CN114933626A - Ginsenoside Rb 1 Derivatives and uses thereof - Google Patents
Ginsenoside Rb 1 Derivatives and uses thereof Download PDFInfo
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- CN114933626A CN114933626A CN202210449816.7A CN202210449816A CN114933626A CN 114933626 A CN114933626 A CN 114933626A CN 202210449816 A CN202210449816 A CN 202210449816A CN 114933626 A CN114933626 A CN 114933626A
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- ginsenoside
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- 238000012827 research and development Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J17/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J17/005—Glycosides
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention discloses ginsenoside Rb with a structural formula shown as the following formula I 1 The derivative or the pharmaceutically acceptable salt thereof has better effect of inhibiting Zika virus or dengue virus and low cytotoxicity; the compound has simple preparation method and low cost, and is suitable for industrial production and market popularization and application;
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to ginsenoside Rb 1 Derivatives, preparation methods thereof and application thereof in preparing medicaments for treating and/or preventing Zika virus and/or dengue virus.
Background
Dengue virus (DENV) and Zika virus (ZIKV) are arboviruses transmitted by bites of Aedes aegypti and Aedes albopictus, and belong to the family of viruses, such as Yellow Fever Virus (YFV), West Nile Virus (WNV), Japanese Encephalitis Virus (JEV), and Hepatitis C Virus (HCV). DENV infection can lead to different forms of the disease, classic dengue fever without clinical symptoms, Dengue Hemorrhagic Fever (DHF), and Dengue Shock Syndrome (DSS), the latter two weighing dengue fever, causing up to 20% of patient deaths. Dengue fever has a number of outbreaks and pandemics worldwide. The prevalence of dengue fever has been on the rise since the 80's of the 20 th century. Dengue fever has spread to 100 countries and regions in tropical and subtropical regions, with about 40% of the world at risk of dengue fever, about 3.9 million people infected each year, and the World Health Organization (WHO) has listed dengue fever as a serious disease that threatens human health as 10.
The pathogenic mechanism of severe dengue fever is not yet fully elucidated. All 4 serotypes of dengue virus (DENV-1, 2, 3, 4) have been found to cause severe dengue fever. After infection with any DENV serotype, the body can only produce specific antibodies against that serotype, but not the other serotypes. Secondary infection with the different serotypes of DENV can lead to more serious conditions in the body. An effective prophylactic or therapeutic measure must be able to target these 4 virus serotypes simultaneously; the prevention and treatment of dengue has become a great challenge for researchers. In the aspect of dengue fever treatment, no specific drug is on the market at present, and dengue fever patients can relieve clinical symptoms only through symptomatic treatment. Ribavirin (ribavirin) is a broad-spectrum nucleoside antiviral drug, has a certain inhibition effect on the replication of various RNA and DNA viruses, and is reported in documents to be capable of inhibiting the replication of dengue viruses, but the exact action mechanism is not clear. By the end of 2015, the first dengue vaccine dengvxia (CYD-TDV) developed by the company cenofibaster was registered in countries such as philippines, brazil, mexico and the like for use by residents 9-45 years of age in the epidemic area, but the safety and effectiveness of the vaccine still remained to be observed and studied. There are currently no anti-DENV drugs on the market, and anti-DENV drugs targeting viral or host factors are under investigation.
The Zika virus was first isolated from a rhesus monkey specimen with Wuganda fever in 1947, and was named Zika virus. ZIKV is transmitted not only by the bite of aedes but also by blood, sex and mother and infant. Most of clinical symptoms caused by ZIKV infection are light, mainly manifested by headache, fever, hypodynamia, rash, conjunctivitis, arthralgia and myalgia, and the like, and the patients can be healed after 2-7 days generally. But can also cause severe damage to the nervous and autoimmune systems. For example: infection of pregnant women with ZIKV may cause congenital malformation of fetal brain, resulting in microcephaly, while infection of adults with ZIKV may cause paralysis and even death of patients due to guillain-barre syndrome. ZIKV was originally found only in sub-africa in sporadic cases of infection, however since 2007 ZIKV was outbreak in oceania and spread to america, over several hundred thousand cases of infection were reported in the americas, caribbean and pacific regions in 2015, and the number of infants with capitulum deformity born in brazil at the same time was significantly increased, causing high global concern. The number of ZIKV infections in south america has reached about 200 million by 2016. In view of the increasing prevalence of ZIKV viruses, which causes a serious burden of diseases, the World Health Organization (WHO) announces the ZIKV epidemic as a global health emergency. Nowadays, 90 countries and regions exist, more than 36 hundred million people live in ZIKV epidemic areas, which poses a huge threat to the global human health, and finding and discovering effective antiviral treatment measures has become a worldwide medical challenge.
To date, there is no FDA-approved vaccine or drug for ZIKV infection prevention or treatment, and although some vaccines against ZIKV have entered clinical trials, long-term effectiveness tests and approval of the vaccines are still long on the market, and zika vaccine may cause antibody-dependent enhanced effect (ADE) of DENV infection, which also brings great hindrance to the development of zika vaccine. In recent years, scientists focus on each link of the life cycle of ZIKV, have searched a plurality of potential drug targets, and combined with virtual screening technology and in vitro tests, have discovered a plurality of small molecular compounds with the activity of inhibiting ZIKV, are expected to bring new breakthroughs for the research and development of anti-ZIKV drugs, but are still far from clinical application. ZIKV epidemic situation is urgent, and scientific researchers are urgently required to jointly make efforts to develop specific antiviral drugs.
The natural product is an important source of antiviral drugs, and the advantages of the natural product, such as stable curative effect, small toxic and side effects, difficulty in drug resistance, difficulty in virus variation and the like, which are incomparable with western medicines attract the attention of numerous scientific researchers. However, natural products often have the defects of complex structure, low bioavailability and the like, so that structural modification on the basis of known effective ingredients of Chinese herbal medicines to improve the activity and the pharmaceutical property becomes an important way for creating new medicines. Notoginseng radix [ panax notogeng (Burk.) F.H.Chen]Is commonly known as Stephania delavayi Diels, belongs to the plant of Panax of Araliaceae, and is a famous Chinese medicine specially produced in Yunnan. Notoginseng radix saponin (PNS) as main active ingredient of Notoginseng radix belongs to dammarane type tetracyclic triterpene saponin, and ginsenoside Rb is mainly used 1 、Rb 2 、Rd、Rg 1 、Rh、Re、Rg 3 And waiting for more than 20 monomeric saponins. PNS has a variety of functions of regulating the immune function of the body, resisting tumors and viruses, protecting the liver, reducing blood levels, regulating the central nervous system, endocrine and respiratory systems, etc., and in recent years, the research on the aspect of resisting viruses is increasing. For example, PNS has resistance to coxsackie virus B 3 Marek's virus (MDV), enterovirus 71, Hepatitis C Virus (HCV), and ginsenoside-Rg 3 、Rb 3 Has anti-herpes simplex virus I (HSV-1) and poliovirus (PoliV) activity, and ginsenoside Re can enhance H 3 N 2 Immunoreaction of influenza virus vaccine, ginsenoside R f 、Rg 2 Has HRV resistance 3 Active ginsenoside Rb 1 Can inhibitInfluenza virus H 1 N 1 Infection of, ginsenoside Rb 1 、Rg 1 Can obviously inhibit the activity of Hepatitis A Virus (HAV) in vitro and the like. In the process of searching and modifying the structure of monomer saponin using PNS antiviral activity as a guide, after the anti-HCV virus activity of PNS is carried out successively, we find that monomer ginsenoside Rb in PNS is subjected to 1 After amino acid esterification and etherification modification, the modified amino acid has very obvious ZIKV and DENV resistant activity. Until now, no report on the application of PNS monomer saponin or derivatives thereof in resisting DENV or ZIKV infection exists.
