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CN-122011064-A - Benzyl isoquinoline alkaloid glycoside compound and preparation method and application thereof

CN122011064ACN 122011064 ACN122011064 ACN 122011064ACN-122011064-A

Abstract

The invention discloses a benzyl isoquinoline alkaloid glycoside compound, and a preparation method and application thereof. The preparation method comprises the steps of soaking tubers of rhizoma corydalis in 6% acetic acid solution, crushing, soaking in water, carrying out ultrasonic extraction to obtain plant extracts, carrying out water dispersion, carrying out chromatographic separation by using HPD100 type macroporous resin column, carrying out gradient elution by using ethanol water solutions with different concentrations, collecting 50% ethanol elution parts to obtain eluted parts YH-D, carrying out chromatographic separation by using MCI column, carrying out gradient elution by using 0% -100% methanol-water solution to obtain 4 parts of eluents, dissolving YH-D-2 in water, filtering, carrying out chromatographic separation on filtrate by using a medium-pressure ODS column, carrying out chromatographic separation by using Sephadex LH-20 column, carrying out chromatographic separation by using a medium-pressure ODS column, and carrying out HPLC purification by using a semi-preparative C 18 column to obtain 6 novel compounds 1-6. In vitro experiments prove that the benzyl isoquinoline alkaloid glycoside compounds 1-6 have NO generation inhibition activity at the eluted part YH-D-2 containing the benzyl isoquinoline alkaloid glycoside, and have good development prospect as anti-inflammatory drugs.

Inventors

  • LIN SHENG
  • WANG LINGYAN
  • Xia guiyang
  • XIA HUAN
  • WEI XIAOHONG

Assignees

  • 北京中医药大学东直门医院

Dates

Publication Date
20260512
Application Date
20251223

Claims (10)

