CN104725393A - Bergenin derivative as well as preparation method and application thereof - Google Patents
Bergenin derivative as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to the field of medicines and particularly relates to a bergenin derivative as well as a preparation method and application thereof. The bergenin derivative disclosed by the invention has a structure shown in the specification, wherein R1 represents one of a benzene ring, differently-substituted phenyl and pyridine and differently-substituted pyridine and aliphatic chain. The derivative is a dihydroisocoumarin type compound; the structure has one lactonic ring and can be applied to an anticancer drug.
Description
Technical field
The present invention relates to field of medicaments, particularly a kind of derivative of Bergeninum, preparation method and application.
Background technology
Cancer (Cancer) is one of serious disease of current harm humans life and health, and current chemotherapy is still one of its essential therapeutic arsenals.Since eighties of last century the nineties, the whole world has had more than 200 to plant cancer therapy drug to be in research and development, and existing tens of kinds of chemotherapy or ancillary drug are used for clinical treatment, but most drug can only mitigate the disease.And existing antitumor drug great majority are chemical synthetic drugs, there is the problems such as large, the easy generation resistance of toxic side effect.So from occurring in nature find high-efficiency low-toxicity natural anti-cancer tumor promotion compound or carry out structure of modification synthesize its derivative just become current antineoplastic medicine research an important trend.
Bergeninum (bergemn) is the main active ingredient in natural phant Rhizome or herb of Purple Bergenia, it is a kind of Dihydroiso-coumarin compounds, having a lactonic ring in structure, be also present in other plant except Rhizome or herb of Purple Bergenia, is a kind of natural monomers compound rich and easy to get.Bergeninum of the present invention is separated to obtain from natural phant Rodgersia podophylla A. Gray, now having isolated finished product (can reference: Wang Junping, Li Baihua. the assay [J] of Bergeninum in Rodgersia podophylla A. Gray. Chinese patent medicine, 1991,13 (2): 31-32.).Shown in the following structural formula of its concrete structure:
The application designs, has synthesized the bergenin derivative of a series of novel structure, and tested by cell levels anti-tumor activity, we find that this compounds has good anti-tumor activity, it is desirable to develop into the new superior drug for cancer.
Summary of the invention
The first object of the present invention is to provide a kind of derivative of Bergeninum.
For achieving the above object, the technical scheme that concrete employing is following:
A derivative for Bergeninum, has following structure,
Wherein, R
1for the one in phenyl ring, different phenyl, pyridine, the different pyridyl that replaces or the aliphatic chain replaced.
Preferably, R
1for at least one hydrogen atom on phenyl ring, phenyl ring is by CH
3-O-,-CN ,-NO
2, halogen or C1-C4 alkyl phenyl, pyridine, at least one hydrogen atom of the replacing pyridyl, ester group, the alkyl of C1-C5 or the aliphatic chain of hydroxyl that are optionally substituted by halogen in one.
More preferably, R
1for a hydrogen atom on phenyl ring, phenyl ring is by CH
3-O-,-CN ,-NO
2,-F or C1-C4 the alkyl phenyl, pyridine, the hydrogen atom that the replace pyridyl, ester group, the alkyl of C4-C5 or the aliphatic chain of hydroxyl that are replaced by-Cl in one.
Preferred forms the most of the present invention, the derivative of Bergeninum has following structure:
(1), compound 1
introduce alkynyl products therefrom on the phenyl of Bergeninum;
(2), formula I
in formula I, R
1for
-CH
2cH (CH
3)
2,-CH
2cH
2cH
2cH
2cH
3,-COOCH
3,-CH
2cOOCH
3, CH
2cH
2cOOCH
2cH
3or-CH
2one in OH, is called compound 2 ~ 17 below successively.
