Synthesis And Stucture Study On Pyroglutamyl Dipeptides And Aminophosphonic Acids

The use of peptides in the field of biology and pharmacy is becoming more and more important, alongside the development of biological technology. Modified pyroglutamyl peptides with increased receptor selectivity, which have better bioavailability and stability than bioactive peptides, increase the pharmacological and medical interest in this class of compounds. Thus, it is of great importance to study approaches for the preparation of pyroglutamyl peptides, especially pyroglutamyl dipeptides, and their properties.A simple, economical and effective way to prepare pyroglutamyl dipeptides has been described. The synthetic route starts with pyroglutamic diketopiperazine, followed by transamidation of amino acids to the trifiuorethyl ester to produce pyroglutamyl dipeptides. A series of pyroglutamyl dipeptides have been synthesized, including pyroglutamylglycine, pyroglutamylβ-alanine, and pyroglutamyl dipeptides, with active side chain groups such as pyroglutamylaspartic acid, pyroglutamylserine and pyroglutamylthreonine, a good yield of products are achived in each case. Further studies showed that the synthetic route circumvented the complicated, expensive and time consuming protection and deprotection ofα-amino,α-carboxyl and active side chain groups. Further more, the reactions proceeded favorably under mild conditions, and the racemization of pyroglutamyl dipeptides was controlled during the coupling reactions. There was also an accidental discovery of the formation of the dimethyl ester of cyclo-glutamylaspartic acid during the esterification of pyroglutamylaspartic acid.Electrospray ionization mass spectrometry (ESI-MS) is a very powerful method for the analysis of compounds. The fragmentation pathways of the [M+Na]⁺ ions of pyroglutamylaspartic acid, pyroglutamylserine and pyroglutamylthreonine were investigated in detail using tandem mass spectrometric (ESI-MS/MS) techniques and the rearrangement ion, m/z 152, was observed. A rearrangement reaction mechanism was proposed, which involved an attack of atom O in a-carboxyl groups on the carbonyl atom C in the amido bond. Additionally, the rearrangement of the ion m/z 128 of pyroglutamylaspartic acid under negative ion mode displayed a similar mechanism. Moreover, the fragmentation pathways of the [M-H]^- ions of pyroglutamylserine and pyroglutamylthreonine behaved similarly. Ions m/z 169 from [M+H-H₂O]⁺-30 of pyroglutamylserine and [M+H-H₂O]⁺-44 of pyroglutamylthreonine were found for these species. The validity of the proposed mechanisms was established using the exchange of the active hydrogens for deuteriums.N-(phosphonomethyl) glycine (glyphosate) was first reported as an effective herbicide. Later studies demonstrated that the aminophosphonic acids were especially effective in suppressing the growth of cancer, tumors, viruses, and bacteria. Hence the synthesis and the structural modification of aminophosphonic acids have been a centre of focus in synthetic organic chemistry, as well as in medicinal chemistry. After considering the reaction conditions, yield, and the separation of products, we chose to employ an efficient synthetic route according to the Fields reaction mechanism, which gave reasonable yields in the preparation of the aminophosphonic acids involving N-(phosphonomethyl)-β-alanine and N-methyl-N-(phosphonomethyl) glycine, by using diisopropyl phosphite as the starting material. These two compounds will be used as the transition-state analogues of phosphoserine phosphatase to help decipher the catalytic mechanism of phosphoserine phosphatase.