  1. 1. A benzylisoquinoline alkaloid glycoside compound, which is characterized by being a compound 1-6, and specifically selected from compounds shown in the following formula: 。
  2. 2. a process for the preparation of a benzylisoquinoline alkaloid glycoside compound according to claim 1, characterized in that the process comprises the steps of: 1) Soaking tuber of rhizoma corydalis in 6% acetic acid solution, oven drying at 40deg.C, pulverizing, soaking in water, ultrasonic extracting, mixing extractive solutions, and concentrating under reduced pressure to obtain plant extract; 2) Dispersing the plant extract obtained in the step 1) in water, separating by HPD100 type macroporous resin column chromatography, gradient eluting with water, 50% ethanol and 95% ethanol, collecting 50% ethanol eluting part, and concentrating under reduced pressure to obtain eluting part YH-D; 3) Separating YH-D) by MCI column chromatography, respectively eluting with 0% -100% methanol-water solution, and recovering solvent under reduced pressure to obtain 4 parts of eluates named YH-D-1-YH-D-4; 4) Dissolving YH-D-2 in water, filtering, subjecting the filtrate to medium pressure ODS column chromatography, eluting with 1% acetic acid water, 5% -60% methanol-acid water and 100% pure methanol in sequence, and recovering solvent under reduced pressure to obtain 5 parts of eluates named as A-E respectively; 5) Dissolving the eluted part A with water, filtering, subjecting the filtrate to Sephadex LH-20 column chromatography, eluting with pure water, concentrating under reduced pressure to obtain 6 parts of eluents named A1-A6 respectively; 6) Eluting the elution part A4 by using 0-30% methanol-water gradient of medium-pressure ODS column chromatography to obtain 7 parts of eluents named A4-1-A4-7 respectively, eluting A4-5 by using Sephadex LH-20 column chromatography, concentrating under reduced pressure, separating to obtain 4 parts of eluents named A4-5-1-A4-5-4 respectively, and purifying A4-5-3 by using semi-preparative C 18 column HPLC to obtain a compound 1; 7) The elution part A5 is subjected to gradient elution by methanol-water with the concentration of 0-30% of medium-pressure ODS column chromatography, and is decompressed and concentrated to obtain 9 parts of eluents which are named as A5-1-A5-9 respectively; 8) Subjecting A5-4 obtained in the step 7) to Sephadex LH-20 column chromatography and pure methanol elution to obtain 2 parts of eluents named A5-4-1 and A5-4-2, respectively, and purifying A5-4-2 by semi-preparative C 18 column HPLC to obtain a compound 2, a compound 3, a compound 4 and a compound 6; 9) Purifying A5-5 obtained in the step 7) by semi-preparative C 18 column HPLC to obtain a compound 5.
  3. 3. The method for preparing the benzylisoquinoline alkaloid glycoside compounds according to claim 2, wherein the ultrasonic extraction time in the step 1) is 3 times, the mass-volume ratio of water to medicinal materials used each time is 1:1, and the ultrasonic time is 1h.
  4. 4. The method for preparing the benzylisoquinoline alkaloid glycoside compounds according to claim 2, wherein each gradient elution in the step 2) is 3 times of the volume of the macroporous resin column, and the volume ratio of the methanol-water solution in the step 3) is 0%, 30%, 60% and 100%, and each gradient elution is 2 times of the volume of the MCI column.
  5. 5. The method for preparing the benzylisoquinoline alkaloid glycoside compounds according to claim 2, wherein in the step 4), the elution time of 1% acetic acid water is 30min, the flow rate is 45ml/min, the elution time of 5% -60% methanol-acid water contains 1% acetic acid, the elution time is 180min, the flow rate is 45ml/min, the elution time of 100% methanol is 20min, and the flow rate is 45ml/min.
  6. 6. The preparation method of the benzylisoquinoline alkaloid glycoside compounds according to claim 2, wherein in the step 6), the gradient elution time of 0-30% of methanol-water is 60 min, the flow rate is 35 ml/min, the HPLC condition of the semi-preparative C 18 column is that the mobile phase is 6% acetonitrile-water, the mobile phase contains 0.1% trifluoroacetic acid, the flow rate is 3ml/min, the detection wavelength is 254 nm, and the column temperature is 25 ℃.
  7. 7. The method for preparing the benzylisoquinoline alkaloid glycoside compounds according to claim 2, wherein the gradient elution time of 0-30% of methanol-water in the step 7) is 60min, and the flow rate is 35ml/min.
  8. 8. The method for preparing the benzylisoquinoline alkaloid glycoside compounds according to claim 2, wherein the HPLC condition of the semi-preparative C 18 column in the step 8) is mobile phase 19% acetonitrile-water containing 0.1% trifluoroacetic acid, the flow rate is 3ml/min, the detection wavelength is 254-nm, the column temperature is 25 ℃, and the HPLC condition of the semi-preparative C 18 column in the step 9) is mobile phase 17% acetonitrile-water containing 0.1% trifluoroacetic acid, the flow rate is 3ml/min, the detection wavelength is 254-nm, and the column temperature is 25 ℃.
  9. 9. A pharmaceutical composition comprising at least one benzylisoquinoline alkaloid glycoside compound of claim 1 and a pharmaceutically acceptable salt or pharmaceutically acceptable carrier or excipient thereof, or the elution site YH-D-2 of claim 2 and a pharmaceutically acceptable carrier or excipient thereof.
  10. 10. Use of the pharmaceutical composition of claim 9 for the preparation of an anti-inflammatory drug.