Another object of the present invention there is provided the preparation method of bergenin derivative, concrete, and the preparation method of compound 1 comprises the following steps:
(1) by Bergeninum, KI and K
2cO
3join in reaction solvent, wherein, Bergeninum in molar ratio: KI:K
2cO
3for 1:(2 ~ 5): (2 ~ 5), be stirred to and dissolve completely, add 3-propargyl bromide, 3-propargyl bromide in molar ratio: Bergeninum is (2 ~ 5): 1, under room temperature to 100 DEG C condition, whether reaction is to transforming completely (transform to be detected by TLC completely and determine);
(2) in the reaction system of step (1) gained, add ethyl acetate and distilled water extracts to obtain organic phase, the water washing of described organic phase saturated common salt, then uses anhydrous Na SO
4powder for drying;
(3) by step (2) products therefrom after filtration, concentrated, with silica gel column chromatography separating purification, during purifying, volume ratio is that the sherwood oil of 5:1 ~ 1:1 and the mixing solutions of ethyl acetate carry out wash-out, and namely concentrate eluant obtains compound 1.
Concrete, the one in step (1) described solvent selected from acetone, DMF or NMP (N-Methyl pyrrolidone), wherein when NMP selected by solvent, best results.The add-on of solvent is best with complete sample dissolution.Reaction solvent NMP boiling point is 203 DEG C, is difficult to distillation removing, and good with water-soluble, and can directly add water extraction removing.
In step (2), ethyl acetate by volume: distilled water: solvent is (5 ~ 10): (5 ~ 10): 1.
In step (2), saturated aqueous common salt by volume: solvent is (3 ~ 5): 1.
In step (2), add anhydrous Na SO
4the amount of powder is 1:10 ~ 1:15 with separating organic phasor by weight (g/g).
In step (2), preferred time of drying is 15 ~ 30min.
As a kind of embodiment of the best, the preparation method of compound 1 comprises the following steps:
(1) by 1mmol Bergeninum, 3mmol KI and 2mmolK
2cO
3join in 3mL NMP, stirring at room temperature is dissolved completely to sample, then adds 3mmol 3-propargyl bromide, reacts 4h under 60 DEG C of conditions;
(2), directly add the distilled water extraction of 15mL ethyl acetate and 15mL in step (1) gained reaction system after, obtain organic phase, the saturated common salt water washing of described organic phase 10mL, then uses anhydrous Na SO
4powder for drying 15 ~ 30min;
(3) by step (2) products therefrom after filtration, concentrated, with silica gel column chromatography separating purification, carry out wash-out by petrol ether/ethyl acetate 1/1 (V/V) during purifying, namely concentrate eluant obtains compound 1 (single white powder).
Technical scheme of the present invention, shown in the following reaction formula of reaction mechanism of the bergenin derivative (compound 2-17) representated by formula I:
Namely the phenyl first utilizing Bergeninum to prepare Bergeninum is replaced by 3-propargyl bromide and obtains compound 1, then utilize the bergenin derivative that compound 1 and triazo-compound utilize click chemistry raw material reaction to obtain representated by formula I.
Current click chemistry reaction mainly contains 4 types: the reaction of cycloaddition reaction, nucleophilic ring opening, the carbonylation of non-alcohol aldehyde and the addition reaction of carbon carbon multikey.The click chemistry reaction of current widespread use is by Cu (I) or Cu (II) catalysis, and alkynyl and azido-react formation zone optionally 1,2,3-triazole.
Concrete, the bergenin derivative utilizing compound 1 (alkynylation products of Bergeninum) and triazo-compound to prepare representated by formula I specifically comprises the following steps: in reaction vessel, add compound 1 and triazo-compound, compound 1 in molar ratio: triazo-compound is 1:(2 ~ 5), then add CuSO
45H
2o and sodium ascorbate, by weight compound 1:CuSO
45H
2o: sodium ascorbate is (0.1 ~ 0.2): (0.1 ~ 0.2): 1, finally adds THF and the H that volume ratio is 1:1 ~ 1:5
2the mixed solvent of O or volume ratio are t-BuOH and the H of 1:1 ~ 1:5
2the mixed solvent of O, makes sample fully dissolve, and carries out 1,3-Dipolar Cycloaddition under room temperature to 100 DEG C condition, namely obtains the bergenin derivative representated by formula I after reaction 0.5 ~ 5h.
