Professor Qin Chuanguang's team at Northwestern Polytechnic University has made important progress in the field of peptide synthesis
Recently, the research paper "liquid phase total synthesis of plecanatide aided by diphenylphosphinyloxyl diphenyl ketone (DDK) innovations" independently completed by the research group of Professor Qin Chuanguang of Northwestern Polytechnic University has been officially published online by the top journal organic letters in the first district of chemistry.
In this paper, a new organophosphorus small molecule was developed as a green peptide synthesis carrier (GPS), and the liquid-phase total synthesis of drug molecule plecanatide (trade name: trulance) was successfully realized. Procanatide is an oral guanylate cyclase C (GC-C) agonist developed by synergy pharmaceuticals. It was first approved by FDA in the United States on January 19, 2017 for the treatment of gastrointestinal diseases, such as constipated irritable bowel syndrome (IBS-C) and chronic idiopathic constipation (CIC). At present, as a candidate drug, the third phase clinical efficacy trial of IBS-C indications is under way.
Compared with the traditional solid-phase peptide synthesis method using resin, this paper proposed a better resin free synthesis strategy to synthesize long-chain bicyclic pukanapeptide, and verified that the target product can be synthesized without resin on organophosphorus small molecule carrier by regulating and optimizing DDK derivatives. It is worth mentioning that without chromatographic separation, the carrier assisted precipitation (SAP) technology omits the purification procedures of various intermediates in the peptide synthesis process, significantly simplifies the cumbersome peptide synthesis steps, improves the feasibility and synthesis efficiency of the reaction, and significantly avoids the excessive use of solvents and raw materials (such as N-terminal protective amino acids, coupling agents, deprotection agents, etc.). In addition, DDK derivatives are used as atomic economy, simple and green small molecule carriers to innovatively reduce PMI, one of the most basic and valuable indicators in green chemistry of peptide synthesis. DDK derivative carrier has the characteristics of convenient synthesis and high yield. It is suitable for large-scale production. It can be recycled and reused after peptide synthesis. Therefore, compared with the traditional peptide synthesis method, the production cost and pollution waste of this method will be greatly reduced, so as to realize greener and large-scale peptide production. Obviously, this method can also be widely used in the field of simplified synthesis of other polypeptide drugs and biomaterials, and promote scientific research and industrial production.
In order to seek new applications of organophosphorus compounds, tris (4-formylphenyl) phosphonate (TFP) derivatives (such as alcohols, oximes and halogenates) were successfully synthesized in this paper, which were used as C-terminal protectors or green equivalent carriers of amino acids in liquid phase peptide synthesis (LPPS). Due to the carrier assisted precipitation (SAP) of TFP derivatives, peptide intermediates in the process of peptide synthesis can be collected through rapid precipitation and simple filtration without chromatographic purification. In addition, after the TFP derivative carrier is cut off from the target polypeptide, it can be directly recycled without further regeneration.
The author simply prepared the designed TFP derivatives and applied them to the innovation and green process of LPPS. At the same time, the new uses of organophosphorus were revealed. The results showed that: (1) TFP derivative carrier had C-terminal protective effect on amino acid synthetic peptides. (2) TFP derivatives have excellent precipitation properties, which is helpful to purify GPS linked peptide intermediates in the process of peptide synthesis. The final target polypeptide can be easily separated and purified by simple precipitation without using preparative HPLC that requires a lot of solvent and time. It is worth noting that the method they established can be applied to convenient large-scale peptide synthesis. (3) The coupling reaction in homogeneous solution mediated by TFP derivative carrier avoids the excessive use of amino acids, greatly reduces the waste of raw materials and effectively reduces the cost. (4) TFP derivative carrier is easy to synthesize and can be directly recycled after cleavage from the target polypeptide without further regeneration, which greatly reduces waste discharge and cost consumption. Because there are three reaction sites on each small molecule carrier, the atomic utilization of the carrier has been greatly improved compared with the traditional low load SPPs. Through the sap effect of TFP derivatives, the large-scale synthesis of peptides can be realized more economically and environmentally friendly. The application of organophosphorus molecules will expand new synthetic tools for scientific research and industrial production in the fields of polypeptide chemicals, polypeptide drugs and polypeptide based biomedical materials.
Source: Northwest University of Technology
Paper link:
https://dx.doi.org/10.1021/acs.orglett.0c00616
https://dx.doi.org/10.1021/acs.joc.9b03023