Description

Benzyl isoquinoline alkaloid glycoside compound and preparation method and application thereof Technical Field The invention relates to the technical field of medicines, in particular to a benzyl isoquinoline alkaloid glycoside compound and a preparation method and application thereof. Background Alkaloid glycoside is an important water-soluble natural product formed by connecting alkaloid with monosaccharide, disaccharide or polysaccharide (glucose, rhamnose, arabinose, etc.) through C-O, C-C or N-C bond. Currently, natural product researchers have found about 230 alkaloid glycosides from plants, and based on the alkaloid aglycone classification, mainly include steroidal alkaloid glycosides (about 120), indole alkaloid glycosides (about 70), and other alkaloid glycosides (about 40). The reported alkaloid glycoside shows a series of biological activities of antibiosis, antivirus, anti-tumor, anti-pain, antipyresis, cholesterol reduction, anti-inflammatory and the like, and is an important component of active natural products. However, in view of the diversity of alkaloid structures (including steroidal alkaloids, indole alkaloids, phenanthridine alkaloids, isoquinoline alkaloids, diterpene alkaloids, etc.), the reported glycosylated alkaloids appear to be only the iceberg horns, and a large number of unknown alkaloid glycosides still exist in traditional Chinese medicine, which deserves further exploration. Benzylisoquinoline alkaloid glycosides are secondary metabolites formed by benzylisoquinoline and mono-, di-or polysaccharides. The number of benzylisoquinoline alkaloid glycosides found at present is very small, only 6 are reported, and only 1 is glucose disaccharide, and the others are glucose monosaccharide glycosides. Therefore, the novel benzylisoquinoline alkaloid glycoside is worthy of systematic excavation and pharmacological activity research. The traditional Chinese medicine rhizoma corydalis, also called rhizoma corydalis, is the dry tuber of corydalis tuber (Corydalis yanhusuo W.T. Wang) of corydalis (Corydalis) of Papaveraceae (PAPAVERACEAE), and has effects of promoting blood circulation, removing blood stasis, regulating qi-flowing, relieving pain, etc. The main chemical components of rhizoma corydalis are isoquinoline alkaloids, especially corydaline, dehydrocorydaline, berberine, palmatine and tetrahydropalmatine, which have analgesic, sedative, antihypertensive, antimalarial and antitumor effects, and are considered as main active components of rhizoma corydalis. At present, the research on the chemical components and pharmacological actions of corydalis tuber is mainly focused on fat-soluble parts, and the research on water-soluble chemical components such as anti-inflammatory is less. Therefore, the benzyl isoquinoline alkaloid glycoside with novel structure and potential anti-inflammatory effect is found to be feasible from rhizoma corydalis. Disclosure of Invention In order to overcome the defects in the prior art, the main purpose of the invention is to provide a benzyl isoquinoline alkaloid glycoside compound, and a preparation method and application thereof. In order to achieve the purpose of the invention, the technical scheme adopted by the invention comprises the following steps: a benzylisoquinoline alkaloid glycoside compound is compounds 1-6, and is specifically selected from compounds shown in the following formula: 。 A process for preparing a benzylisoquinoline alkaloid glycoside compound, the process comprising the steps of: 1) Soaking tuber of rhizoma corydalis in 6% acetic acid solution, oven drying at 40deg.C, pulverizing, soaking in water, ultrasonic extracting, mixing extractive solutions, and concentrating under reduced pressure to obtain plant extract; 2) Dispersing the plant extract obtained in the step 1) in water, separating by HPD100 type macroporous resin column chromatography, gradient eluting with water, 50% ethanol and 95% ethanol, collecting 50% ethanol eluting part, and concentrating under reduced pressure to obtain eluting part YH-D; 3) Separating YH-D) by MCI column chromatography, respectively eluting with 0% -100% methanol-water solution, and recovering solvent under reduced pressure to obtain 4 parts of eluates named YH-D-1-YH-D-4; 4) Dissolving YH-D-2 in water, filtering, subjecting the filtrate to medium pressure ODS column chromatography, eluting with 1% acetic acid water, 5% -60% methanol-acid water and 100% pure methanol in sequence, and recovering solvent under reduced pressure to obtain 5 parts of eluates named as A-E respectively; 5) Dissolving the eluted part A with water, filtering, subjecting the filtrate to Sephadex LH-20 column chromatography, eluting with pure water, concentrating under reduced pressure to obtain 6 parts of eluents named A1-A6 respectively; 6) Eluting the elution part A4 by using 0-30% methanol-water gradient of medium-pressure ODS column chromatography to obtain 7 parts of eluents named A4-1-A4-7 respectively, eluting