As a kind of concrete embodiment, the bergenin derivative utilizing the alkynylation products of Bergeninum and triazo-compound to prepare representated by formula I specifically comprises the following steps:
Get 0.1mmol compound 1 with 0.25mmol triazo-compound in the round-bottomed flask of 25mL drying, add the CuSO of 5mg
45H
2the sodium ascorbate of O, 5mg, at 3mLTHF-H
2o (V/V=1/1) or 3mL t-BuOH-H
2the bergenin derivative representated by 1,3-Dipolar Cycloaddition and formula I is carried out under normal temperature condition in O (V/V=1/1) solvent.
The alkynylation products of described Bergeninum can adopt preparation method provided by the invention to be prepared.
Described triazo-compound can select any products of the prior art, is preferably prepared by following preparation method and obtains.
The preparation method of triazo-compound comprises the following steps:
(1) in reaction vessel, add halogenated compound and sodiumazide, in molar ratio halogenated compound: sodiumazide is 1:1 ~ 1:5, then add DMF and sample is fully dissolved, under 25 ~ 100 DEG C of conditions, react 0.5 ~ 12h;
(2) reaction terminates to add ether in backward reaction solution and distilled water extracts, and organic phase saturated common salt water washing, separates organic phase, use anhydrous Na SO
4drying, filters, concentrates and obtain triazo-compound.
Concrete, halogenated compound described in step (1) be selected from cylite, 4-methyl benzyl chloride, 4-ethyl benzyl chloride, 4-tertiary butyl benzyl chloride, to methoxyl group benzyl chloride, to fluorobenzyl chloride, to the one in cyano group benzyl chloride, p-nitrobenzyl chloride, CCMP, 2-chloromethylpyridine, 1-bromo iso-pentane, bromohexane, methyl bromoacetate, 3-methyl bromide c, 4-bromobutyrate or ethylene bromohyrin.
In step (2), ether by volume: distilled water: DMF is (5 ~ 10): (5 ~ 10): 1.
In step (2), saturated aqueous common salt by volume: DMF is (3 ~ 5): 1.
In step (2), anhydrous Na SO
4the add-on of powder is 1:10 ~ 1:15 with separating organic phasor by weight (g/g).
In step (2), preferred time of drying is 15 ~ 30min.
The present invention with a kind of with Bergeninum rich and easy to get for raw material, the design and synthesis bergenin derivative of a series of novel structure, this analog derivative is Dihydroiso-coumarin compounds, there is in structure a lactonic ring, have and significantly suppress esophageal carcinoma 9706 cells, gastric cancer cell line MGC-803, Melanoma B16 cell propagation, Clone formation, cell cycle and apoptotic effect, can be applied in cancer therapy drug.
Embodiment
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.
Embodiment 1: the preparation of compound 1
(1) 1mmol Bergeninum and 3mmol KI, 2mmolK is got
2cO
3in reaction solvent 3mL NMP, stirring at room temperature is dissolved completely to sample, then adds 3mmol 3-propargyl bromide, reacts 4h under 60 DEG C of conditions, detects through TLC, and reaction terminates.
(2) after directly adding the distilled water extraction of 15mL ethyl acetate and 15mL in the reaction system obtained to (1), the saturated common salt water washing of organic layer 10mL.Organic phase anhydrous Na SO
4powder for drying 15 ~ 30min.
(3) by step (2) products therefrom after filtration, concentrated, with silica gel column chromatography separating purification, petrol ether/ethyl acetate 1/1 (V/V) carries out wash-out, and elution fraction concentrates and obtains single desired product as white powder.Productive rate is 66.7%.
Warp
1h NMR detects, and the structural characterization of compound 1 is as follows:
1H NMR(400MHz,DMSO-d
6,ppm,TMS)δ7.49(s,1H),5.60(d,J＝5.8Hz,1H),5.31(d,J＝5.2Hz,1H),4.94(s,2H),4.85(d,J＝10.4Hz,1H),4.68(t,J＝11.3Hz,2H),4.51(s,1H),3.92(t,J＝9.7Hz,1H),3.86(s,3H),3.65(s,2H),3.53(s,2H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 1.
