Nankai team has developed a new synthesis method of cyclopeptide to promote the development of polypeptide drugs

　　   Nankai news (reporter Wu Junhui) recently, Professor Chen Gong, National Key Laboratory of elemental organic chemistry, Nankai University, developed a powerful chemical synthesis method of cyclic polypeptide compounds, which made the "highly difficult polypeptide cyclization" reaction, which has puzzled the chemical industry for many years, efficient and controllable As an important breakthrough in the field of cyclopeptide molecular synthetic chemistry, this work also provides a novel design tool for the development of peptide drugs On April 2, the paper introducing the work was published in the international well-known academic journal Nature chemistry 　　   Schematic diagram of "hydrocarbon bond activation" peptide cyclization strategy This method adopts the unconventional synthesis strategy of "hydrocarbon bond activation", which can overcome the substrate dependence of "polypeptide cyclization" for a long time Preliminary biological research shows that there is a kind of lead drug compound with high activity for specific tumor cells in the small molecular library which contains more than 40 structures randomly prepared in the laboratory This efficient method of cyclopeptide synthesis is helpful to shorten the research and development cycle of peptide drugs In recent years, in response to the increasingly important biological target research in the development of new drugs, the exploration and construction of "macrocyclic framework" molecular structure has attracted much attention in the field of pharmaceutical chemistry Compared with the traditional small molecular compounds, the polypeptides which are composed of a variety of amino acid units in series have unique advantages and potential in building a larger molecular framework Previous studies have shown that the chain like polypeptide "ring" can significantly improve the drug-forming properties of polypeptide in many aspects, such as structural robustness, cell transmembrane, metabolic stability and so on Known cyclopeptide compounds have many biological activities, including anti-tumor, anti HIV, antibacterial, anti malaria, sleeping, platelet aggregation inhibition, immunosuppression and so on However, how to make these "big" polypeptide molecules "shape" into an ideal three-dimensional structure (cyclopeptide) and have good pharmacological properties remains a huge challenge Although the synthetic chemistry of cyclopeptides has made great progress in the past few decades, it still has great limitations "Whether the chain peptide substrate can form a ring usually depends on the composition of amino acids and the size of the final ring A lot of chain polypeptides are very 'stubborn', no matter how 'hard' they can not be linked into a ring To solve these problems, we must develop unconventional strategies " Chen Gong said 　　   Molecular diagram of cyclic peptide "buckled" by benzene ring Inspired by the biosynthesis of natural products of cyclopeptides, Chen Gong's group selectively activated the originally inert alkyl hydrocarbon bond on the chain peptide substrate through metal catalysis, and carried out intramolecular coupling with the aromatic amino acid side chain with iodine substitution to generate various ring products "The reaction mode based on hydrocarbon bond activation is a very important and popular research direction in organic chemistry, which has great potential However, there are still many bottlenecks in the practical application of this kind of reaction In our work, palladium catalyzed activation of alkyl hydrocarbon bonds is cleverly used in the synthesis of complex polypeptides, which can "tame" many chain like polypeptide precursors that are difficult to form a ring, and make them "obediently" close the ring " Chen Gong said According to reports, this new method of cyclopeptide synthesis is simple and efficient, with a wide range of substrates, and can generate a three-dimensional cyclopeptide skeleton with a unique "benzene ring support" structure, which provides a general way for the construction of cyclopeptide compounds with different volumes To the researchers' surprise, in addition to the large ring, the small cyclic peptide compounds with ultra-high ring tension can also be efficiently prepared by the above method The single crystal structure shows that some benzene rings, as supporting structures, bend rarely under the action of ring tension, from the original plane structure to the "ship like" structure "It is understood that the 12 membered ring we obtained by this method is the most tensive asymmetric cyclophenyl ring compound that can be prepared by people at present It can be said that the cyclization chemistry provides an efficient and reliable synthesis method for the bent benzene ring compounds which are very difficult to be made originally " Chen Gong said These cyclopeptide compounds with "benzene ring support" have unique three-dimensional structure, filling the so-called "new chemical space", the researchers also introduced Through cooperation with the research group of Shen Weijun of caliber biomedical research center, the research team successfully found a kind of leading drug compounds with high activity and high selectivity for cancer cells dependent on myc factor from the synthesized cyclopeptide molecular library, which laid an important foundation for downstream drug development Professor Liu Peng's research group of Pittsburgh University in the United States has done a detailed calculation of the reaction mechanism for the study, and Qi Xiangbing's research group of Beijing Institute of life sciences in China has done the related work of drug cell transmembrane test for the study Professor Chen Gong's research group and its partners hope to find more new cyclopeptides with good leading drug activity through the follow-up in-depth mining of the cyclization reaction and biological activity screening, so as to meet the current challenging biological targets and promote the research and development of related peptide drugs Thesis link: https://www.nature.com/articles/s41557-018-0006-y