CN108929353B - A kind of rhamnose or the berberine salt derivative and its preparation method and application of ribose modification - Google Patents
A kind of rhamnose or the berberine salt derivative and its preparation method and application of ribose modification Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/056—Triazole or tetrazole radicals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
- C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
Abstract
The invention discloses the berberine salt derivatives and its preparation method and application that rhamnose or ribose are modified, rhamnose of the invention or the berberine salt derivative of ribose modification, it is keyed by triazole or amide, into in vivo after be not easy to be digested by glycosidase, stability in vivo greatly improves, to increase the medicinal activity of berberinc derivate, and readily soluble in water, various conventional galenic preparations are conveniently prepared into, are had a wide range of application；Rhamnose of the invention or the berberinc derivate of ribose modification, are keyed carbohydrate moieties using triazole or amide, on the one hand, improve the stability of berberine salt derivative, while having lower cytotoxicity；On the other hand; the presence of carbohydrate moieties can promote the combination of jamaicin and action target spot, improve its biocompatibility, compare existing berberine salt derivative; its antitumor, hypoglycemic and neuroprotective function, which has, to be significantly improved, and is substantially reduced to the toxicity of cell.
Description
Technical field
The present invention relates to technical field of medical chemistry, and in particular to a kind of rhamnose or the berberine salt of ribose modification are derivative
Object and its preparation method and application.
Background technique
Active constituent is excavated from natural products and structure of modification and modification are carried out to it, and being traditional Chinese medicine research, persons develop newly
The important channel of medicine.At present in the various kinds of drug of clinical use, many is from natural products or their derivative.It is small
Bark of a cork tree alkali is that isolated Isoquinolinium Alkaloid is extracted from the plants such as the Chinese herbal medicine coptis, for controlling in Traditional Chinese Medicine
Treat the gastrointestinal disease as caused by bacterium infection.Recent study finds jamaicin and its derivative pharmacological function very abundant, such as
Antimalarial, antibacterial, antitumor, anti-arrhythmia, hypoglycemic, tune rouge, treatment Alzheimer disease, osteoporosis etc., but jamaicin
Bioavilability in vivo is excessively poor, and intestinal wall absorptivity is less than 5%.And drug administration by injection then can easily cause hemolytic anemia, mistake
The toxic side effects such as quick property shock, drug rash.Therefore, structural modification or transformation are carried out to jamaicin, or studies its mechanism of action, with
Seeking the method for improving bioavilability is particularly important.Patent CN102079765A discloses a kind of 9-O- glucosides jamaicin
Salt uses glucosyl group, mannose group, malt-base, lactose base, galactosyl, fructosyl, xylosyl or Arab in structure
Glycosyl modified, bioavilability increases compared with jamaicin, but the 9-O- glucosides berberine salt stability is bad, room temperature item
It can be decomposed under part, after in vivo, due to containing glycosidase in human body, glycosidic bond can be broken rapidly, hydrolysis,
It is further broken into berberrubine, seriously affects its bioactivity.
Summary of the invention
Berberine salt derivative modified the object of the present invention is to provide a kind of rhamnose or ribose and preparation method thereof and
Purposes, highly stable in physiological conditions compared with existing berberinc derivate, neuroprotection, antitumor and hypoglycemic work
Property is significantly improved.
To achieve the above object, it is achieved through the following technical solutions:
A kind of rhamnose or the berberine salt derivative of ribose modification, shown in structural formula such as formula (I):
Wherein, R is
Preferably, R is
Preferably, R is
The invention also includes a kind of preparation method for the berberine salt derivative that rhamnose or ribose are modified,
When R isWhen, comprising the following steps:
9-O- (propinyl) berberine hydrochloride and nitrine sugar are dissolved in organic solvent, open stirring, is added at 0~40 DEG C
Enter copper catalyst and ligand, reaction temperature is risen to 50~100 DEG C, be stirred to react 1~5 hour, vacuum distillation removes organic molten
Agent, obtained solid residue recrystallizing methanol, obtains target product；
The wherein molal volume of 9-O- (propinyl) berberine hydrochloride, nitrine sugar, organic solvent, copper catalyst and ligand
Than for 1mol:1~1.5mol:3~5L:0.1~2mol:0.1~2mol；
The nitrine sugar is
The organic solvent be one of acetonitrile, methanol or N,N-dimethylformamide or any two；
The copper catalyst is copper sulphate, cupric sulfate pentahydrate or cuprous iodide；
The ligand is N, N- diisopropylethylamine, sodium ascorbate, triethylamine or diisopropylamine.
The preparation method of a kind of rhamnose or the berberine salt derivative of ribose modification, when R isWhen, comprising the following steps:
9- Carboxvmethoxv berberine hydrochloride and amino sugar are dissolved in the first solvent, open stirring, is added at 0~40 DEG C
Enter condensing agent and organic base, reaction is stirred 1~12 hour at 0~40 DEG C, and vacuum distillation removes the first solvent, and obtained solid is residual
Slag is recrystallized with the second solvent, obtains yellow powdery solid.The solid is dissolved in third solvent, inorganic base is added, reaction solution is 0
It is stirred 0.5~10 hour at~40 DEG C, vacuum distillation removes third solvent, and obtained solid residue obtains yellow powder with recrystallizing methanol
Last shape solid, as target product；
Wherein the molar ratio of 9- Carboxvmethoxv berberine hydrochloride, amino sugar, condensing agent, organic base and inorganic base is 1:
1~3:1~3:0.1~1:0.1~3；
The amino sugar is
First solvent is N,N-dimethylformamide or/and methylene chloride；
Condensing agent is N, N- dicyclohexylcarbodiimide or 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine hydrochloric acid
Salt；
Organic base is triethylamine or N, N- diisopropylethylamine；
Second solvent is methanol, ethyl alcohol or acetonitrile；
Inorganic base is sodium hydroxide, sodium methoxide or potassium hydroxide；
Third solvent by volume ratio be 1:3~10:1 methylene chloride and low-carbon alcohols form, wherein low-carbon alcohols be methanol or
Ethyl alcohol.