Embodiment 2: the preparation of compound 2
1, triazo-compound is prepared
Get 1mmol cylite and 2mmol sodiumazide in the round-bottomed flask of 5mL drying, add 2mL DMF, react 10h under 30 DEG C of conditions, TLC detection reaction terminates.The distilled water adding 10mL ether and 10mL in reaction solution extracts, the saturated common salt water washing of organic phase 6mL, organic over anhydrous NaSO
4dry 15 ~ 30min, filters, the triazo-compound that concentrated benzyl replaces.
2, click chemistry principle is utilized to prepare compound 2
Get triazo-compound that 0.1mmol compound 1 (40.2mg) and 0.25mmol benzyl replace in the round-bottomed flask of 25mL drying, add the CuSO of 5mg
45H
2the sodium ascorbate of O, 5mg, at 3mL THF-H
2o (V/V=1/1) or 3mL t-BuOH-H
2carry out 1,3-Dipolar Cycloaddition under normal temperature condition in O (V/V=1/1) solvent and namely generate compound 2, productive rate is 86.9%.
Warp
1h NMR detects, and the structural characterization of compound 2 is as follows:
1H NMR(400MHz,DMSO-d
6,ppm,TMS)δ8.30(s,1H),8.27(s,1H),7.56(s,1H),7.40-7.25(m,10H),5.63(s,2H),5.61(s,2H),5.34(d,J＝5.5Hz,1H),5.25(s,2H),5.07(q,J＝11.3Hz,2H),4.89(t,J＝5.8Hz,1H),4.76(d,J＝10.3Hz,1H),4.02(q,J＝7.1Hz,1H),3.91(t,J＝ 9.9Hz,1H),3.72(s,3H),3.37(s,2H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 2.
Embodiment 3: the preparation of compound 3
The preparation method of compound 3 and the preparation method of compound 2 its distinguish and be only, utilize 4-methyl benzyl chloride and reaction of sodium azide to prepare and produce 4-methyl-benzyl nitrine.Productive rate when utilizing click chemistry principle to prepare compound 3 is 88.8%.
Warp
1h NMR detects, and the structural characterization of compound 3 is as follows:
1H NMR(400MHz,CD
3OD)δ8.02(s,1H),7.94(s,1H),7.51(s,1H),7.15(dd,J＝14.2,10.1Hz,8H),5.51(s,2H),5.47(s,2H),5.15(d,J＝11.5Hz,1H),5.05(d,J＝11.5Hz,1H),4.46(d,J＝10.3Hz,1H),3.88-3.77(m,2H),3.76(s,3H),3.68(dd,J＝11.4,6.6Hz,1H),3.39(dd,J＝18.1,9.8Hz,1H),3.29(s,2H),2.28(s,6H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 3.
Embodiment 4: the preparation of compound 4
The preparation method of compound 4 and the preparation method of compound 2 its distinguish and be only, utilize 4-ethyl benzyl chloride and reaction of sodium azide to prepare and produce 4-Ethylbenzyl nitrine.Productive rate when utilizing click chemistry principle to prepare compound 4 is 91.3%.
Warp
1h NMR detects, and the structural characterization of compound 4 is as follows:
1H NMR(400MHz,CD
3OD)δ8.02(s,1H),7.96(s,1H),7.52(s,1H),7.19-7.14(m,8H),5.60(d,J＝11.3Hz,1H),5.52(s,2H),5.49(s,2H),5.18(s,2H),5.05(d,J＝11.4Hz,1H),4.52(d,J＝10.2Hz,1H),3.90-3.81(m,2H),3.76(s,3H),3.40(t,J＝6.7Hz,2H),3.34(s,2H),2.59(q,J＝7.6Hz,4H),1.17(t,J＝7.6Hz,6H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 4.
Embodiment 5: the preparation of compound 5
The preparation method of compound 5 and the preparation method of compound 2 its distinguish and be only, utilize 4-tertiary butyl benzyl chloride and reaction of sodium azide to prepare and produce 4-t-butylbenzyl nitrine.Productive rate when utilizing click chemistry principle to prepare compound 5 is 80.8%.
