Controversy of Peptide Cyclization from Tripeptide

Chung-Yin Lin,Subrata Chakraborty,Dar-Fu Tai,Chia-Wei Wong

doi:10.3390/molecules26020389

Abstract

The present investigation reports an attempt to synthesize naturally occurring α-cyclic tripeptide cyclo(Gly-l-Pro-l-Glu) 1, [cyclo(GPE)], previously isolated from the Ruegeria strain of bacteria with marine sponge Suberites domuncula. Three linear precursors, Boc-GPE(OBn)2, Boc-PE(OBn)G and Boc-E(OBn)GP, were synthesized using a solution phase peptide coupling protocol. Although cyclo(GPE) 1 was our original target, all precursors were dimerized and cyclized at 0 °C with high dilution to form corresponding α-cyclic hexapeptide, cyclo(GPE(OBn))2 7, which was then converted to cyclic hexapeptide cyclo(GPE)2 2. Cyclization at higher temperature induced racemization and gave cyclic tripeptide cyclo(GPDE(OBn)) 9. Structure characteristics of the newly synthesized cyclopeptides were determined using 1H-NMR, 13C-NMR and high-resolution mass spectrometry. The chemical shift values of carbonyls of 2 and 7 are larger than 170 ppm, indicating the formation of a cyclic hexapeptide.

Highlights

Marine sponge-derived natural cyclic peptides have generated much interest in recent years due to their privileged structures and persuasive biological activities
An α-cyclic hexapeptide cyclo(GPE)2 2 was synthesized via cyclization of fully deprotected linear precursor with a series of coupling reagents in DMF
Even though the characterization data of the reported natural product and our synthetic cyclo(GPE)2 indicate that the reported compound may be a dimer of cyclo(GPE), this strategy still provided a way to synthesize cyclic peptide of varying ring size

Summary

Introduction

Marine sponge-derived natural cyclic peptides have generated much interest in recent years due to their privileged structures and persuasive biological activities (therapeutic potential). Several studies have increased interest in sponge-associated bacteria recently by proving that these bioactive compounds, when isolated from marine sponges, are symbiotically produced microorganisms [2]. Among these cyclic peptides, naturally occurring α-cyclic tripeptides and tetrapeptides are highly constrained because they have a small ring size [3]. Many biologically active cyclic peptides have been isolated [8,9,10,11,12], but not fully characterized [13,14] Another hurdle is to meet the supply problem and target identification. Synthesis [15,16] is useful for biological applications as well as to confirm the actual structure of natural products and target identification to overcome the hurdle

Methods

Results

Conclusion