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.
This publication is dedicated to the memory of Professor Vadim Ivanov.Oral delivery of peptide pharmaceuticals has long been a fundamental challenge in drug development. A new chemical platform has been developed based on branched 2,5-diketopiperazines for creating orally active peptidomimetics. The platform includes a diketopiperazine bio-carrier with "built-in" functionally active peptide fragments or molecules coupled via linkers, transforming it into an orally available compound displaying the same type of activity. Based on this approach, we prepared several compounds that exhibit hemostimulating, hemosuppressing, and adjuvant activity. In this work, we screened the activity of substituted piperazine-2,5-dione deriv-atives in two experimental models: human neuroblastoma MC-65 cells and as an adjuvant in response to ovalbumin invasion. As a result, some original cyclopeptide derivatives have demonstrated neuroprotective and adjuvant activity. The maximum neuroprotective activity was shown by cyclo-[Glu(Ile)Glu( Trp)] and cyclo-[AlaGlu(Trp)]; branched cyclopeptides containing a disaccharide component cyclo-[L-Lys(Nacetyl-Glucosamine-N-acetyl-muramyl)-L-Glu(L-Trp-OH)] and palmitic acid cyclo-[L-Lys (Palmitoyl)-L-Glu(L-Trp-OH)] showed the highest adjuvant activity.
A series of linear peptides with the general formula H-Glu(R1)-Glu(R2)-OH was subjected to cyclization under standard conditions. Formation of respective 2,5-diketopiperazines was accompanied by transformation of the N-terminal Glu(R1) to pyroglutamic acid residue. Even in the case R1 is an amino acid residue attached to the N-terminal γ-carboxyl group, lactamization leads to its elimination. The observed reaction has not been reported so far in the literature. Correspondingly, an alternative route to Glu(R1)-Glu(R2)-containing 2,5-diketopiperazines was applied to improve the overall yields.
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