Chemical Platform for the Preparation of Synthetic Orally Active Peptidomimetics with Hemoregulating Activity

Abstract

A novel chemical platform based on branched piperazine‐2,5‐dione derivatives (2,5‐diketopiperazines) for creating orally available biologically active peptidomimetics has been developed. The platform includes a diketopiperazine scaffold with “built‐in” functionally active peptide fragments covalently attached via linkers. The concept was applied to two hemostimulatory drugs, the dipeptide thymogen (GluTrp) and the tripeptide stemokin (IleGluTrp). Preparation of a series of respective derivatives is described. Of the five synthesized analogues, three demonstrated high hemostimulatory activity in vivo on intact mice and on ex vivo irradiated bone marrow cells. Prospects of further development of the concept are discussed.

Novel side reaction accompanying cyclization of Glu(R1)‐Glu(R2) dipeptides via lactamization of the Glu(R1) residue

“…In our recent publication, we described the synthesis and hemoregulatory activity of a series of Glu‐Trp (Thymogen) analogs 1 to 5 contained at the N‐terminus a 2,5‐diketopiperazine moiety which protects the peptides from rapid proteolysis and endows oral bioavailability to the peptides 1 , 4 , and 5 (Figure ).…”

“…Applying this synthetic route and the conditions reported, a library of over 50 DKP derivatives with the general formula cyclo‐[Xaa‐Glu(Trp‐R)] was obtained in yields of over 60% when Xaa was one of the common amino acid residues, except Glu and Gln . However, performing the synthesis of 5 under identical conditions, only 28% of the protected intermediate was obtained …”

“…In our recent publication, 1 we described the synthesis and hemoregulatory activity of a series of Glu-Trp (Thymogen) analogs 1 to 5 contained at the N-terminus a 2,5-diketopiperazine moiety which protects the peptides from rapid proteolysis and endows oral bioavailability to the peptides 1, 4, and 5 (Figure 1 There are various cyclization methods of dipeptides leading to DKP derivatives, including cyclization of dipeptides bearing C-terminal methyl esters or active esters. [2][3][4][5] In our preceding work, the cyclopeptides 1 to 5 were prepared via direct cyclization of the linear peptides H-Xaa-Glu(Trp)-OH by refluxing in pyridine, whereby as Xaa residues Ala, Val, Trp, Glu(Ile), or Lys(Boc) were used.…”

“…[2][3][4][5] In our preceding work, the cyclopeptides 1 to 5 were prepared via direct cyclization of the linear peptides H-Xaa-Glu(Trp)-OH by refluxing in pyridine, whereby as Xaa residues Ala, Val, Trp, Glu(Ile), or Lys(Boc) were used. 1 In the latter case, acidolytic removal of the Boc protecting group was required to obtain the lysine derivative 4.…”

“…5 However, performing the synthesis of 5 under identical conditions, only 28% of the protected intermediate was obtained. 1,5 To disclose the origin of the low yield and bearing in mind the potential interest of bifunctional 2,5-diketopiperazine derivatives in the present work, we studied in detail the cyclization of substituted H-Glu(R1)-Glu(R2)-OH peptides. Besides the unsubstituted glutamic acid (R 1 =OH) and glutamine (R 1 =NH 2 ), we used as R 1 the tBu, Ile, Ile-…”