Preferred preparation method, 9-O- (propinyl) berberine hydrochloride, nitrine sugar, organic solvent, copper catalyst and matches
The molal volume ratio of body is 1mol:1mol:5L:1mol:0.5mol.
Preferred preparation method, 9- Carboxvmethoxv berberine hydrochloride, amino sugar, condensing agent, organic base and inorganic base
Molar ratio be 1:2:1.2:0.1:0.2.
Preferred preparation method, third solvent are made of the methylene chloride that volume ratio is 1:1 and methanol.
The invention also discloses a kind of purposes for the berberine salt derivative that rhamnose or ribose are modified, and are used for neuroprotection
Drug, anti-tumor drug or hypoglycemic drug.
Compared to the prior art, the present invention has the following advantages:
Rhamnose of the invention or the berberine salt derivative of ribose modification, are keyed by triazole or amide, into
It is not easy to be digested by glycosidase after entering in vivo, stability in vivo greatly improves, to increase the doctor of berberinc derivate
Medicine activity, and it is readily soluble in water, various conventional galenic preparations are conveniently prepared into, are had a wide range of application；
Rhamnose of the invention or the berberinc derivate of ribose modification, are keyed carbohydrate mould using triazole or amide
Block, on the one hand, improve the stability of berberine salt derivative, while there is lower cytotoxicity；On the other hand, carbohydrate mould
The presence of block can promote the combination of jamaicin and action target spot, improve its biocompatibility, derivative compared to existing berberine salt
Object, antitumor, hypoglycemic and neuroprotective function, which has, to be significantly improved, and is substantially reduced to the toxicity of cell；
Preparation method of the invention, yield is high, and side reaction is few, and product is easy to purify requirement of this method to consersion unit
It is low, it is easy to accomplish industrialized production.
Detailed description of the invention
Fig. 1 is the nuclear magnetic resonance spectroscopy of three-O- acetyl group-α-L- rhamnose of 1- azido -2,3,4-；
Fig. 2 is the nuclear magnetic resonance spectroscopy of compound 1；
Fig. 3 is the nuclear magnetic resonance spectroscopy of compound 2；
Fig. 4 is the nuclear magnetic resonance spectroscopy of compound 5；
Fig. 5 is the nuclear magnetic resonance spectroscopy of compound 6.
Specific embodiment
A kind of rhamnose or the berberine salt derivative of ribose modification, shown in structural formula such as formula (I):
Wherein, R is
Preferably, R is
Preferably, R is
The invention also includes a kind of preparation method for the berberine salt derivative that rhamnose or ribose are modified,
When R isWhen, comprising the following steps:
9-O- (propinyl) berberine hydrochloride and nitrine sugar are dissolved in organic solvent, open stirring, is added at 0~40 DEG C
Enter copper catalyst and ligand, reaction temperature is risen to 50~100 DEG C, be stirred to react 1~5 hour, vacuum distillation removes organic molten
Agent, obtained solid residue recrystallizing methanol, obtains target product；
The wherein molal volume of 9-O- (propinyl) berberine hydrochloride, nitrine sugar, organic solvent, copper catalyst and ligand
Than for 1mol:1~1.5mol:3~5L:0.1~2mol:0.1~2mol；
The nitrine sugar is
The organic solvent be one of acetonitrile, methanol or N,N-dimethylformamide or any two；
The copper catalyst is copper sulphate, cupric sulfate pentahydrate or cuprous iodide；
The ligand is N, N- diisopropylethylamine, sodium ascorbate, triethylamine or diisopropylamine.
Rhamnose or the berberine salt derivative of ribose modification are closed when rhamnose or ribose are keyed with triazole
At route are as follows:
The preparation method of a kind of rhamnose or the berberine salt derivative of ribose modification, when R isWhen, comprising the following steps:
9- Carboxvmethoxv berberine hydrochloride and amino sugar are dissolved in the first solvent, open stirring, is added at 0~40 DEG C
Enter condensing agent and organic base, reaction is stirred 1~12 hour at 0~40 DEG C, and vacuum distillation removes the first solvent, and obtained solid is residual
Slag is recrystallized with the second solvent, obtains yellow powdery solid.The solid is dissolved in third solvent, inorganic base is added, reaction solution is 0
It is stirred 0.5~10 hour at~40 DEG C, vacuum distillation removes third solvent, and obtained solid residue obtains yellow powder with recrystallizing methanol
Last shape solid, as target product；
Wherein the molar ratio of 9- Carboxvmethoxv berberine hydrochloride, amino sugar, condensing agent, organic base and inorganic base is 1:
1~3:1~3:0.1~1:0.1~3；
The amino sugar is
First solvent is N,N-dimethylformamide or/and methylene chloride；
Condensing agent is N, N- dicyclohexylcarbodiimide or 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine hydrochloric acid
Salt；
Organic base is triethylamine or N, N- diisopropylethylamine；
Second solvent is methanol, ethyl alcohol or acetonitrile；
Inorganic base is sodium hydroxide, sodium methoxide or potassium hydroxide；
Third solvent by volume ratio be 1:3~10:1 methylene chloride and low-carbon alcohols form, wherein low-carbon alcohols be methanol or
Ethyl alcohol.
