively exploited in the last decade for the generation of αVβ3 integrin ligands and drug conjugates. [8h,i],[9f-h] As a completion of our studies on pipecolic acid derivatives, [4,[10][11][12]13] in this paper we wish to report on our efforts to prepare orthogonally protected cis and trans 4-aminopipecolic acids suitable for peptide synthesis and their use in the construction of RGD peptidomimetics as integrin antagonists.…”

Stereodivergent routes in organic synthesis: carbohydrates, amino acids, alkaloids and terpenes

“…Hydrogenolysis of the azido group and guanidine formation led to the trans-arginineprotected cis- 5- Enantioenriched 5-aminopipecolic acids have been diastereodivergently prepared from commercially available (S)-γ-(hydroxymethyl)butyrolactone by the Contini and Occhiato group. 43 This lactone was transformed into methyl cis-5-hydroxypipecolate which, by functional and protecting group manipulation, provided protected trans-4aminopipecolic acid (Scheme 29). For the preparation of the cis-derivative the configuration of the hydroxyl group at the 5-position was inverted under Mitsunobu conditions.…”