Warp
1h NMR detects, and the structural characterization of compound 5 is as follows:
1H NMR(400MHz,Acetone,ppm,TMS)δ8.17(s,2H),7.59(s,1H),7.39(dd,J＝8.5,3.4Hz,4H),7.27(dd,J＝13.5,8.5Hz,4H),5.59(s,4H),5.27(s,2H),5.16(d,J＝10.8Hz,1H),5.06(d,J＝10.8Hz,1H),4.69(d,J＝10.3Hz,1H),3.96-3.90(m,2H),3.80(s,3H),3.75(dd,J＝12.5,5.0Hz,1H),3.47(d,J＝7.9Hz,1H),3.40(s,2H),1.26(s,18H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 5.
Embodiment 6: the preparation of compound 6
The preparation method of compound 6 and the preparation method of compound 2 its distinguish and be only, utilize to prepare methoxyl group benzyl chloride and reaction of sodium azide and produce methoxy-benzyl nitrine.Productive rate when utilizing click chemistry principle to prepare compound 6 is 91.7%.
Warp
1h NMR detects, and the structural characterization of compound 6 is as follows:
1H NMR(400MHz,Acetone,ppm,TMS)δ8.14(s,1H),8.12(s,1H),7.55(s,1H),7.34-7.26(m,4H),6.92-6.87(m,4H),5.55(s,2H),5.53(s,2H),5.26(s,2H),5.18-4.99(m,2H),4.62(d,J＝10.3Hz,1H),4.03(q,J＝7.1Hz,1H),3.95-3.91(m,1H),3.91-3.88(m,1H),3.79(s,3H),3.75(s,3H),3.75(s,3H),3.72(d,J＝4.8Hz,1H),3.43(s,2H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 6.
Embodiment 7: the preparation of compound 7
The preparation method of compound 7 and the preparation method of compound 2 its distinguish and be only, utilize to prepare fluorobenzyl chloride and reaction of sodium azide and produce luorobenzyl nitrine.Productive rate when utilizing click chemistry principle to prepare compound 7 is 96.3%.
Warp
1h NMR detects, and the structural characterization of compound 7 is as follows:
1H NMR(400MHz,Acetone,ppm,TMS)δ8.22(s,1H),8.21(s,1H),7.57(s,1H),7.47-7.37(m,4H),7.13(ddd,J＝8.8,6.0,3.4Hz,4H),5.65(s,2H),5.64(s,2H),5.28(s,2H),5.19-5.02(m,2H),4.69(d,J＝ 10.3Hz,1H),4.03(q,J＝7.1Hz,1H),3.95(t,J＝7.6Hz,1H),3.93-3.89(m,1H),3.81(s,3H),3.74(dd,J＝12.5,5.0Hz,1H),3.41(s,2H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 7.
Embodiment 8: the preparation of compound 8
The preparation method of compound 8 and the preparation method of compound 2 its distinguish and be only, utilize to prepare cyano group benzyl chloride and reaction of sodium azide and produce cyanobenzyls nitrine.Productive rate when utilizing click chemistry principle to prepare compound 8 is 74.7%.
Warp
1h NMR detects, and the structural characterization of compound 8 is as follows:
1H NMR(400MHz,DMSO-d
6,ppm,TMS)δ8.35(s,1H),8.31(s,1H),7.84(dd,J＝7.8,3.6Hz,4H),7.56(s,1H),7.47-7.39(m,4H),5.75(s,2H),5.74(s,2H),5.59(d,J＝4.6Hz,1H),5.27(s,2H),5.08(q,J＝11.3Hz,2H),4.79(s,1H),3.91(t,J＝9.9Hz,1H),3.74(s,3H),3.65(d,J＝5.0Hz,1H),3.60-3.53(m,1H),3.33(s,2H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 8.
Embodiment 9: the preparation of compound 9
The preparation method of compound 9 and the preparation method of compound 2 its distinguish and be only, utilize p-nitrobenzyl chloride and reaction of sodium azide to prepare and produce nitrobenzyl nitrine.Productive rate when utilizing click chemistry principle to prepare compound 9 is 74.4%.