Rhamnose or the berberine salt derivative of ribose modification, when rhamnose or ribose are keyed with amide, synthesis
Route are as follows:
Preferred preparation method, 9-O- (propinyl) berberine hydrochloride, nitrine sugar, organic solvent, copper catalyst and matches
The molal volume ratio of body is 1mol:1mol:5L:1mol:0.5mol.
Preferred preparation method, 9- Carboxvmethoxv berberine hydrochloride, amino sugar, condensing agent, organic base and inorganic base
Molar ratio be 1:2:1.2:0.1:0.2.
Preferred preparation method, third solvent are made of the methylene chloride that volume ratio is 1:1 and methanol.
The invention also discloses a kind of purposes for the berberine salt derivative that rhamnose or ribose are modified, and are used for neuroprotection
Drug, anti-tumor drug or hypoglycemic drug.
In order to achieve the object of the present invention, below in conjunction with specific embodiment, the invention will be further described.
Raw material used in the embodiment of the present invention, 9- Carboxvmethoxv berberine salt can market purchase or according to document into
Row self-control, Design, synthesis and biological evaluation of berberine-benzimidazole
hybrids as new type of potentially DNA-targeting antimicrobial agents.Ponmani
Jeyakkumar,Ling Zhang,Srinivasa Rao Avula,Cheng-He Zhou.European Journal of
Medicinal Chemistry。
1,2,3,4- tetra--O- acetyl group-L- rhamnose can be bought on the market or make by oneself according to following documents,
Streamlined Synthesis of Per-O-acetylated Sugars,Glycosyl Iodides,or
Thioglycosides from Unprotected Reducing Sugars 1.Balaram Mukhopadhyay,
K.P.Ravindranathan Kartha,David A.Russell,andRobert A.Field*.J.Org.Chem.2004,
69,7758-7760。
9-O- (propinyl) berberine hydrochloride can be made by oneself with outsourcing or with reference to following documents, bibliography:
Design,synthesis,and anticancer activity of novel berberine derivatives
Prepared via CuAAC " click " chemistry as potential anticancer agents, Drug
Design,Development and Therapy 2014:81047-1059。
Bis--O- acetyl group-β of 1- azido -2,3--D-ribose can be made by oneself with outsourcing or with reference to following documents, join
Examine document Tetrahedron Letters, 2008,49:4491.
Embodiment 1
The preparation of three-O- acetyl group-α-L- rhamnose of 1- azido -2,3,4-: tetra--O- acetyl group-L- of 1,2,3,4- is taken
Rhamnose (332g, 1mol) is dissolved in 1L methylene chloride, opens stirring, is added azidotrimethylsilane (230g, 2mol).Reaction solution
It is cooled to 0 DEG C, anhydrous stannic chloride (130g, 0.5mol) slowly is added dropwise into system, after being added dropwise, reaction solution is slowly increased to
Room temperature is stirred to react 2 hours, and the aqueous solution (1L) that saturated sodium bicarbonate is then slowly added dropwise neutralizes tin tetrachloride.It is added dropwise
Afterwards, mixed liquor stratification, organic phase twice (0.5L × 2 time), are spin-dried for 1L water washing, gained grease recrystallizing methanol
Obtain transparent acicular crystal (243g, 77%).1H NMR(400MHz,CDCl3): δ 5.31 (d, J=1.2Hz, 1H, rhamnose-H1),
5.21 (dd, J=3.2,10Hz, 1H), 5.15-5.14 (m, 1H), 5.09 (t, J=10Hz, 1H), 4.07-4.00 (m, 1H),
2.16(s,3H,CH3CO),2.06(s,3H,CH3CO),1.99(s,3H,CH3), CO 1.29 (d, J=8.4Hz, 3H, CH3)；
ESI-TOF HRMS (m/z): theoretical value: C12H18N3O7,[M+H]+,316.1139；Measured value: 316.1135.
The preparation of 1- azido-α-L- rhamnose: upper step is reacted into resulting transparent acicular crystal (315g, 1mol) and is dissolved in
1L methanol opens stirring, the sodium hydroxide (4g, 0.1mol) of catalytic amount is added, and reaction solution is stirred at room temperature 3 hours, decompression
Distillation for removing methanol obtains light yellow oil, is not required to purifying and is directly used in reaction in next step.ESI-TOF HRMS (m/z): theoretical
Value: C6H12N3O4, [M+H]+, 190.0822；Measured value: 190.0812.
Embodiment 2
The preparation of compound 1:
By 9-O- (propinyl) berberine hydrochloride (395g, 1mol) and the resulting 1- azido-α-L- sandlwood of embodiment 1
Sugared crude product (189g, 1mol) is dissolved in 5L acetonitrile, opens stirring, and cuprous iodide (190g, 1mol) and N, N- bis- are added at 20 DEG C
Reaction temperature is risen to 80 DEG C by wopropyl ethyl amine (64.5g, 0.5mol), is stirred to react 3 hours, and vacuum distillation removes acetonitrile, is subtracted
Solvent is distilled off in pressure, and obtained solid residue obtains the sugar-modified berberine salt derivative of triazole sandlwood with recrystallizing methanol, i.e.,
Compound 1 (427g, 73%).