Disclosure of Invention
The invention provides ginsenoside Rb 1 Derivative or pharmaceutically acceptable salt thereof, ginsenoside Rb 1 The structural formula of the derivative is as follows:
in the formula: r is selected from H, C 1 -C 6 Straight or branched alkyl of (2), C 3 -C 6 A cycloalkyl group;
R 1 、R 2 or R 3 Each independently selected from R or
n is any integer between 0 and 3;
R 1 selected from H, C 1 -C 6 Straight or branched alkyl of (2), C 3 -C 6 Cycloalkyl, -C 1 -C 6 Linear or branched alkyl-NH of 2 、-C 1 -C 6 Linear or branched alkyl-OH, NH of 2 C(＝O)-、C 1 -C 6 Linear or branched alkoxy of (C) 1 -C 6 Straight-chain or branched alkylthio of (C) 6 -C 10 Aryl of (C) 2 -C 10 The heteroaryl group of (a);
R 2 selected from H, tert-butyloxycarbonyl, or R 2 And R 1 Is connected to form C 2 -C 6 A heterocycloalkyl group.
Ginsenoside Rb related to the structural formula 1 The specific structure of the derivative is as follows:
another object of the present invention is to provide the above ginsenoside Rb 1 The preparation method of the derivative comprises the step of reacting ginsenoside Rb in the presence of a solvent and an alkaline catalyst 1 With respective halogenated hydrocarbons (RX) or amino acids
Uniformly mixing according to a certain proportion, stirring and reacting for 0.5-12 h at 0-80 ℃, separating and purifying reaction products to obtain the ginsenoside Rb1 derivative, wherein the reaction formula is as follows:
wherein, ginsenoside Rb 1 Halogenated hydrocarbons (RX, 1) or amino acids (A)
2) The molar ratio of (A) to (B) is 1: 1-36.
The alkaline catalyst is potassium carbonate (K) 2 CO 3 ) One or more of sodium hydrogen (NaH), N' -Diisopropylcarbodiimide (DIC), 4-Dimethylaminopyridine (DMAP); the solvent is one or more of tetrahydrofuran, toluene, acetonitrile, dichloromethane, N-dimethylformamide and pyridine.
The invention also aims to use the ginsenoside Rb 1 Derivatives or thereofThe pharmaceutically acceptable salt is applied to preparing medicaments for treating and/or preventing the Zika virus and/or the dengue virus.
The drug for treating and/or preventing Zika virus and/or dengue virus comprises ginsenoside Rb as a component (or active ingredient) 1 The derivative or the pharmaceutically acceptable salt thereof can be added with one or more pharmaceutically acceptable auxiliary materials to improve the absorption effect of the medicine or facilitate the taking, such as capsules or pills, powder, tablets, granules, oral liquid, injection and the like, and the pharmaceutically acceptable use dosage form is prepared; can also be combined with other active ingredients to prepare a medicament for treating and/or preventing Zika virus and/or dengue virus.
The invention has the advantages and technical effects that:
1. the compound of the invention has simple preparation method and can realize industrial production;
2. experiments prove that the compound has a good inhibition effect on the Zika virus and/or the dengue virus and has very low cytotoxicity.
Detailed Description
The present invention is described in detail below by way of examples, but is not meant to be limited to any of the disadvantages of the present invention. Having described the invention in detail and having disclosed specific embodiments thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.
The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions. The starting materials may be obtained from commercial sources or prepared by methods known in the art or according to the methods described herein. The structure of the compound is determined by nuclear magnetic resonance 1 H NMR or 13 C NMR) and Mass Spectrometry (MS), wherein the NMR measurement is performed using a BrukeraV-400 type nuclear magnetic resonance apparatus, and the measurement solvent is deuterated pyridine (C) 5 D 5 N), TMS is an internal standard.
Example 1: ginsenoside Rb 1 Preparation of methyl ether derivative I-1
Adding ginsenoside Rb into a 50mL round-bottom flask 1 Dissolving (200mg, 0.18mmol) in 10mL DMF, adding sodium hydride (130mg, 5.41mmol) at room temperature, stirring for 30min, adding iodomethane (337 μ L, 5.41mmol), reacting at room temperature for 6h, adjusting pH to about 7 with dilute hydrochloric acid, extracting with ethyl acetate, drying, and concentrating; separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol 60:1, v/v), collecting eluent, concentrating and drying to obtain white solid compound I-1 with yield of 70%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.79(d, J-12.0 Hz, 1H), 0.88(s, 3H), 0.99(s, 6H), 1.07(s, 3H), 1.25(s, 3H), 1.50(s, 3H), 1.70(s, 6H), 3.36(s, 3H), 3.40(s, 3H), 3.43(s, 3H), 3.51(s, 3H), 3.54(s, 3H), 3.55(s, 3H), 3.56(s, 3H), 3.62(s, 3H), 3.68(s, 6H), 3.69(s, 3H), 3.70(s, 3H), 3.73(s, 3H), 3.77(s, 3H), 4.22-4.25(d, J-12.0, 1H), 4.60-4.8 (s, 4H), 4.8H, 4H, 8H, 4H, 8(s, 8H), 4.8H), 4.5H, 4H, 8(s, 8H), 4H), 4.5H, 8H, 1H, 4H, 8H, 1H, 4H, 5H, 1H, 5H, 4H, 1H, 4H, 5H, 4H, 1H, 4H, 1H, 5H, 4H, 1H, 4H, 1H, 5H, 4H, 1H, 4H, 5H, 1H, 4H, 5H, 4H, 5H, 1H, 4H, 1H, 4H, 1H, 4H, 1H, 4H, 1H, 4H, and 1H, 4H, 1H, 4H, 1H, 4, 5.31-5.34(t, J ═ 6.0Hz, 1H), with overlaps on the mother nucleus and other H on 1.06-2.38, sugar rings and other H on 3.10-3.90; ESI-MS1327.8199[ M + Na ]] + 。
Example 2: ginsenoside Rb 1 Preparation of Ether-modified derivative I-2
The preparation method is the same as that of example 1, except that bromoethane is used for replacing iodomethane in example 1, the reaction is carried out for 8h at room temperature, separation and purification are carried out by silica gel column chromatography (eluent: dichloromethane: methanol: 60:1), the eluent is collected, concentrated and dried to obtain the compound I-2 which is white solid, and the yield is 78%. 1 H NMR(400M Hz，C 5 D 5 N)δ0.75-0.79(d，J＝12.0Hz，1H)，0.89(s，3H)，0.97(s，6H)，0.99(s6H), 1.06(s, 9H), 1.16(s, 18H), 1.17(s, 6H), 1.18(s, 9H), 1.25(s, 3H), 1.70(s, 3H), 1.81(s, 6H), 4.23-4.25(d, J ═ 12.0Hz, 1H), 4.60-4.62(d, J ═ 8.0Hz, 1H), 4.70-4.73(d, J ═ 8.0Hz, 1H), 4.81-4.83(d, J ═ 8.0Hz, 1H), 5.01-5.04(d, J ═ 8.0Hz, 1H), 5.31-5.34(t, J ═ 6.0Hz, 1H), the parent nucleus and other H overlap 1.06-2.38, the sugar ring and the other H overlap 3.00-20.00; ESI-MS1193.7041[ M + H ]] + 。
