Pick To:ginsengPanax ginsengAs the "king of herbs", ginseng has a long history of medicine. With the continuous deepening of scientific research, the pharmaceutical material basis of ginseng is more clear, the pharmacological activity is more clear, and the mechanism of action is constantly clarified. The research and development of innovative drugs based on ginseng has stepped into a fast lane, especially the proposal of the technical scheme for the comprehensive development of ginsenosides, which provides a new idea for the development of innovative drugs of ginsenosides. It will certainly produce a series of innovative drugs for the treatment of cardiovascular and cerebrovascular diseases, the treatment of nervous system diseases, the improvement of immune function and antitumor, enhance the high-tech content of the ginseng industry, and promote the high-quality development of the mass health industry.
Note: Chengdu puruifa pharmaceutical R & D Co., Ltd. can provide feasible R & D and industrialization solutions for the comprehensive technology development of ginsenosides. There are many rare ginsenosides (such as ginsenosides Rg3, Rh2,,Ginsenoside compound K, protopanaxadiol, protopanaxatriol, etc.) have mature production processes. For details, please contact sales@biopurify.cn Or 13541283596, Mr. Xie.
ginsengPanax ginseng C. A. MeyerIt is a Panax genus plant of Acanthopanax family, and is highly respected by Chinese and Western medicine because of its high medicinal value. As early as in the "Shennong materia medica classic", it has been recorded that "ginseng mainly supplements the five internal organs, calms the spirit, calms the soul, stops palpitations, eliminates evil Qi, brightens the eyes, increases intelligence and happiness, and prolongs life after long service".2012In, China officially approved ginseng as a new resource food, thus ginseng, as a dual-use natural resource for medicine and food, ushered in a new era of industrial development, expanded the application scope of ginseng, and extended the industrial chain of ginseng. Ginseng is rich in ginsenosides, ginseng polysaccharides, ginseng polypeptides, sterols, proteins, amino acids, flavonoids, nucleotides, organic acids, vitamins and inorganic elements, which are the material basis of ginseng as the "king of herbs". since20century50Since the s, scientific research on ginseng has made great progress, and fruitful achievements have been made in ginseng planting and new quality cultivation, pharmacology, pharmacology, pharmacology, biochemistry, toxicology, blood components and mechanism of action, structural modification and innovative drug development, including Chinese ginseng, GinsenosideNMRStandard atlas[1], ginseng nutritional components and functional factors[2]andGinseng Nutritional Componentsand Functional Factors[3].
Ginsenosides are the main nutritional components and functional factors of ginseng.At present, the ginsenosides isolated from ginseng plants are about300species[4]，Ginsenosides (yuan) found from different parts of ginseng and structurally modified ginsenosides (yuan)200. In recent years, a large number of researches on the development of ginsenoside innovative drugs have made many significant scientific research progress.
1 Structure and pharmacological effects of ginsenosides
Ginsenosides belong to triterpenoid saponins, which can be divided into dammarane type, oleanolic acid type and octreon Type Ginsenosides according to the different mother nuclei (Fig1）. Among them, the parent nucleus of dammarane ginsenoside is tetracyclic triterpene, which is also based onC-6Whether there are substituents at the position can be divided into Ginsenosides of Panaxadiol group and Ginsenosides of Panaxatriol group. Oleanolic Acid Type Ginsenosides belong to pentacyclic triterpene saponins, which are Ginsenosides with oleanolic acid as the parent nucleus. .
The pharmacological effects of ginsenosides are mainly manifested in the protection of the heart[5], antitumor[6], relieve diabetes and complications[7], protecting the nervous system[8]Etc. (table1）These diseases are characterized by complex causes.
Among them, oxidative stress reaction and inflammatory reaction widely exist in the pathogenesis site, which are common mechanisms. The antioxidant and anti-inflammatory activities of ginsenosides have been confirmed by a large number of experimental data[9-11]A variety of ginsenosides can also inhibit myocardial apoptosis[12-15], maintain mitochondrial function and reduce calcium overload[16-17]Protect the heart and relieve coronary heart disease. 10The tumor has significant inhibitory effect. Ginsenosides inhibit tumor cell proliferation by[18-23], induction of tumor apoptosis[24-30], enhance human immune response to tumor cells[31-33]As well as tumor cell inhibitingInvasion and metastasis[34-41]. And ginsenosides combined with other drugs can enhance its anti-tumor effect[42-43]。Ginsenosides can also significantly alleviate Alzheimer's disease, Parkinson's disease and other diseases caused by neuropathy[44-54]In addition, a variety of ginsenosides can alleviate a variety of diabetic complications from different mechanisms, which involve multiple systems such as heart and nerve[55-60]。
1981—2019In, natural products and their semi synthetic derivatives accounted for23%, while semi synthetic derivatives constitute the main part（19%）[61]Natural products have long been considered as a resource for the development of new drugs due to their novel structure, significantly diverse biological activities and unique mechanism of action[62]The research of finding new drugs or lead compounds from natural products has become an active field in the research and development of new drugs at home and abroad[63].