1H NMR(400MHz,DMSO-d6): δ 9.65 (s, 1H, CH=N), 8.92 (s, 1H, ArH), 8.42 (s, 1H,
), triazole-H 8.22 (d, J=9.2Hz, 1H, ArH), 8.00 (d, J=9.2Hz, 1H, ArH), 7.78 (s, 1H, ArH),
7.09(s,1H,ArH),6.17(s,2H,-OCH2), O- 5.88 (d, J=2.0Hz, 1H, rhamnose-H1), 5.48 (s, 2H,
CH2), 5.26 (d, J=4.8Hz, 1H), 5.02 (t, J=5.6,8.4Hz, 2H, CH2), 4.89 (t, J=6.0Hz, 2H, CH2),
4.39-4.36(m,1H),4.10(s,3H,CH3), 3.77-3.73 (m, 1H), 3.19 (t, J=6.4Hz, 2H), 1.10 (d, J=
6.4Hz,3H,CH3)；
ESI-TOF HRMS (m/z): theoretical value: C28H29N4O8 +,[M-Cl]+,549.1980；Measured value: 549.1986.
Embodiment 3
The preparation of compound 1:
By 9-O- (propinyl) berberine hydrochloride (395g, 1mol) and 1- azido-α-L- rhamnose crude product (94.5g,
0.5mol) be dissolved in 4L methanol, open stirring, be added at 20 DEG C copper sulphate (16g, 0.1mol) and sodium ascorbate (19.8g,
0.1mol), reaction temperature is risen to 80 DEG C, be stirred to react 3 hours, vacuum distillation removes acetonitrile, and vacuum distillation removes solvent, institute
It obtains solid residue and obtains the sugar-modified berberine salt derivative of triazole, i.e. compound 1 with recrystallizing methanol.
Embodiment 4
The preparation of compound 1:
By 9-O- (propinyl) berberine hydrochloride (395g, 1mol) and 1- azido-α-L- rhamnose crude product (945g,
It 5mol) is dissolved in the in the mixed solvent of 2.5L acetonitrile and 0.5L n,N-Dimethylformamide, stirring is opened, is added five at 20 DEG C
Brochanite (500g, 2mol) and triethylamine (202g, 2mol), rise to 80 DEG C for reaction temperature, are stirred to react 3 hours, decompression
Acetonitrile is distilled off, vacuum distillation removes solvent, and obtained solid residue obtains the sugar-modified jamaicin of triazole with recrystallizing methanol
Salt derivative, i.e. compound 1.
Embodiment 5
1- azido-beta-D-ribose preparation: bis--O- acetyl group-β of 1- azido -2,3--D-ribose (301g, 1mol)
It is dissolved in 1L methanol, stirring is opened, the sodium hydroxide (4g, 0.1mol) of catalytic amount is added, reaction solution is stirred at room temperature 3 hours,
Vacuum distillation removes methanol, obtains light yellow oil, is not required to purifying and is directly used in reaction in next step.ESI-TOF HRMS (m/z):
Theoretical value: C5H10N3O4, [M+H]+, 176.0666；Measured value: 176.0653.
The preparation of compound 2:
9-O- (propinyl) berberine hydrochloride (395g, 1mol) and 1- azido-beta-D-ribose (175g, 1mol) is molten
In 5L methanol, stirring is opened, cuprous iodide (38g, 0.2mol) and triethylamine (20.2g, 0.2mol) are added at 20 DEG C, it will be anti-
It answers temperature to rise to 60 DEG C, is stirred to react 3 hours, vacuum distillation removes solvent, and obtained solid residue obtains three nitrogen with recrystallizing methanol
The berberine salt derivative of azoles ribose modification, i.e. compound 2 (399g, 70%).
1H NMR(400MHz,DMSO-d6): δ 9.65 (s, 1H, CH=N), 8.93 (s, 1H, ArH), 8.53 (s, 1H,
), triazole-H 8.24 (d, J=8.4Hz, 1H, ArH), 8.03 (d, J=8.8Hz, 1H, ArH), 7.79 (s, 1H, ArH),
7.09(s,1H,ArH),6.18(s,2H,-OCH2), O- 5.94 (d, J=4.4Hz, 1H, H1), 5.56 (d, J=6.0Hz, 1H),
5.47 (s, 2H), 5.28 (d, J=4.4Hz, 1H), 4.98 (t, J=3.6Hz, 1H), 4.89 (t, J=4.2Hz, 2H), 4.36-
4.32(m,1H),4.10(s,3H,CH3),3.96(s,1H),3.61-3.56(m,1H),3.52-3.46(m,2H),3.19(t,J
=6.4Hz, 2H)；
ESI-TOF HRMS (m/z): theoretical value: C27H27N4O8 +,[M-Cl]+,535.1823；Measured value: 535.1828.
Embodiment 6
1- azido-beta-D-ribose preparation process reference implementation example 5, the preparation of compound 2 the following steps are included:
By 9-O- (propinyl) berberine hydrochloride (395g, 1mol) and 1- azido-beta-D-ribose (87.5g,
It 0.5mol) is dissolved in the in the mixed solvent of 2L methanol and 2L acetonitrile, opens stirring, copper sulphate (64g, 0.4mol) is added at 20 DEG C
With diisopropylamine (50.5g, 0.5mol), reaction temperature is risen to 60 DEG C, is stirred to react 3 hours, vacuum distillation removes solvent, institute
It obtains solid residue and obtains the sugar-modified berberine salt derivative of ribavirin, i.e. compound 2 with recrystallizing methanol.
Embodiment 7
1- azido-beta-D-ribose preparation process reference implementation example 5, the preparation of compound 2 the following steps are included:
9-O- (propinyl) berberine hydrochloride (395g, 1mol) and 1- azido-beta-D-ribose (525g, 3mol) is molten
In 1L methanol and 2LN, the mixed solvent of dinethylformamide opens stirring, be added at 20 DEG C cupric sulfate pentahydrate (50g,
0.2mol) with sodium ascorbate (198g, 1mol), reaction temperature is risen to 60 DEG C, is stirred to react 3 hours, vacuum distillation removes
Solvent, obtained solid residue obtain the sugar-modified berberine salt derivative of ribavirin, i.e. compound 2 with recrystallizing methanol.