Warp
1h NMR detects, and the structural characterization of compound 9 is as follows:
1H NMR(400MHz,DMSO-d
6,ppm,TMS)δ8.36(s,1H),8.33(s,1H),8.24(d,J＝2.4Hz,2H),8.22(d,J＝2.4Hz,2H),7.56(s,1H),7.51(t,J＝9.1Hz,4H),5.82(s,2H),5.80(s,2H),5.58(d,J＝5.2Hz,1H),5.29(s,3H),5.08(q,J＝11.4Hz,2H),4.78(d,J＝2.8Hz,1H),3.91(t,J＝9.9Hz,1H),3.75(s,2H),3.64(dd,J＝13.9,8.8Hz,1H),3.59-3.52(m,1H),3.32(s,2H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 9.
Embodiment 10: the preparation of compound 10
The preparation method of compound 10 and the preparation method of compound 2 its distinguish and be only, utilize CCMP and reaction of sodium azide to prepare and produce 2-chloro-5-azido-methyl pyridine.Productive rate when utilizing click chemistry principle to prepare compound 10 is 62.8%.
Warp
1h NMR detects, and the structural characterization of compound 10 is as follows:
1H NMR(400MHz,Acetone,ppm,TMS)δ8.46(s,1H),8.46(s,1H),8.31(s,2H),7.82(td,J＝8.2,2.6Hz,2H),7.57(s,1H),7.47(dd,J＝8.3,3.3Hz,2H),5.76(s,2H),5.76(s,2H),5.30(s,2H),5.19-5.04(m,2H),4.74(d,J＝10.3Hz,1H),4.03(q,J＝7.1Hz,1H),4.00-3.94(m,1H),3.91(dd,J＝12.4,1.7Hz,1H),3.81(s,3H),3.74(dd,J＝12.4,5.2Hz,1H),3.41(s,2H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 10.
Embodiment 11: the preparation of compound 11
The preparation method of compound 11 and the preparation method of compound 2 its distinguish and be only, utilize 2-chloromethylpyridine and reaction of sodium azide to prepare and produce 2-azido-methyl pyridine.Productive rate when utilizing click chemistry principle to prepare compound 11 is 71.2%.
Warp
1h NMR detects, and the structural characterization of compound 11 is as follows:
1H NMR(400MHz,C
5D
5N,ppm,TMS)δ8.79(s,2H),8.66-8.61(m,3H),8.53(s,1H),8.07(s,1H),7.63(s,1H),7.61-7.54(m,2H),7.25-7.20(m,1H),7.15(ddd,J＝18.6,7.5,4.9Hz,2H),5.93(s,2H),5.89(s,2H),5.68(d,J＝11.0Hz,1H),5.55(d,J＝11.0Hz,1H),5.50(s,2H),5.12(d,J＝10.2Hz,1H),4.76-4.70(m,1H),4.63(t,J＝9.8Hz,1H),4.53(d,J＝8.4Hz,1H),4.41-4.35(m,1H),4.02(s,3H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 11.
Embodiment 12: the preparation of compound 12
The preparation method of compound 12 and the preparation method of compound 2 its distinguish and be only, utilize 1-bromo iso-pentane and reaction of sodium azide to prepare and produce 1-nitrine iso-pentane.Productive rate when utilizing click chemistry principle to prepare compound 12 is 76.5%.
Warp
1h NMR detects, and the structural characterization of compound 12 is as follows:
1H NMR(400MHz,CD
3OD)δ8.12(s,1H),8.07(s,1H),7.57(s,1H),5.24(s,2H),5.16(d,J＝11.1Hz,1H),5.08(d,J＝11.2Hz,1H),4.68(d,J＝10.4Hz,1H),4.43(dd,J＝16.3,7.6Hz,4H),4.00-3.93(m,1H),3.86(s,3H),3.81-3.73(m,2H),3.45(dd,J＝15.5,7.5Hz,1H),3.29(s,2H),1.83-1.72(m,4H),1.48(ddd,J＝18.2,13.4,6.7Hz,2H),0.94(t,J＝6.3Hz,12H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 12.