Example 3 ginsenoside Rb 1 Preparation of amino acid derivative I-3
Adding ginsenoside Rb into a 50mL round-bottom flask 1 (200mg, 0.18mmol) was dissolved in 10mL pyridine, Boc-D-valine (313mg, 1.44mmol) was added at room temperature and stirred to dissolve it, N' -diisopropylcarbodiimide (224. mu.L, 1.44mmol) was added, the progress of the reaction was monitored by TLC, after about 2 hours, the reaction was stopped, the reaction was purified by silica gel column chromatography (eluent: dichloromethane: methanol 7:1), and the eluent was collected, concentrated and dried to give compound I-3 (R) as a white solid f 0.25), yield 28%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.78(d, J ═ 12.0Hz, 1H), 0.87(s, 3H), 0.96(s, 6H), 0.97(s, 6H), 1.01(s, 3H), 1.02(s, 3H), 1.25(s, 3H), 1.39(s, 9H), 1.66(s, 3H), 1.79(s, 3H), 4.23-4.25(d, J ═ 12.0Hz, 1H), 4.61-4.62(d, J ═ 8.0Hz, 1H), 4.70-4.73(d, J ═ 8.0Hz, 1H), 4.81-4.84(d, J ═ 8.0Hz, 1H), 5.02-5.04(d, J ═ 8.0, 1H), 5.31-5.34.76, 6H), 5.31-5, 6H, 1H, 5.31, 6H, 1H, 3H, 6H, 5H, 6H, and other active nuclear activity peaks overlap with the hydrogen; ESI-MS 1330.7138[ M + Na ]] + 。
Example 4 ginsenoside Rb 1 Preparation of amino acid derivative I-4
The reaction was carried out in the same manner as in example 3, with the progress of the reaction monitored by TLC for about 2 hours, then the reaction was stopped, and the reaction mixture was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol: 12:1), and the eluent was collected and concentrated to dryness to obtain compound I-4 (R) as a white solid f 0.50), yield 28%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.80(d, J ═ 12.0Hz, 1H), 0.87(s, 3H), 0.96(s, 6H), 0.97(s, 6H), 0.99(s, 6H), 1.01(s, 3H), 1.03(s, 3H), 1.25(s, 3H), 1.39(s, 9H), 1.41(s, 9H), 1.66(s, 3H), 1.79(s, 3H), 4.22-4.25(d, J ═ 12.0Hz, 1H), 4.60-4.63(d, J ═ 8.0Hz, 1H), 4.71-4.73(d, J ═ 8.0Hz, 1H), 4.82-4.84(d, J ═ 8.0Hz, 1H), 5.02-5.5.05 (d, J ═ 8.0, 5, 5.0H), 5.5.5H, 3H), 3H, 4.7-4.06 (d, 3H), 3H, and the active peaks overlap on the other active nuclei; ESI-MS 1529.8334[ M + Na ]] + 。
Example 5 ginsenoside Rb 1 Preparation of amino acid derivative I-5
The same procedure as in example 3 was repeated, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-glycine for Boc-D-valine of example 3, followed by TLC monitoring for the progress of the reaction, which was stopped after about 2 hours, followed by silica gel column chromatography (eluent: dichloromethane: methanol: 7:1), followed by collecting the eluent, concentrating and drying to give compound I-5 (R) -5 as a white solid f 0.25), yield 29%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.75-0.77(d, J ═ 12.0Hz, 1H), 0.87(s, 3H), 0.96(s, 6H), 0.99(s, 6H), 1.25(s, 3H), 1.40(s, 9H), 1.69(s, 3H), 1.79(s, 3H), 4.23-4.26(d, J ═ 12.0Hz, 1H), 4.60-4.62(d, J ═ 8.0Hz, 1H), 4.70-4.72(d, J ═ 8.0Hz, 1H), 4.82-4.85(d, J ═ 8.0Hz, 1H), 5.01-5.04(d, J ═ 8.0Hz, 1H), 5.31-5.34(t, J ═ 6.0, 1H), and the parent ring overlaps with other sugar rings in the 3.06-3H, and overlaps with other sugar rings in the other rings0 to 4.24, overlapping active hydrogen at 5.76 to 6.40, and blunting the peak; ESI-MS 1288.6669[ M + Na ]] + 。
Example 6 ginsenoside Rb 1 Preparation of amino acid derivative I-6
The same procedure as in example 3 was repeated, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-glycine for Boc-D-valine of example 3, followed by TLC monitoring for the progress of the reaction, which was stopped after about 3 hours, followed by silica gel column chromatography (eluent: dichloromethane: methanol: 12:1), followed by collecting the eluent, concentrating and drying to give compound I-6 (R) -6) as a white solid f 0.50), the yield was 35%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.79(d, J ═ 12.0Hz, 1H), 0.88(s, 3H), 0.96(s, 6H), 0.99(s, 6H), 1.25(s, 3H), 1.40(s, 18H), 1.41(s, 9H), 1.69(s, 3H), 1.79(s, 3H), 4.21-4.24(d, J ═ 12.0Hz, 1H), 4.62-4.64(d, J ═ 8.0Hz, 1H), 4.70-4.73(d, J ═ 8.0Hz, 1H), 4.82-4.86(d, J ═ 8.0Hz, 1H), 5.00-5.03(d, J ═ 8.0Hz, 1H), 5.30-5.34(t, J ═ 8.0Hz, 1H), 5.01-5.76H, 6H, 21H, 3H, 21H, 3H, and the other active peaks overlap in the sugar; ESI-MS 1580.8319[ M + Na ]] + 。
Example 7 ginsenoside Rb 1 Preparation of amino acid derivative I-7
The same procedure as in example 3 was repeated, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-leucine for Boc-D-valine in example 3, followed by TLC monitoring of the reaction progress for about 2 hours, followed by stopping the reaction, followed by purification through silica gel column chromatography (eluent: dichloromethane: methanol: 7:1), followed by collection of the eluent, concentration and drying to give compound I-7 (R) as a white solid f 0.25) yield 27%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.78(d, J ═ 12.0Hz, 1H), 0.87(s, 3H), 0.92(s, 6H), 0.98(s, 6H), 0.99(s, 6H), 1.25(s, 3H), 1.40(s, 9H), 1.69(s, 3H), 1.79(s, 3H), 1.85(m, 2H), 4.21-4.24(d, J ═ 12.0Hz, 1H), 4.60-4.62(d, J ═ 8.0Hz, 1H), 4.70-4.72(d, J ═ 8.0Hz, 1H), 4.82-4.84(d, J ═ 8.0Hz, 1H), 5.02-5.05(d, J ═ 8.0, 1H), 5.30-5.34H (t, 6.01-6H), t ═ 6H, and other active in the active nuclear nuclei; ESI-MS 1344.7293[ M + Na ]] + 。
Example 8 ginsenoside Rb 1 Preparation of amino acid derivative I-8