Embodiment 8
The preparation of three-O- acetyl group-α-L- rhamnose of 1- amino -2,3,4-: by three-O- acetyl of 1- azido -2,3,4-
Base-α-L- rhamnose (315g, 1mol) is dissolved in 500mL methanol, and 500mL methylene chloride and 50mL water is added, and opens stirring, ice bath
It is cooled to 0~10 DEG C.It is added chloride solid (321g, 6mol), is then slowly added into zinc powder (261g, 4mol), 1~2 hour
It adds, temperature is controlled in adition process at 0~10 DEG C.It adds rear reaction solution to heat up naturally, stir 2 hours.It is filtered to remove solid
500mL methylene chloride is added in impurity, and (200mL × 3) three times are washed with water in mixed liquor, and organic phase is spin-dried for obtaining colorless oil, no
It need to purify to be directly used in and react in next step.ESI-TOF HRMS (m/z): theoretical value: C12H20NO7,[M+H]+,290.1234；It is real
Measured value: 290.1245.
The preparation of compound 5: amino sugar grease (145g, 0.5mol) and 9- Carboxvmethoxv jamaicin obtained by step are taken
Salt (207.5g, 0.5mol) is dissolved in n,N-Dimethylformamide, opens stirring, N, N- dicyclohexylcarbodiimide are added at room temperature
(123.5g, 0.6mol) and triethylamine (5g, 0.05mol), reaction are stirred at room temperature 3 hours, and vacuum distillation removes solvent, institute
Solid residue recrystallizing methanol is obtained, yellow powdery solid is obtained, is compound 3.By the solid be dissolved in methylene chloride 300mL and
The mixed liquor of methanol 300mL is added sodium methoxide (5.5g, 0.1mol), and reaction solution is stirred at room temperature 1 hour, and vacuum distillation removes
Solvent is removed, obtained solid residue obtains yellow powdery solid, as compound 5 (221g, 79%) with recrystallizing methanol.
1H NMR(400MHz,DMSO-d6): δ 9.95 (s, 1H, CH=N), 8.95 (s, 1H, ArH), 8.45 (s, 1H, C (O)
), NH 8.21 (d, J=8.8Hz, 1H, ArH), 8.01 (d, J=8.8Hz, 1H, ArH), 7.81 (s, 1H, ArH), 7.10 (s, 1H,
ArH),6.18(s,2H,-OCH2), O- 5.77 (d, J=4.0Hz, 1H, H1), 5.46 (d, J=6.0Hz, 1H), 5.12 (m,
1H), 5.07 (s, 2H), 4.94 (t, J=4.0Hz, 2H), 4.38 (m, 1H), 4.02 (s, 3H, CH3),3.67-3.66(m,1H),
3.23-3.20 (m, 2H), 1.19 (t, J=6.0Hz, 2H)；
ESI-TOF HRMS (m/z): theoretical value: C27H29N2O9 +,[M-Cl]+,525.1868；Measured value: 525.1860.
Embodiment 9
The preparation of three-O- acetyl group-α-L- rhamnose of 1- amino -2,3,4-: by three-O- acetyl of 1- azido -2,3,4-
Base-α-L- rhamnose (315g, 1mol) is dissolved in 500mL methanol, and 400mL methylene chloride and 100mL water is added, and opens stirring, ice
Bath is cooled to 0~10 DEG C.It is added chloride solid (160.5g, 3mol), is then slowly added into zinc powder (130.5g, 2mol), 1~
It adds within 2 hours, temperature is controlled in adition process at 0~10 DEG C.It adds rear reaction solution to heat up naturally, stir 2 hours.It is filtered to remove
400mL methylene chloride is added in solid impurity, and (150mL × 3) three times are washed with water in mixed liquor, and organic phase is spin-dried for obtaining colorless oil
Object is not required to purifying and is directly used in reaction in next step.
The preparation of compound 5: amino sugar grease (174g, 0.6mol) and 9- Carboxvmethoxv jamaicin obtained by step are taken
Salt (83g, 0.2mol) is dissolved in n,N-Dimethylformamide, opens stirring, N, N- dicyclohexylcarbodiimide are added at room temperature
(41.2g, 0.2mol) and n,N-diisopropylethylamine (25.8g, 0.2mol), reaction are stirred at room temperature 3 hours, are evaporated under reduced pressure
Solvent is removed, obtained solid residue recrystallizing methanol obtains yellow powdery solid, is compound 3.The solid is dissolved in dichloro
The mixed liquor of methane 40mL and methanol 120mL are added sodium hydroxide (0.8g, 0.02mol), and it is small that reaction solution is stirred at room temperature 1
When, vacuum distillation removes solvent, and obtained solid residue obtains yellow powdery solid, as compound 5 with recrystallizing methanol.
Embodiment 10
The preparation of three-O- acetyl group-α-L- rhamnose of 1- amino -2,3,4-: by three-O- acetyl of 1- azido -2,3,4-
Base-α-L- rhamnose (315g, 1mol) is dissolved in 400mL methanol, and 600mL methylene chloride and 40mL water is added, and opens stirring, ice bath
It is cooled to 0~10 DEG C.It is added chloride solid (481.5g, 9mol), is then slowly added into zinc powder (391.5g, 6mol), 1~2
Hour adds, and temperature is controlled in adition process at 0~10 DEG C.It adds rear reaction solution to heat up naturally, stir 2 hours.It is filtered to remove
600mL methylene chloride is added in solid impurity, and (250mL × 3) three times are washed with water in mixed liquor, and organic phase is spin-dried for obtaining colorless oil
Object is not required to purifying and is directly used in reaction in next step.