2 Innovative drug development of ginsenosides
2.1 Marketed drugs
At present, many important achievements have been made in the research and development of innovative drugs based on ginseng (table2）. Zhenyuan capsule, with total saponins of ginseng fruit as the main effective component, has been used in clinic for many years. It has dual functions of treating coronary heart disease and diabetes mellitus, with good clinical efficacy and good economic and social benefits[64]Ginseng stem and leaf saponins capsules, with ginseng stem and leaf saponins as the main effective component, can strengthen the spleen and replenish qi, which is used for palpitation, shortness of breath, fatigue and weakness, and stupor caused by qi deficiency, as well as auxiliary medication for coronary heart disease, menopausal syndrome, recessive diabetes mellitus, and tumor[65]Xinyue capsule, with total saponins of Panax quinquefolium stems and leaves as the main effective component, is used for patients with angina pectoris of coronary heart disease with deficiency of both qi and Yin[66]。
With ginsenosideRg3Shenyi capsule with monomer as raw material has the effect of strengthening the yuan and strengthening the foundation, supplementing qi and blood. It can be used in combination with chemotherapy, improve the immune function of the body, improve the Qi deficiency symptoms of tumor patients, and help improve the curative effect of primary lung cancer and liver cancer[67], which opened the precedent for the development of ginsenoside monomer innovative drugs and ushered in a new era of ginsenoside innovative drug development.
2.2 Clinical investigational drug
At present, ginsenosides developed by Guangdong Taihe biopharmaceutical Co., Ltd. and the science and technology development center of Sun Yat Sen Medical College of Sun Yat sen University have successfully developed and carried out clinical researchRdAPI and its ginsenosidesRdInjection（1.1Chemical drugs for the treatment of acute cerebral infarction), developed by Jilin University and Beijing xinliheng science and Technology Development Co., Ltd20(S)-GinsenosidesRg3API and20(S)-GinsenosidesRg3Eye ointment（1.1Chemical drugs, antiviral)20(S)-GinsenosidesRg3Injection（1.1Chemical drugs, anticancer), ginsenosidesReAPI, GinsenosideReTablets（1.2Chemical drugs, promoting intelligence), developed by Zhejiang Yake Pharmaceutical Co., Ltd. and Hainan Asia Pharmaceutical20(S)-protopanaxadiol（1Traditional Chinese medicine, anticancer), pseudoginsenosides developed by Jilin University and Jilin Huakang Pharmaceutical Co., LtdGQCrude drug and pseudo ginsenosideGQInjection（1.1Chemical drugs, anti myocardial ischemia) and other innovative drugs have obtained the approval documents for clinical research from the State Food and drug administration, and others have been approved by the State Drug Administration-See table for the drugs recorded on the drug clinical trial registration and information publicity platform3The listing of these innovative drugs will greatly solve the major problems and scientific bottlenecks that restrict the development of ginseng industry and benefit mankind.
3 Key technology of ginsenoside structure modification and technical scheme of developing innovative drugs
Ginsenosides with higher content of monomeric ginsenosidesRe、Rd、Rb1、Rg1The amount of industrial production can be obtained by extraction and separation. The amount of other ginsenosides (yuan) is small, and only through structural modification technology can we achieve the purpose of industrial production and industrialization, such as rare ginsenosidesRg3、Rh2Et al. In addition, although many naturally occurring ginsenosides have certain pharmacological activities, they can rarely be directly applied to the clinic due to the deficiency of drug likeness. Structural modification can make up for the deficiency of natural product drug likeness to a certain extent[68]. Through the structure oriented modification technology of ginsenosides, the problem that the content of monomeric ginsenosides is low and cannot be developed is solved. Using chemical synthesis, our research group realized rare20(S)-GinsenosidesRg3、Rh2and20(S)-protopanaxadiol（PPD）, pseudoginseng saponinGQIndustrialization of.among20(S)-GinsenosidesRg3Eye ointment（1Chemotherapeutic, antiviral) was completedIIIPhase I clinical study, clinical approval No2004L04263, pseudoginseng saponinGQInjection（1Chemotherapeutic drugs, anti myocardial ischemia), carried outIIPhase I clinical study, clinical approval No2010L2645。
3.1 Key techniques for structural modification of ginsenosides
Aiming at the major problems such as low content of monomeric ginsenosides, difficult industrialization, and biological activity to be improved, under the support of the "Eleventh Five Year Plan" science and technology support plan, Jilin Province "Double Ten Project" science and technology research and other projects, the research of ginsenoside directed structural modification has been carried out, and fruitful results have been achieved in the research fields of structural modification, activity screening and ginsenoside industrialization of human ginsenosides.