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-D-valine by Boc-L-leucine in example 3, monitoring the progress of the reaction by TLC, stopping the reaction after about 3 hours, separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol, 12:1), collecting the eluent, concentrating and drying to give compound I-8 (R) as a white solid f 0.50), the yield was 26%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.78(d, J ═ 12.0Hz, 1H), 0.86(s, 6H), 0.88(s, 6H), 0.92(s, 3H), 0.97(s, 6H), 1.00(s, 6H), 1.27(s, 3H), 1.45(s, 18H), 1.68(s, 3H), 1.75(s, 3H), 3.31-3.34(d, J ═ 12.0Hz, 1H), on the mother nucleus and other H overlap 0.80-2.70, on the sugar ring and other positions H overlap 3.82-5.51, active hydrogen overlap 5.80-6.60, blunt peaks; ESI-MS 1557.8658[ M + Na ]] + 。
Example 9 ginsenoside Rb 1 Preparation of amino acid derivative I-9
Same procedure as in example 3, same procedure as in example 3The compound of formula I-3 was prepared except that Boc-L-leucine was used instead of Boc-D-valine in example 3, the progress of the reaction was monitored by TLC, after about 3 hours, the reaction was stopped, and the mixture was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol, 12:1), and the eluent was collected, concentrated and dried to give compound I-9 (R) -9 (a white solid) f 0.45), yield was 26%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.77-0.79(d, J ═ 12.0Hz, 1H), 0.88(s, 6H), 0.89(s, 6H), 0.94(s, 3H), 0.98(s, 6H), 1.01(s, 6H), 1.26(s, 3H), 1.46(s, 18H), 1.69(s, 3H), 1.78(s, 3H), 3.31-3.34(d, J ═ 12.0Hz, 1H), on the mother nucleus and other H overlap 0.80-2.70, on the sugar ring and other positions H overlap 3.82-5.51, active hydrogen overlap 5.80-6.60, blunt peaks; ESI-MS 1557.8662[ M + Na ]] + 。
Example 10: ginsenoside Rb 1 Preparation of amino acid derivative I-10
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-valine for Boc-D-valine of example 3, followed by monitoring the progress of the reaction by TLC, stopping the reaction after about 2 hours, separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol: 7:1), collecting the eluent, concentrating and drying to give compound I-10 (R) as a white solid f 0.25), yield was 27%. 1 H NMR(400M Hz，C 5 D 5 N)δ0.76-0.79(d，J＝12.0Hz，1H)，0.87(s，3H)，0.96(s，6H)，0.97(s，6H)，1.01(s，3H)，1.05(s，3H)，1.25(s，3H)，1.39(s，9H)，1.66(s，3H)，1.79(s，3H)，4.22-4.25(d，J＝12.0Hz，1H)，4.60-4.62(d，J＝8.0Hz，1H)，4.70-4.72(d，J＝8.0Hz，1H)，4.82-4.84(d，J＝8.0Hz，1H)，5.02-5.04(d，J＝8.0Hz，1H)，5.31-5.34(t，J＝6.0Hz，1H) The parent nucleus and other H are overlapped on 1.06-2.38, the sugar ring and other H are overlapped on 3.01-4.30, the active hydrogen is overlapped on 5.80-6.60, and the peak is blunt; ESI-MS 1330.7133[ M + Na ]] + 。
Example 11 ginsenoside Rb 1 Preparation of amino acid derivatives
The same procedure as in example 3 was repeated, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-valine for Boc-D-valine of example 3, followed by monitoring the progress of the reaction by TLC, stopping the reaction after about 2 hours, separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol: 7:1), collecting the eluent, concentrating and drying to give a white solid compound I-11 (R-11) f 0.30), the yield was 27%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.75-0.78(d, J ═ 12.0Hz, 1H), 0.87(s, 3H), 0.96(s, 6H), 0.97(s, 6H), 1.01(s, 3H), 1.02(s, 3H), 1.25(s, 3H), 1.39(s, 9H), 1.68(s, 3H), 1.79(s, 3H), 4.23-4.26(d, J ═ 12.0Hz, 1H), 4.60-4.62(d, J ═ 8.0Hz, 1H), 4.70-4.72(d, J ═ 8.0Hz, 1H), 4.82-4.84(d, J ═ 8.0Hz, 1H), 5.00-5.03(d, J ═ 8.0, 1H), 5.30-5.30.34H, t ═ 30, 1H, t ═ 6.0, 1H, t ═ 2, 3H, t ═ 20, t, H, t ═ 6.0, t, H, t, H, t, H, t, H, t, H, t, H, t, H, t, H, t, H; ESI-MS 1330.7137[ M + Na ]] + 。
Example 12: ginsenoside Rb 1 Preparation of amino acid derivative I-12
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-D-valine for Boc-L-valine in example 3, monitoring the progress of the reaction by TLC, stopping the reaction after about 3 hours, purifying by silica gel column chromatography (eluent: dichloromethane: methanol: 12:1), collecting the eluent, and concentratingCondensing and drying to obtain a white solid compound I-12 (R) f 0.50), yield 27%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.78(d, J ═ 12.0Hz, 1H), 0.96(s, 3H), 0.97(s, 6H), 0.99(s, 6H), 1.00(s, 6H), 1.03(s, 6H), 1.26(s, 3H), 1.44(s, 18H), 1.71(s, 3H), 1.76(s, 3H), 3.27-3.30(d, J ═ 8.0Hz, 1H), 4.29-4.31(d, J ═ 8.0Hz, 1H), 4.47-4.49(d, J ═ 8.0Hz, 1H), 5.36-5.37(d, J ═ 4.0Hz, 1H), on the mother nucleus and other H overlap 0.70-2.70, on the sugar ring and other positions overlap 3.80H, 5.76-5.40H, inactive hydrogen peaks; ESI-MS 1529.8344[ M + Na ]] + 。
Example 13 ginsenoside Rb 1 Preparation of amino acid derivative I-13
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-valine for Boc-D-valine of example 3, followed by monitoring the progress of the reaction by TLC, stopping the reaction after about 3 hours, separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol: 12:1), collecting the eluent, concentrating and drying to give compound I-13 (R) as a white solid f 0.45), yield was 25%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.79(d, J ═ 12.0Hz, 1H), 0.96(s, 6H), 0.98(s, 6H), 0.99(s, 3H), 1.00(s, 6H), 1.02(s, 6H), 1.26(s, 3H), 1.45(s, 18H), 1.68(s, 3H), 1.75(s, 3H), 3.28-3.31(d, J ═ 8.0Hz, 1H), 4.28-4.31(d, J ═ 8.0Hz, 1H), 4.47-4.49(d, J ═ 8.0Hz, 1H), 5.36-5.37(d, J ═ 4.0Hz, 1H), on the mother nucleus and other H overlap 0.70-2.70, on the sugar ring and other positions overlap 3.80H, 5.76-5.40H, inactive hydrogen peaks; ESI-MS 1529.8341[ M + Na ]] + 。
Example 14 ginsenoside Rb 1 Preparation of amino acid derivative I-14
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-tryptophan for Boc-D-valine of example 3, followed by monitoring the progress of the reaction by TLC, stopping the reaction after about 3 hours, separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol: 8:1), collecting the eluent, concentrating and drying to give compound I-14 (R) as a white solid f 0.30), yield 25%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.77-0.79(d, J ═ 12.0Hz, 1H), 0.97(s, 3H), 0.98(s, 3H), 1.00(s, 3H), 1.01(s, 3H), 1.03(s, 3H), 1.25(s, 3H), 1.43(s, 9H), 1.69(s, 3H), 1.79(s, 3H), 3.28-3.31(d, J ═ 8.0Hz, 1H), 4.28-4.31(d, J ═ 8.0Hz, 1H), 4.47-4.49(d, J ═ 8.0Hz, 1H), 4.69(m, 1H), 5.36-5.37(d, J ═ 4.0Hz, 1H), 6.99-7.60(m, 5H), 10.69(s, 1H), 5.70H, 5H, and other active nuclear peaks overlapping with the hydrogen in the nuclei; ESI-MS 1395.7421[ M + H ]] + 。