The preparation of compound 5: by amino sugar oily obtained by 9- Carboxvmethoxv berberine salt (166g, 0.4mol) and upper step
Object is dissolved in n,N-Dimethylformamide, opens stirring, and 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine is added at room temperature
Hydrochloride (229.2g, 1.2mol) and triethylamine (20.2g, 0.2mol), reaction are stirred at room temperature 3 hours, and vacuum distillation removes
Solvent is removed, obtained solid residue recrystallizing methanol obtains yellow powdery solid, is compound 3.The solid is dissolved in dichloromethane
The mixed liquor of alkane 320mL and ethyl alcohol 32mL are added potassium hydroxide (22.4g, 0.4mol), and reaction solution is stirred at room temperature 1 hour,
Vacuum distillation removes solvent, and obtained solid residue obtains yellow powdery solid, as compound 5 with recrystallizing methanol.
Embodiment 11
Two-O- acetyl group-β of 1- amino -2,3--D-ribose preparation: by two-O- acetyl group-D- core of 1- azido -2,3-
Sugared (1505g, 5mol) is dissolved in 2.5L methanol, and 2.5L methylene chloride and 250mL water is added, and opens stirring, and ice bath is cooled to 0~10
℃.It is added chloride solid (1605g, 30mol), is then slowly added into zinc powder (1305g, 20mol), adds within 1~2 hour, add
Control temperature is at 0~10 DEG C during entering.It adds rear reaction solution to heat up naturally, stir 2 hours.It is filtered to remove solid impurity, is added
Enter 2.5L methylene chloride, (1000mL × 3) three times are washed with water in mixed liquor, and organic phase is spin-dried for obtaining colorless oil, are not required to purify
It is directly used in and reacts in next step.ESI-TOF HRMS (m/z): theoretical value: C11H18NO7,[M+H]+,276.1078；Measured value:
276.1082。
The preparation of compound 6: amino sugar grease (552g, 2mol) and 9- Carboxvmethoxv berberine salt obtained by step are taken
(415g, 1mol) is dissolved in methylene chloride, opens stirring, N, N- dicyclohexylcarbodiimide (247g, 1.2mol) are added at room temperature
With triethylamine (10g, 0.1mol), reaction is stirred at room temperature 3 hours, and vacuum distillation removes solvent, obtained solid residue first
Alcohol recrystallization, obtains yellow powdery solid, is compound 4.The solid is dissolved in the mixed of methylene chloride 600mL and methanol 600mL
Liquid is closed, is added sodium hydroxide (8g, 0.2mol), reaction solution is stirred at room temperature 1 hour, and vacuum distillation removes solvent, and gained is solid
Body residue obtains yellow powdery solid, as compound 6 (377g, 69%) with recrystallizing methanol.
1H NMR(400MHz,DMSO-d6): δ 9.64 (s, 1H, CH=N), 9.48 (s, 1H, C (O) NH), 8.97 (s, 1H,
), ArH 8.20 (d, J=8.8Hz, 1H, ArH), 8.00 (d, J=8.4Hz, 1H, ArH), 7.79 (s, 1H, ArH), 7.11 (s,
1H,ArH),6.17(s,2H,-OCH2), O- 5.90 (d, J=4.0Hz, 1H, H1), 5.52 (s, 1H), 5.34 (d, J=4.4Hz,
1H), 5.09 (s, 2H), 5.03 (d, J=4.0Hz, 1H), 4.89 (s, 1H), 4.42 (s, 1H), 4.11 (s, 3H, CH3),3.83
(s, 1H), 3.54-3.51 (m, 1H), 3.24 (t, J=6.4Hz, 2H)；
ESI-TOF HRMS (m/z): theoretical value: C26H27N2O9 +,[M-Cl]+,511.1711；Measured value: 511.1701.
Embodiment 12
Two-O- acetyl group-β of 1- amino -2,3--D-ribose preparation: by two-O- acetyl group-β-D- of 1- azido -2,3-
Ribose (1505g, 5mol) is dissolved in 400mL methanol, and 3L methylene chloride and 500mL water is added, and opens stirring, and ice bath is cooled to 0~
10℃.It is added chloride solid (802.5g, 15mol), is then slowly added into zinc powder (652.5g, 10mol), add within 1~2 hour
It is complete, temperature is controlled in adition process at 0~10 DEG C.It adds rear reaction solution to heat up naturally, stir 2 hours.It is miscellaneous to be filtered to remove solid
2L methylene chloride is added in matter, and (750mL × 3) three times are washed with water in mixed liquor, and organic phase is spin-dried for obtaining colorless oil, is not required to pure
Change is directly used in reacts in next step.
The preparation of compound 6: amino sugar grease (828g, 3mol) and 9- Carboxvmethoxv berberine salt obtained by step are taken
(415g, 1mol) is dissolved in methylene chloride, opens stirring, is added N at room temperature, N- dicyclohexylcarbodiimide (412g, 2mol) and
Triethylamine (101g, 1mol), reaction are stirred at room temperature 3 hours, and vacuum distillation removes solvent, obtained solid residue methanol weight
Crystallization, obtains yellow powdery solid, is compound 4.The solid is dissolved in the mixed liquor of methylene chloride 700mL and methanol 700mL,
It is added sodium hydroxide (4g, 0.1mol), reaction solution is stirred at room temperature 1 hour, and vacuum distillation removes solvent, obtained solid residue
Yellow powdery solid, as compound 6 are obtained with recrystallizing methanol.
