[field view] Hu Wenhao: Innovation of new multi-component reaction from drug source

At present, the development of innovative drugs is divided into two categories, one is macromolecular drugs, the other is small molecule drugs Due to the high price of macromolecular drugs, most of the clinical prescriptions are small molecule drugs In addition, 55% of the global candidate drugs are small molecule drugs It is reported that among 1800 small molecule drugs used in clinic, the proportion of chiral drugs is as high as 62% Among 79 new chemical drugs approved by FDA in 2015-2017, 55 are chiral drugs On June 21, at the 2019 China Pharmaceutical Health Industry Development Conference and the fourth China Pharmaceutical R & D Innovation Summit (PDI Conference) held in Chongqing, Mr Hu Wenhao, Dean, professor and doctoral supervisor of the school of pharmacy of Sun Yat sen University, who mainly focused on the innovation from the source of innovative drugs and the research of new technologies of chiral drugs, so as to solve the material basis problems in the research of chiral drugs, wrote the new multi The report of component reaction and its application in the field of drug research and development shares the viewpoint on the research of multi-component reaction chiral drugs What is chiral medicine? Chiral drug is the concept of chirality, which refers to a feature that mirrors each other in space but cannot overlap It looks like two hands of a person, but it's not a substance There is the same situation in drugs Many drug molecules are mirror like hands, which can't overlap at all The target of human whole organism is chiral Only the right chiral drugs can enter into the target If they are not correct, they will not enter, and even have side effects In history, the understanding of adversarial drugs is a long process, and the real understanding originated in the 1950s and 1960s At that time, a drug was produced in Europe Because researchers didn't realize the problem of chirality at that time, they mixed two enantiomers into a drug to calm pregnant women and effectively prevent women from vomiting in the early stage of pregnancy However, after taking the drug, a large number of deformed babies were produced in Europe At that time, the drug was not popular in the United States Rich people in the United States heard that Europe had the drug and went to Europe to buy it However, after taking it, they had side effects China calls this drug thalidomide It is precisely because of thalidomide that people realize the chirality problem of the drug, and all departments pay attention to it So far, the research and development of chiral drugs have attracted people's attention What are the main challenges in the basic research of chiral drugs? How to solve it? First, because the two substances with chiral relationship are very similar, the problem of highly selective synthesis of chiral drugs arises How to synthesize only one drug without another? Secondly, is there a good way to synthesize the most chiral molecules in the shortest time for drug screening and discovery? It is worth mentioning that due to the importance of chirality of chiral drugs, three experts in highly selective synthesis won the Nobel Prize in 2012, which can be environmentally friendly to obtain some chiral molecules with high selectivity Based on the multi-component reaction, Professor Hu Wenhao mixed several substrates to form multiple chemical bonds in one step, so as to improve the synthesis efficiency of chiral molecules and realize the most ideal green economic reaction "Trapidir" is a typical multi-component synthetic drug It takes 18 steps to synthesize the drug by the traditional two-component synthesis method, with a long synthesis route and a total yield of no more than 10% However, using the new multi-component synthesis strategy, in fact, only two three-component reactions, including the Passerini reaction and the enzyme reaction, are used to obtain trapidir The early development of multicomponent reaction is based on the accidental discovery The earliest multicomponent reaction was in 1850 What we saw in 1966 was also based on the accidental discovery However, with the improvement of scientific development on cognition, multicomponent reaction has obvious advantages, and more and more multicomponent reactions have been found Since 2009, the number of articles published in the field of multicomponent reaction research has continued to increase Based on the advantage of multi-component reaction, Professor Hu Wenhao's research team designed rationally and developed new strategies of multi-component reaction They found that multicomponent reactions are based on the capture of active intermediates generated in two-component reactions to form new multicomponent reactions In fact, it is to change the traditional chemical reaction way and form a new reaction This reaction has the advantages of traditional multi-component reaction, but also has the characteristics of rapid and efficient reaction At the same time, new challenges have come, that is, the issue of selectivity Based on this, Professor Hu Wenhao's team has done new research work Professor Hu Wenhao's team accidentally got a three-component product during a chemical synthesis reaction After analysis and research, it was found that the multi-component reaction which changed the traditional chemical reaction path was accidentally found The target molecules can be captured by adding corresponding intermediates The active intermediates, such as amino ylide and hydroxyylide, were found after extraction And through unremitting research, it is found that the corresponding selectivity of multicomponent reactions can be controlled if some new catalytic strategies such as co catalysis and co catalysis are adopted For example, three very simple substances, mixed in one step, can form multifunctional chiral substances in an instant, and these chiral substances will be very important intermediates in drugs It is worth mentioning that this research work has aroused some international repercussions At that time, a laboratory in the United States took a fancy to the study After repeated experiments, it was included in the manual of organic synthesis, which was published in 1921 Up to now, only 2000-3000 reaction methods have been included in the manual, and all of them are the most innovative reactions Professor Hu's team's study was fortunately included after repeated experiments Methods the practical application can reflect the value Professor Hu's team used it in the synthesis of drugs to synthesize chiral molecules For example, in the synthesis of taxol derivatives, one side point can be obtained from three simple alcohol imines and alcohol nitrogen in one step, and functional groups can be prefabricated at the same time In addition, these methods are not only applied to known drugs, but also to natural molecular drugs, which are simple and convenient At the same time, they can also be used for post modification of drugs, modification into more new compound entities, and screening of early drugs The result shows that it has a high bid winning rate, which reflects the activity of the compound, and then it becomes a very good compound We know that the route of new drug research and development is particularly long, but the source innovation is to see if there is an up-to-date result and where is the future The new multi-component reaction has laid the material foundation for the initial compounds of chiral drugs and innovated the innovative drugs from the source Click "read the original" to enter the "2019 China Pharmaceutical Health Industry Development Conference and the fourth China Pharmaceutical R & D Innovation Summit" (PDI Conference) Xinhua special page, zero distance direct attack on the conference graphic live broadcast, high-end interviews, wonderful reports Statement: this opinion only represents the author, not the position of yaozhi.com, welcome to exchange and supplement in the message area; 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