3.1.1 Innovate and break through the key technology of ginsenoside structure modification to achieve20(S)-GinsenosidesRg3、GinsenosidesRh2andPPDIndustrialization of other rare ginsenosides (yuan) It is well known that ginsenosides are the main effective components of ginseng, among which20(S)-GinsenosidesRg3、Rh2andPPDThey have strong anticancer activity, but their content in nature is very low, such as ginsenosides in GinsengRg3only0.000 003%It is difficult to realize industrial production, which is one of the main bottlenecks restricting its development of anticancer drugs.At present, there are acid hydrolysis of total ginsenosides to prepare ginsenosidesRg3(Shenyi capsule)[69], but what it gains is20(S/R)-GinsenosidesRg3A pair of enantiomers, only50%The product is available.
Through the first chiral structure modification technology, our research group will contain the same20(S)-GinsenosidesRg3Ginsenosides of structural unitsRbFamilyRc、RdIsodiol saponins, hydrolyzed under strong alkaline and high temperature conditions, retain the sameR1Group, remove different groupsR2, which were efficiently transformed into rare ginsenosides (yuan), respectively20(S)-GinsenosidesRg3、Rh2andPPDSingle component with mass fraction reaching98%Above, it has reached the kilogram level and broken through the key technology of industrialization. Its core technology is to maintain ginsenosideC-20The site configuration is unchanged. The specific technical route is shown in Fig2。
3.1.2 It is the first time to carry out the transformation of dammarane Type Ginsenosides to octeron Type Ginsenosides to realize the pseudo ginsenosidesF11、GQandDQIndustrialization of Our research group[70]Through the invention of ginsenoside side chain directional oxidative cyclization technology, the side chain double bond of dammarane ginsenoside is oxidized to obtain epoxy compounds, which are further combined withC-20position-OHThe affinity substitution reaction was carried out to form an oxygen-containing five membered ring, and the ginsenosides were innovatively transformed into octelon type saponins unique to American ginseng, and a series of new pseudo ginsenosides were obtained, including20(R)-Pseudoginseng saponinF11, pseudo ginsenosidesGQ, pseudoginsenosideDQThe biological activity is significantly enhanced, and its core technology is to maintain the stability of octreon type ginsenosideC-20andC-24The site configuration is unchanged. Product conversion rate reaches90%Above, the product quality score reaches98%Above. The reaction mechanism is shown in Fig3。
3.2 It is the first time to put forward the technical scheme for the comprehensive development of innovative drugs of monomeric ginsenosides
For the first time, our research group proposed a technical scheme for the comprehensive development of innovative drugs of monomeric ginsenosides. Through the key technology of ginsenoside structure modification, the industrialization problem of low content and weak biological activity of monomeric ginsenosides was solved; Determine the adaptation of innovative drugs according to the different efficacy of ginsengSyndrome, taking different routes of administration, developing monomeric ginsenosides according to clinical needs; The core goal is to carry out the comprehensive development of monomer ginsenoside innovative drugs in an orderly manner according to the different content and biological activity.
The technical scheme for comprehensive development of ginsenoside innovative drugs is shown in Fig4。
4 epilogue
With the continuous excavation of ginsenosides and the continuous synthesis of their derivatives, as well as the development of modern pharmacology, ginsenosides have made gratifying achievements in anti-cancer, anti-inflammatory, anti obesity, regulating metabolic disorders, improving memory and protecting cardiovascular system, especially in anti-tumor clinical treatment[71-72]. It is believed that with the systematic research of ginsenosides, a batch of innovative drugs for the treatment of cardiovascular and cerebrovascular diseases, intelligence promotion and anti-tumor will emerge in the future, which will benefit the great health industry of mankind. At the same time, it is imperative to carry forward the essence of traditional Chinese medicine, inherit the essence, keep the innovation, and realize the historical mission and responsibility of innovating and developing traditional Chinese medicine in China from the perspective of history and development, so that ginseng, a treasure, can play the function and efficacy of "king of herbs" in the process of modernization of traditional Chinese medicine in the future.
Remarks:Chengdu puruifa pharmaceutical R & D Co., Ltd. can provide feasible R & D and industrialization solutions for the comprehensive technology development of ginsenosides. Many rare ginsenosides (such as ginsenosides Rg3, Rh2, ginsenoside F11, ginsenoside compound K, protopanaxadiol, protopanaxatriol, etc.) have mature production processes. For details, please contactsales@biopurify.cnOr 13541283596, Mr. Xie.
References (omitted)
Come Source: lipingya, Feng Hao, liujinping, wangcuizhu, Li Zhuo. Research and development of innovative drugs based on Ginseng——Ginsenoside comprehensive technology development plan [J] . Chinese herbal medicine, 2021, 52 (17): 5350-5357