Example 15: ginsenoside Rb 1 Preparation of amino acid derivative I-15
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-tryptophan for Boc-D-valine of example 3, followed by monitoring the progress of the reaction by TLC, stopping the reaction after about 3 hours, separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol: 8:1), collecting the eluent, concentrating and drying to give compound I-15 (R) as a white solid f 0.25), yield 25%. 1 H NMR(400M Hz，C 5 D 5 N)δ0.76-0.78(d，J＝12.0Hz，1H)，0.96(s，3H)，0.98(s，3H)，0.99(s, 3H), 1.01(s, 3H), 1.02(s, 3H), 1.26(s, 3H), 1.43(s, 9H), 1.69(s, 3H), 1.78(s, 3H), 3.29-3.31(d, J ═ 8.0Hz, 1H), 4.29-4.31(d, J ═ 8.0Hz, 1H), 4.46-4.49(d, J ═ 8.0Hz, 1H), 4.69(m, 1H), 5.35-5.37(d, J ═ 4.0Hz, 1H), 6.99-7.60(m, 5H), 10.69(s, 1H), parent nucleus and other H overlaps 0.70-2.70, sugar rings and other positions H overlap 3.80-5.20, hydrogen overlaps 5.76, 6.76-50.76, 50 peaks, inactive; ESI-MS 1395.7420[ M + H ]] + 。
Example 16 ginsenoside Rb 1 Preparation of amino acid derivative I-16
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-cysteine for Boc-D-valine in example 3, followed by monitoring the progress of the reaction by TLC, stopping the reaction after about 2 hours, separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol: 7:1), collecting the eluent, concentrating and drying to give a white solid compound I-16 (R-16) f 0.30) in 28% yield. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.78-0.80(d, J ═ 12.0Hz, 1H), 0.87(s, 3H), 0.96(s, 6H), 0.97(s, 6H), 1.25(s, 3H), 1.40(s, 9H), 1.69(s, 3H), 1.79(s, 3H), 4.21-4.24(d, J ═ 12.0Hz, 1H), 4.60-4.62(d, J ═ 8.0Hz, 1H), 4.70-4.73(d, J ═ 8.0Hz, 1H), 4.82-4.84(d, J ═ 8.0Hz, 1H), 5.02-5.04(d, J ═ 8.0Hz, 1H), 5.30-5.34(t, J ═ 6.0, 1H), the parent nucleus and other nuclei overlap with active hydrogen peaks in the active peaks in the 5.3.06-5.06-6.0 Hz, 1H, and overlap with active hydrogen in the other nuclei in the 1.76, 3.40H; ESI-MS 1312.6719[ M + H ]] + 。
Example 17 ginsenoside Rb 1 Preparation of amino acid derivative I-17
Same procedure as in example 3, withExample 3 a compound of formula I-3 was prepared except that Boc-L-cysteine was used instead of Boc-D-valine in example 3, the progress of the reaction was monitored by TLC, and after about 2 hours, the reaction was stopped, separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol ═ 7:1), and the eluent was collected, concentrated and dried to give compound I-17 (R) as a white solid f 0.25), yield 28%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.78(d, J ═ 12.0Hz, 1H), 0.88(s, 3H), 0.97(s, 6H), 0.98(s, 6H), 1.26(s, 3H), 1.40(s, 9H), 1.69(s, 3H), 1.80(s, 3H), 4.20-4.24(d, J ═ 12.0Hz, 1H), 4.59-4.61(d, J ═ 8.0Hz, 1H), 4.71-4.73(d, J ═ 8.0Hz, 1H), 4.82-4.85(d, J ═ 8.0Hz, 1H), 5.02-5.04(d, J ═ 8.0Hz, 1H), 5.31-5.35(t, J ═ 6.0, 1H), the parent nucleus and other nuclei overlap with active hydrogen peaks in the active peaks in the 5.76-3.3.1H, 6.06-6.0 Hz, 1H, 5.06-40H, and overlap with other nuclei in the active peaks in the active hydrogen; ESI-MS 1312.6718[ M + H ]] + 。
Example 18 ginsenoside Rb 1 Preparation of amino acid derivative I-18
The same procedure as in example 3 was conducted, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-cysteine for Boc-D-valine in example 3, followed by TLC monitoring of the reaction progress for about 3 hours, followed by stopping the reaction, separation and purification by silica gel column chromatography (eluent: dichloromethane: methanol: 10:1), followed by collection of the eluent, concentration and drying to give compound I-18 (R) -18 (as a white solid) f 0.50), the yield was 28%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.75-0.79(d, J ═ 12.0Hz, 1H), 0.86(s, 3H), 0.95(s, 6H), 0.96(s, 6H), 1.25(s, 3H), 1.40(s, 18H), 1.68(s, 3H), 1.78(s, 3H), 4.22-4.26(d, J ═ 12.0Hz, 1H), 4.61-4.64(d, J ═ 8.0Hz, 1H), 4.69-4.72(d, J ═ 8.0Hz, 1H), 4.82-4.85(d, J ═ 8.0Hz, 1H), 5.00-5.03(d, J ═ 8.0Hz, 1H), 5.30-5.34(t, J ═ 6.0, 1H), and the parent ring overlaps with other sugar rings in the 3.06-3H, and overlaps with other sugar rings in the other rings20, overlapping active hydrogen at 5.76-6.50, blunt peak; ESI-MS 1515.7334[ M + H ]] + 。
Example 19 ginsenoside Rb 1 Preparation of amino acid derivative I-19
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-D-valine by Boc-L-threonine and monitoring the progress of the reaction by TLC, after about 2 hours, the reaction was stopped, and the reaction mixture was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol: 7:1), and the eluent was collected and concentrated to dryness to give compound I-19 (R) as a white solid f 0.30), the yield was 29%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.75-0.78(d, J ═ 12.0Hz, 1H), 0.87(s, 3H), 0.97(s, 6H), 0.98(s, 6H), 1.25(s, 3H), 1.40(s, 9H), 1.69(s, 3H), 1.80(s, 3H), 4.21-4.26(d, J ═ 12.0Hz, 1H), 4.61-4.64(d, J ═ 8.0Hz, 1H), 4.70-4.73(d, J ═ 8.0Hz, 1H), 4.82-4.84(d, J ═ 8.0Hz, 1H), 5.02-5.04(d, J ═ 8.0Hz, 1H), 5.30-5.34(t, J ═ 6.0, 1H), and the parent ring overlaps with other active hydrogen peaks in the active sugars, overlapping peaks at 3.06-3.06, 6.0Hz, 1H, 5.01-5.76H; ESI-MS 1310.7103[ M + H ]] + 。
Example 20 ginsenoside Rb 1 Preparation of amino acid derivative I-20