Embodiment 13
Two-O- acetyl group-β of 1- amino -2,3--D-ribose preparation: by two-O- acetyl group-β-D- of 1- azido -2,3-
Ribose (301g, 1mol) is dissolved in 600mL methanol, and 400mL methylene chloride and 80mL water is added, and opens stirring, and ice bath is cooled to 0~
10℃.It is added chloride solid (481.5g, 9mol), is then slowly added into zinc powder (391.5g, 6mol), adds within 1~2 hour,
Temperature is controlled in adition process at 0~10 DEG C.It adds rear reaction solution to heat up naturally, stir 2 hours.Solid impurity is filtered to remove,
600mL methylene chloride is added, (250mL × 3) three times are washed with water in mixed liquor, and organic phase is spin-dried for obtaining colorless oil, is not required to pure
Change is directly used in reacts in next step.
The preparation of compound 6: by amino sugar and oil obtained by 9- Carboxvmethoxv berberine salt (207.5g, 0.5mol) and upper step
Shape object is dissolved in methylene chloride, opens stirring, and 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate is added at room temperature
(191g, 1mol) and n,N-diisopropylethylamine (32.3g, 0.25mol), reaction are stirred at room temperature 3 hours, and vacuum distillation removes
Solvent is removed, obtained solid residue recrystallizing methanol obtains yellow powdery solid, is compound 4.The solid is dissolved in dichloromethane
The mixed liquor of alkane 200mL and ethyl alcohol 400mL, are added sodium hydroxide (4g, 0.1mol), and reaction solution is stirred at room temperature 1 hour, subtracts
Solvent is distilled off in pressure, and obtained solid residue obtains yellow powdery solid, as compound 6 with recrystallizing methanol.
Neuroprotective activity evaluation
It is derivative with cell inhibitory effect test (MTT colorimetric method) measurement berberine hydrochloride and present invention gained berberine salt
Object is to A β25~35Replicate the influence of AD cell model cell survival.The wistar rat taken out raw 24 hours (is purchased from triumphant student's object
Scientific and technological (Shanghai) Co., Ltd.), with 75% ethyl alcohol soaking disinfection, hippocampal tissue is isolated under aseptic condition, it is molten to be placed in ice bath PBS
It is careful to reject blood vessel and fascia in liquid, it is rinsed well, is shredded with PBS solution.Then it is added the 2.5g/L's of 30 times of tissue volumes
Trypsin solution, 37 DEG C of oscillations digest 15 minutes, and FBS liquid terminates digestion, crosses 75 μm of sieve.1000 revs/min of centrifugations 10
Minute, cell is collected, 15mL kind plant liquid (DMEM/F12 contains 10% fetal calf serum) is added and is resuspended, with 1 × 106A cell will be extra large
Horse neuron is inoculated in 96 well culture plates for being coated with poly-D-lysine, sets 37 DEG C, 5%CO2, saturated humidity incubator in training
It supports, was culture the 1st day with the inoculation same day, until culture the 3rd day is added the cytarabine of final concentration of 10 μm of ol/L to inhibit non-mind
Proliferation through member, the cell culture fluid next day, half amount changed liquid, cultivated 7 days.It is separately added into the A β of final concentration of 25 μm of ol/L25~35, after
Continuous culture 36 hours, replicates AD cell model.
Experiment is divided into control group, model group, serial barberry alkali cpd group.Cellular control unit is normally cultivated, and A is added without
β25~35.The A β of final concentration of 25 μm of ol/L is added in model group and serial barberry alkali cpd group25~35, continue culture 36 hours, it is multiple
AD cell model processed.It, Jia Ru not berberine hydrochloride and compound to serial jamaicin compound component in 96 well culture plates
1,2,5,6 solution cultivates its final concentration of 1,2,4 μm of ol/L, control group and model group containing 10% serum DMEM with equivalent
Base replaces, and the morphological change of group of cells is observed in culture under the microscope after 24 hours.Every group sets 4 parallel holes.It is being protected from light
Under the conditions of, 20 μ L of MTT is added in every hole, and (concentration 5mg/mL) continues culture 4 hours, and every hole adds 100 μ of DMSO after abandoning supernatant
L vibrates 10 minutes in 37 DEG C, after completely dissolution to purple crystal, is placed in microplate reader the measurement absorbance value at 570nm.Take 4
The mean value computation cell survival rate in hole.
As can be seen from Table 1, present invention gained berberine salt derivative has hippocampus of rats cell preferable
Protective effect.The cellular control unit survival rate normally cultivated is 100%, and A β is added25~35Model group cell survival rate only have
45.63%, illustrate this experiment modeling success.After berberine hydrochloride is added, cell survival rate is significantly improved, and with the increasing of concentration
Height is improved by 61.89% to 78.24%.Under same concentrations, the berberine salt derivative prepared by us is to rat hippocampus mind
Protective effect through first cell is remarkably reinforced, and when administration concentration is 4 μm of ol/L, cell survival rate exists compound 1,2,5 and 6
90% or more, especially compound 1 and compound 2, when administration concentration is 4 μm of ol/L, cell survival rate is respectively 96.45%
With 98.70%, close to 100%, it is extraordinary that this illustrates that compound 1 and compound 2 have hippocampus of rats cell
Protective effect.