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-D-valine by Boc-L-threonine and monitoring the progress of the reaction by TLC, after about 2 hours, the reaction was stopped and the reaction was carried out on silica gelSeparating and purifying by column chromatography (eluent: dichloromethane: methanol: 7:1), collecting eluent, concentrating, and drying to obtain white solid compound I-20 (R) f 0.25), the yield was 29%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.79(d, J ═ 12.0Hz, 1H), 0.87(s, 3H), 0.95(s, 6H), 0.97(s, 6H), 1.26(s, 3H), 1.40(s, 9H), 1.68(s, 3H), 1.78(s, 3H), 4.22-4.25(d, J ═ 12.0Hz, 1H), 4.60-4.62(d, J ═ 8.0Hz, 1H), 4.69-4.72(d, J ═ 8.0Hz, 1H), 4.82-4.84(d, J ═ 8.0Hz, 1H), 5.02-5.05(d, J ═ 8.0Hz, 1H), 5.30-5.34(t, J ═ 6.0, 1H), and the parent ring overlaps with other active hydrogen peaks in the active sugars, overlapping with 3.06-3.06, 6.0Hz, 1H, 5.01-40H, and with other inactive hydrogen; ESI-MS 1310.7103[ M + H ]] + 。
Example 21: ginsenoside Rb 1 Preparation of amino acid derivative I-21
The same procedure as in example 3 was repeated, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-histidine for Boc-D-valine in example 3, followed by TLC monitoring for about 3 hours, stopping the reaction, separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol: 8:1), collecting the eluent, concentrating and drying to give a white solid compound I-21 (R) as a white solid f 0.30), the yield was 28%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.78(d, J ═ 12.0Hz, 1H), 0.88(s, 3H), 0.96(s, 6H), 0.97(s, 6H), 1.26(s, 3H), 1.40(s, 9H), 1.69(s, 3H), 1.81(s, 3H), 4.21-4.25(d, J ═ 12.0Hz, 1H), 4.60-4.62(d, J ═ 8.0Hz, 1H), 4.70-4.72(d, J ═ 8.0Hz, 1H), 4.84-4.86(d, J ═ 8.0Hz, 1H), 5.00-5.03(d, J ═ 8.0Hz, 1H), 5.31-5.34(t, J ═ 6.0, 1H), 7.32 (H), 1.01-5.06H), 1H, 6.0H, 1H, 5.06-6H, 1H, 6H, 1H, 6H, 3H, and other active peaks; ESI-MS 1346.7216[ M + H ]] + 。
Example 22: ginsenoside Rb 1 Preparation of amino acid derivative I-22
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-histidine for Boc-D-valine of example 3, followed by TLC monitoring for about 3 hours, stopping the reaction, separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol: 8:1), collecting the eluent, concentrating and drying to give compound I-22 (R) as a white solid f 0.25), yield 28%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.77-0.79(d, J ═ 12.0Hz, 1H), 0.85(s, 3H), 0.95(s, 6H), 0.97(s, 6H), 1.27(s, 3H), 1.40(s, 9H), 1.70(s, 3H), 1.80(s, 3H), 4.23-4.26(d, J ═ 12.0Hz, 1H), 4.60-4.62(d, J ═ 8.0Hz, 1H), 4.70-4.73(d, J ═ 8.0Hz, 1H), 4.82-4.84(d, J ═ 8.0Hz, 1H), 5.03-5.05(d, J ═ 8.0Hz, 1H), 5.31-5.34(t, J ═ 6.0, 7.0 Hz, 7.32H), 7.7.45-8.7H, 7.8H, 8H, 33, 33.06-8H, 33, 33.06, 33, 8H, 33, 40H, 3H, and other active peaks in the sugar; ESI-MS 1346.7216[ M + H ]] + 。
Example 23 ginsenoside Rb 1 Preparation of amino acid derivative I-23
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-proline for Boc-D-valine of example 3, followed by TLC monitoring the progress of the reaction for about 3 hours, stopping the reaction, separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol: 7:1), collecting the eluent, concentrating and drying to give compound I-23 (R) as a white solid f 0.30), the yield was 28%. 1 H NMR(400M Hz，C 5 D 5 N)δ0.77-0.80(d，J＝12.0Hz，1H)，0.86(s，3H)，0.95(s，6H)，0.97(s，6H) 1.25(s, 3H), 1.40(s, 9H), 1.70(s, 3H), 1.78(s, 3H), 1.77-2.02(m, 4H), 4.21-4.25(d, J ═ 12.0Hz, 1H), 4.59-4.62(d, J ═ 8.0Hz, 1H), 4.70-4.72(d, J ═ 8.0Hz, 1H), 4.82-4.84(d, J ═ 8.0Hz, 1H), 5.00-5.04(d, J ═ 8.0Hz, 1H), 5.31-5.35(t, J ═ 6.0Hz, 1H), the parent nucleus and other H overlap 1.06-2.56, the sugar rings and other H overlap 3.01-4.20, the hydrogens overlap 5.76, 40 peaks inactive; ESI-MS 1306.7155[ M + H ]] + 。
Example 24: ginsenoside Rb 1 Preparation of amino acid derivative I-24
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-proline for Boc-D-valine of example 3, followed by TLC monitoring the progress of the reaction for about 3 hours, stopping the reaction, separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol: 7:1), collecting the eluent, concentrating and drying to give compound I-24 (R) as a white solid f 0.25), yield 28%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.75-0.78(d, J ═ 12.0Hz, 1H), 0.88(s, 3H), 0.96(s, 6H), 0.97(s, 6H), 1.27(s, 3H), 1.41(s, 9H), 1.67(s, 3H), 1.78(s, 3H), 1.77-2.09(m, 4H), 4.21-4.25(d, J ═ 12.0Hz, 1H), 4.60-4.63(d, J ═ 8.0Hz, 1H), 4.69-4.72(d, J ═ 8.0Hz, 1H), 4.82-4.85(d, J ═ 8.0Hz, 1H), 5.01-5.04(d, J ═ 8.0, 1H), 5.30-5.34(t, t ═ 6.34, 6.5.01-5.5H), 3.06-5H, 6H, 5H, 40H, 3H, and the other active peaks overlap on the nuclei; ESI-MS 1306.7154[ M + H ]] + 。
Example 25 ginsenoside Rb 1 Preparation of amino acid derivative I-25
Same procedure as in example 3The procedure was carried out in the same manner as in example 3 except that the compound of formula I-3 was prepared by substituting Boc-L-lysine for Boc-D-valine in example 3, TLC was used to monitor the progress of the reaction, the reaction was stopped after about 3 hours, the reaction mixture was separated and purified by silica gel column chromatography (eluent: dichloromethane: methanol: 7:1), and the eluate was collected, concentrated and dried to give compound I-25 (R) as a white solid f 0.30), the yield was 27%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.77-0.79(d, J ═ 12.0Hz, 1H), 0.86(s, 3H), 0.95(s, 6H), 0.97(s, 6H), 1.26(s, 3H), 1.29(m, 2H), 1.41(s, 9H), 1.55(m, 2H), 1.69(s, 3H), 1.79(s, 3H), 1.88(m, 2H), 2.65(m, 2H), 4.22-4.25(d, J ═ 12.0Hz, 1H), 4.60-4.62(d, J ═ 8.0Hz, 1H), 4.71-4.73(d, J ═ 8.0Hz, 1H), 4.83-4.85(d, J ═ 8.0Hz, 1H), 5.01-5.04(d, J ═ 8.0Hz, 5.01-5.5H), t, 3H, 31H, 3H, and the active in the other active peaks overlap on the nuclei; ESI-MS 1337.7577[ M + H ]] + 。
Example 26 ginsenoside Rb 1 Preparation of amino acid derivative I-26
The same procedure as in example 3 was conducted, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-lysine for Boc-D-valine in example 3, followed by TLC monitoring of the reaction progress for about 3 hours, followed by stopping the reaction, separation and purification by silica gel column chromatography (eluent: dichloromethane: methanol: 7:1), followed by collection of the eluent, concentration and drying to give compound I-26 (R) as a white solid (R: C, H: E: 7:1) f 0.25), yield was 27%. 1 H NMR(400M Hz，C 5 D 5 N)δ0.76-0.78(d，J＝12.0Hz，1H)，0.87(s，3H)，0.96(s，6H)，0.97(s，6H)，1.26(s，3H)，1.28(m，2H)，1.40(s，9H)，1.55(m，2H)，1.70(s，3H)，1.80(s，3H)，1.88(m，2H)，2.65(m，2H)，4.22-4.26(d，J＝12.0Hz，1H)，4.60-4.62(d，J＝8.0Hz，1H)，4.70-4.72(d，J＝8.0Hz，1H)，4.82-4.84(d，J＝8.0Hz，1H)，5.03-5.06(d，J ═ 8.0Hz, 1H), 5.31 to 5.35(t, J ═ 6.0Hz, 1H), overlaps on the mother nucleus and other H in the range of 1.06 to 2.55, overlaps on the sugar ring and other H in the range of 3.01 to 4.20, overlaps on the active hydrogen in the range of 5.76 to 6.40, blunt peak; ESI-MS 1337.7576[ M + H ]] + 。
Example 27 ginsenoside Rb 1 Preparation of amino acid derivative I-27
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-L-asparagine for Boc-D-valine in example 3, followed by TLC monitoring for about 3 hours, stopping the reaction, separating and purifying by silica gel column chromatography (eluent: dichloromethane: methanol: 7:1), collecting the eluent, concentrating and drying to give compound I-27 (R) as a white solid f 0.25), yield 28%. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.79(d, J ═ 12.0Hz, 1H), 0.87(s, 3H), 0.96(s, 6H), 0.97(s, 6H), 1.25(s, 3H), 1.41(s, 9H), 1.68(s, 3H), 1.79(s, 3H), 2.65-2.86(m, 2H), 4.22-4.25(d, J ═ 12.0Hz, 1H), 4.60-4.62(d, J ═ 8.0Hz, 1H), 4.70-4.72(d, J ═ 8.0Hz, 1H), 4.82-4.84(d, J ═ 8.0Hz, 1H), 5.02-5.04(d, J ═ 8.0, 1H), 5.31-5.34(t, t ═ 6.0, 1H), 5.01-5.06H, 6.6H, 6H, 3H, and the active peaks overlap on the other active nuclei; ESI-MS 1323.7056[ M + H ]] + 。
Example 28 ginsenoside Rb 1 Preparation of amino acid derivative I-28
The same procedure as in example 3 was followed, except that the compound of formula I-3 of example 3 was prepared by substituting Boc-D-cyclohexylalanine for Boc-D-valine in example 3, and the progress of the reaction was monitored by TLC, after about 3.5 hours, the reaction was stopped, and the residue was purified by silica gel column chromatography (eluent:separating and purifying dichloromethane and methanol 9:1, collecting eluent, concentrating and drying to obtain white solid compound I-28 (R) f 0.30) in 28% yield. 1 H NMR(400M Hz，C 5 D 5 N) δ 0.76-0.78(d, J-12.0 Hz, 1H), 0.88(s, 3H), 0.95(s, 6H), 0.97-1.10(m, 5H), 1.25(s, 3H), 1.41(s, 9H), 1.44-1.56(m, 5H), 1.59-1.68(m, 1H), 1.68(s, 3H), 1.79(s, 3H), 1.87(m, 2H), 2.65-2.86(m, 2H), 4.22-4.25(d, J-12.0 Hz, 1H), 4.60-4.62(d, J-8.0 Hz, 1H), 4.70-4.06 (d, J-8.0 Hz, 1H), 4.82-4.84(d, J-8.0H), 1H, 8.84H, 1H), 1H, 5H, 1H, 5H, 1H, 5H, 1H, 5H, 1H, 5H, 1H, 5H, 1H, 5H, 1H, 1H, 1H, H, overlapping sugar ring and other H on 3.01-4.20, overlapping active hydrogen on 5.76-6.50, and blunt peak; ESI-MS1362.7780[ M + H ]] + 。
Effect example 1: ZIKV resistance activity test
Ribavirin (Ribavirin) is selected as a positive control drug, Vero cells are selected as experimental cells, and ZIKV SZ-WIV01(GenBank: KU963796) strain is selected as an experimental strain. Based on the results of the cytotoxicity test and the plaque inhibition test, Read was used&The Muench method calculates the Concentration of Compound (CC) that inhibits 50% of viral replication in the sample 50 ) Effective concentration of sample to inhibit 50% of cell growth (CC) 50 ) And is represented by the formula TI ═ CC 50 /EC 50 And calculating to obtain a selectivity index TI value. The specific method is described as follows:
vero cytotoxicity experiments: toxicity of the compounds to cells was determined by the MTT method. Vero cells were seeded in 96-well plates (4X 10) 4 One/well), 5% CO at 37 ℃ 2 The culture was carried out overnight in an incubator. After the cells grew into monolayers, the culture supernatant was discarded, and medium containing a gradient of diluted compound was added, 3 replicate wells were set for each concentration, and a control containing no compound was set. After 4 days of culture, 20 μ L of 5mg/mL MTT is added to each well, incubation is carried out at 37 ℃ for 4h, 100 μ L of supernatant is discarded, 100 μ L of 12% SDS-50% DMF solution is added, incubation is carried out overnight at 37 ℃, formazan to be crystallized is completely dissolved, a Bio-TEK microplate reader is used for detecting the OD value, the determination wavelength is 570nm, and the reference wavelength is 630 nm; calculating the half cell toxicity concentration CC 50 I.e. the concentration of drug that is toxic to 50% Vero cells.
Plaque inhibition assay: according to the experimental results of the cytotoxicity of the compound, the concentration of the compound is diluted to a concentration which is not toxic to cells. Screening was performed by classical plaque methods: vero cells were seeded in 12-well plates (3X 10) 5 One/well), 5% CO at constant temperature of 37 ℃ 2 The culture was carried out overnight in an incubator. After the cells grew into a monolayer, the culture supernatant was discarded, washed with PBS 1 time, adsorbed by ZIKV virus (MOI. about.0.5) for 2 hours, and then 2% low melting point agarose DMEM (4% FBS) medium containing a gradient diluent compound was added thereto, and the mixture was incubated at 37 ℃ with 5% CO 2 After 4 days of culture, fixation with 4% paraformaldehyde for 15min, washing, staining with 0.8% crystal violet for 10min, image acquisition with an enzyme-linked fluorescent spot analyzer (CTL, Immunospot S6 Universal) and plaque counting. Drawing a dose response curve according to the plaque number, and calculating the half effective concentration EC 50 I.e., the drug concentration at which the inhibition of plaque formation after infection of Vero cells with ZIKV was 50%.