1 berberine hydrochloride of table and compound 1,2,5,6 are directed to the cell survival rate on hippocampus of rats cell
Experimental result table
Internal hypoglycemic activity evaluation
BALB/c mouse (purchased from Kai Xue biotechnology (Shanghai) Co., Ltd.) is taken, 6~8 week old, are randomly divided into 8 by 80
Group: Normal group (10), model control group (10), melbine group (10), berberine hydrochloride group (10) and
1,2,5,6 groups of compound (every group 10)；Normal group is normally raised, remaining each group injects four oxygen by the dosage of 200mg/kg
Pyrimidine establishes diabetes model, and after 48 hours, melbine group and 1,2,5,6 groups of compound are respectively according to the dosage of 30mg/kg
Stomach-filling, model control group stomach-filling same amount of normal saline measure blood glucose with blood glucose meter after successive administration 30 days.It the results are shown in Table 2, model
After control group alloxan modeling, stomach-filling drug is not carried out, so its blood glucose maintains a higher level.It is hypoglycemic
The stomach-filling of common drug melbine the result shows that, melbine has good hypoglycemic activity in Mice Body, can make
Its blood glucose is dropped to close to normal level.And compound 1,2,6 have preferable hypoglycemic activity in Mice Body, fill through drug
After stomach, the blood glucose value of mouse can drop to normal level, especially compound 2, fully achieve euglycemia after continuous medication
It is horizontal.
The internal hypoglycemic experimental result table of 2. berberine hydrochloride of table and compound 1,2,5 and 6
Anti tumor activity in vitro evaluation
Respectively by following several cancer cell strains: HCT-15 cell strain (Hunan Feng Hui Biotechnology Co., Ltd), HCT-
116 cell strains (Hunan Feng Hui Biotechnology Co., Ltd), SW-480 cell strain (Shanghai Mei Yan Biotechnology Co., Ltd),
BGC-823 cell strain (Shanghai Ge Fan Biotechnology Co., Ltd) suspension is inoculated in 96 orifice plates (100 hole μ L/), and cell concentration 1 ×
105A cells/well, cell incubation for 24 hours after, former culture medium is sucked out, 100 μ L berberinc derivates containing various concentration are added in every hole
Culture medium (0.2,1.0,5,25,125,625 μ g/mL), each concentration sets 6 multiple holes, and the hole that compound is not added in refinement born of the same parents is made
Compound blank well, adriamycin make positive control.In 37 DEG C, 5%CO2Middle incubation 12h, every hole are added 20 μ L 0.5mg/ml's
After continuing 1~4h of incubation, culture solution is sucked out in MTT, and the DMSO of 100 μ L is added in every hole.Sufficiently oscillation mix, in microplate reader in
The absorbance OD value that every hole is measured at 570nm (absorbing wavelength), is calculated with OD570.Inhibitory rate of cell growth is counted as the following formula
It calculates:
The IC50 of every plant of cell is measured under above-mentioned similarity condition, every plant of cell experiment is continuously repeated three times, is averaged.
The results are shown in Table 3 for it, and wherein it is living to show extracorporeal anti-tumor more better than jamaicin and adriamycin for compound 1,2 and 5
Property, compound 1, which is directed to stomach cancer cell BGC-823, extraordinary inhibiting effect, and it is thin that compound 2 is directed to people's Colon and rectum gland cancer
Born of the same parents HCT-15 has extraordinary inhibiting effect, and compound 5 has extraordinary inhibiting effect to colon cancer cell SW-480.
The half-inhibitory concentration of 3. berberine hydrochloride of table and 1,2,5 and 6 pair of compound different tumour cells
Claims (5)
1. a kind of rhamnose or the berberine salt derivative of ribose modification, which is characterized in that shown in its structural formula such as formula (I):
Wherein, R is
2. a kind of rhamnose according to claim 1 or the berberine salt derivative of ribose modification, which is characterized in that R is
3. the preparation method of a kind of rhamnose or the berberine salt derivative of ribose modification, which is characterized in that when R isWhen, comprising the following steps:
9- Carboxvmethoxv berberine hydrochloride and amino sugar are dissolved in the first solvent, open stirring, contracting is added at 0~40 DEG C
Mixture and organic base, reaction are stirred 1~12 hour at 0~40 DEG C, and vacuum distillation removes the first solvent, and obtained solid residue is used
Second solvent recrystallization, obtains yellow powdery solid, which is dissolved in third solvent, inorganic base is added, reaction solution is 0~40
It is stirred 0.5~10 hour at DEG C, vacuum distillation removes third solvent, and obtained solid residue obtains yellow powder with recrystallizing methanol
Solid, as target product；
Wherein the molar ratio of 9- Carboxvmethoxv berberine hydrochloride, amino sugar, condensing agent, organic base and inorganic base be 1:1~
3:1~3:0.1~1:0.1~3；
The amino sugar is
First solvent is N,N-dimethylformamide or/and methylene chloride；
Condensing agent is N, N- dicyclohexylcarbodiimide or 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate；
Organic base is triethylamine or N, N- diisopropylethylamine；
Second solvent is methanol, ethyl alcohol or acetonitrile；
Inorganic base is sodium hydroxide or potassium hydroxide；
Third solvent is made of the methylene chloride that volume ratio is 1:3~10:1 and low-carbon alcohols, and wherein low-carbon alcohols are methanol or ethyl alcohol.
4. the preparation method of a kind of rhamnose according to claim 3 or the berberine salt derivative of ribose modification, special
Sign is, 9- Carboxvmethoxv berberine hydrochloride, amino sugar, condensing agent, organic base and inorganic base molar ratio be 1:2:
1.2:0.1:0.2.
5. the preparation method of a kind of rhamnose according to claim 3 or the berberine salt derivative of ribose modification, special
Sign is that third solvent is made of the methylene chloride that volume ratio is 1:1 and methanol.
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