Virus yield reduction experiment: vero cells were seeded in 24-well plates at 1.5X 10 per well 5 Cell line, 5% CO at 37 ℃ 2 The culture was carried out overnight in an incubator. After the cells grow into a monolayer, removing the culture supernatant, adding ZIKV virus (MOI is approximately equal to 1) to adsorb for 2h, removing virus liquid, washing with PBS for 3 times, adding a compound containing gradient dilution, washing with 37 deg.C 5% CO 2 After culturing for 72h in an incubator, collecting virus supernatant, and extracting RNA in the virus supernatant by adopting a Kit Roche High Pure Viral RNA Kit; performing real-time fluorescent quantitative PCR by using a quantitative PCR kit RNA-directTM Realtime PCR Master Mix and a TaqMan probe under a QuantStudio5 quantitative PCR system; calculating the EC of the drug according to the inhibition rate of the compounds with different concentrations on ZIKV RNA replication 50 。
The concentration of the compound is diluted to a concentration which does not have toxicity on cells, screening is carried out by a classical plaque method, and the result shows that the compound prepared in the embodiment has an obvious inhibition effect on ZIKV, the formation of ZIKV plaque can be inhibited by 100% under the condition of 20 mu M primary screening concentration, and further anti-ZIKV activity research by an RT-PCR (reverse transcription-polymerase chain reaction) and plaque method shows that the target compound shown in the table 2 has stronger anti-ZIKV activity, the inhibition activity of the target compound is improved by 20-65 times compared with that of a positive control Ribavirin (Ribavirin), the target compound has lower cytotoxicity, and the target compound can be further researched and developed as an anti-ZIKV drug candidate.
TABLE 2
Effect example 2: anti-DENV Activity test
Ribavirin (Ribavirin) is selected as a positive control drug, Vero cells are taken as experimental cells, and DENV-II D01090(GenBank: KY882458) strain is taken as an experimental strain. Based on the results of cytotoxicity experiments and cytopathogenic inhibition experiments, Read was used&The Muench method calculates the Effective Concentration (EC) of the sample for inhibiting 50% of virus replication 50 ) Effective concentration of sample to inhibit 50% of cell growth (CC) 50 ) And is represented by the formula TI ═ CC 50 /EC 50 And calculating to obtain a selectivity index TI value. The specific method is described as follows:
plaque inhibition assay: the compounds were diluted to 20. mu.M and verified by classical plaque assay using Vero cells plated on 12 well plates at 3X 10 5 Culturing for 24 hr, adding DENV-2 type virus (MOI 0.5) for 2-4 hr, adding DMEM medium containing 1% low melting point agarose and 2% FBS with different drug concentrations, and culturing at 37 deg.C with 5% CO 2 Culturing for 5 days, observing the number of plaques, fixing with 4% paraformaldehyde for 15min, blowing off agar block, staining with 0.8% crystal violet for 10min, collecting pictures with enzyme-linked fluorescent dot analyzer (CTL, Immunospot S6 Universal), counting plaques, and calculating half effective drug concentration EC 50 。
Vero cytotoxicity experiments: toxicity of the compound on cells was determined by MTT method using Vero cells at 3X 10 5 Inoculating to 96-well culture plate at 37 deg.C with 5% CO 2 And culturing for 24 h. After the cells grow into a monolayer, abandoning the culture mediumAnd (3) clearing, adding DMEM medium containing the compound to be detected in gradient dilution, setting 3 multiple wells for each concentration, and setting a normal cell control group. After 5 days of incubation, 20. mu.L of 5mg/mL MTT was added to each well, incubated at 37 ℃ for 4 hours, 100. mu.L of the supernatant was discarded, 100. mu.L of 12% SDS-50% DMF solution was added, and incubated at 37 ℃ overnight; and (3) after the crystal is completely dissolved, shaking and uniformly mixing, and detecting the OD value (the detection wavelength is 570nm and the reference wavelength is 630nm) by using a Bio-TEK enzyme-linked immunosorbent assay (ELISA) instrument. And (4) drawing a dose response curve according to the experimental result, and calculating the concentration of the cytotoxicity to the half number of cells.
The results show that the compound prepared in the above example can achieve 100% inhibition on DENV-II at 50 mu M, and effective compounds are rescreened by a plaque method to obtain EC thereof 50 The compounds shown in Table 3 have significantly better DENV-II inhibitory activity than the positive control Ribavirin (Ribavirin), and have lower cytotoxicity. Therapeutic Index (TI) is the median toxic concentration CC of a compound on cells 50 And half the effective compound concentration EC for viruses 50 The ratio of (b) represents the safety of the compound, and the larger the value, the safer the compound. The compounds in Table 3 have obvious inhibition effect on DENV replication, and the therapeutic index of the compounds is 2-10 times higher than that of positive control ribavirin, so that the compounds can be developed and applied as anti-DENV drug candidates;
TABLE 3
As shown in tables 2 and 3, compounds I-1, I-3, I-7, I-8, I-10, I-12, I-28, etc. exhibit strong inhibitory activity against both ZIKV and DENV, and their EC' s 50 The value is obviously superior to that of a positive control ribavirin, and the ribavirin can be used as a drug candidate for resisting ZIKV or DENV infection to be developed and applied.
The applicants state that the present invention is illustrated by the above examples of ginsenoside Rb of the present invention 1 Derivatives and their preparationMethods and uses, but the invention is not limited to the above examples, which do not mean that the invention must be practiced in reliance on the above examples. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (6)
1. Ginsenoside Rb with the structural formula shown in formula I 1 Derivative or pharmaceutically acceptable salt thereof:
in the formula: r is selected from H, C 1 -C 6 Straight or branched alkyl of (2), C 3 -C 6 A cycloalkyl group;
R 1 、R 2 or R 3 Each independently selected from R or
n is any integer between 0 and 3;
R 1 selected from H, C 1 -C 6 Straight or branched alkyl of (2), C 3 -C 6 Cycloalkyl, -C 1 -C 6 Straight or branched alkyl-NH of 2 、-C 1 -C 6 Linear or branched alkyl-OH, NH of 2 C(＝O)-、C 1 -C 6 Linear or branched alkoxy of (C) 1 -C 6 Straight-chain or branched alkylthio of (C) 6 -C 10 Aryl of (C) 2 -C 10 The heteroaryl group of (a);
R 2 selected from H, tert-butyloxycarbonyl, or R 2 And R 1 Is connected to form C 2 -C 6 A heterocycloalkyl group.
2. Ginsenoside Rb according to claim 1 1 The derivatives are characterized by the following specific structures:
3. a process for the preparation of a ginsenoside Rb1 derivative of claim 1, wherein: in the presence of a solvent and an alkaline catalyst, uniformly mixing ginsenoside Rb1 with halohydrocarbon or amino acid, stirring at 0-80 ℃ for reaction for 0.5-12 h, and separating and purifying a reaction product to obtain the ginsenoside Rb1 derivative, wherein the reaction formula is as follows:
4. the production method according to claim 3, characterized in that: ginsenoside Rb 1 The molar ratio of the halogenated hydrocarbon to the amino acid is 1: 1-36.
5. The production method according to claim 3, characterized in that: the alkaline catalyst is one or more of potassium carbonate, sodium hydrogen, N' -diisopropylcarbodiimide and 4-dimethylaminopyridine; the solvent is one or more of tetrahydrofuran, toluene, acetonitrile, dichloromethane, N-dimethylformamide and pyridine.
6. A ginsenoside Rb as in claim 1 1 Derivative or pharmaceutically acceptable salt thereof in preparation of medicine for treating and/or preventing Zika virus and/or dengue virusThe use of (1).
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