Embodiment 13: the preparation of compound 13
The preparation method of compound 13 and the preparation method of compound 2 its distinguish and be only, utilize bromohexane and reaction of sodium azide to prepare and produce nitrine hexane.Productive rate when utilizing click chemistry principle to prepare compound 13 is 87.8%.
Warp
1h NMR detects, and the structural characterization of compound 13 is as follows:
1H NMR(400MHz,CD
3OD)δ8.11(s,1H),8.08(s,1H),7.61(s,1H),5.27(s,2H),5.18(d,J＝11.1Hz,1H),5.11(d,J＝11.2Hz,1H),4.72(d,J＝10.4Hz,1H),4.41(q,J＝7.3Hz,4H),4.02-3.91(m,2H),3.87(s,3H),3.82-3.78(m,1H),3.47(d,J＝7.9Hz,1H),3.31(s,2H),1.95-1.83(m,4H),1.29(dd,J＝13.1,10.9Hz,12H),0.88(dd,J＝8.7,4.3Hz,6H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 13.
Embodiment 14: the preparation of compound 14
The preparation method of compound 14 and the preparation method of compound 2 its distinguish and be only, utilize methyl bromoacetate and reaction of sodium azide to prepare and produce 4-nitrine ethyl butyrate.Productive rate when utilizing click chemistry principle to prepare compound 14 is 91.6%.
Warp
1h NMR detects, and the structural characterization of compound 14 is as follows:
1H NMR(400MHz,DMSO-d
6)δ8.25(s,1H),8.23(s,1H),7.59(s,1H),5.61(s,1H),5.45(s,2H),5.43(s,2H),5.29(s,2H),5.15-5.04(m, 2H),4.87-4.75(m,2H),3.94(t,J＝9.8Hz,1H),3.79(s,1H),3.76(s,3H),3.72(s,6H),3.35(s,2H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 14.
Embodiment 15: the preparation of compound 15
The preparation method of compound 15 and the preparation method of compound 2 its distinguish and be only, utilize 3-methyl bromide c and reaction of sodium azide to prepare and produce 3-nitrine methyl propionate.Productive rate when utilizing click chemistry principle to prepare compound 15 is 68.1%.
Warp
1h NMR detects, and the structural characterization of compound 15 is as follows:
1H NMR(400MHz,Acetone,ppm,TMS)δ8.15(s,1H),8.15(s,1H),7.59(s,1H),5.29(s,2H),5.15(d,J＝10.8Hz,1H),5.06(d,J＝10.8Hz,1H),4.71(ddd,J＝8.1,7.1,3.7Hz,4H),4.00(t,J＝9.8Hz,1H),3.93(dd,J＝12.4,1.7Hz,1H),3.86(s,3H),3.82(d,J＝9.1Hz,1H),3.76(dd,J＝12.4,5.4Hz,1H),3.63(s,3H),3.62(s,3H),3.48(d,J＝8.4Hz,1H),3.41(s,2H),3.03(td,J＝6.6,2.2Hz,4H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 15.
Embodiment 16: the preparation of compound 16
The preparation method of compound 16 and the preparation method of compound 2 its distinguish and be only, utilize 4-bromobutyrate and reaction of sodium azide to prepare and produce 4-nitrine ethyl butyrate.Productive rate when utilizing click chemistry principle to prepare compound 16 is 68.1%.
Warp
1h NMR detects, and the structural characterization of compound 16 is as follows:
1H NMR(400MHz,Acetone,ppm,TMS)δδ8.62(s,2H),8.06(s,1H),5.76(s,2H),5.64(d,J＝10.8Hz,1H),5.54(d,J＝10.8Hz,1H),5.21(d,J＝10.3Hz,1H),4.95(td,J＝6.9,1.5Hz,4H),4.52(q,J＝7.1Hz,4H),4.47-4.41(m,1H),4.39(dd,J＝12.4,1.8Hz,1H),4.34(s,3H),4.31-4.26(m,1H),4.22(dd,J＝12.4,5.3Hz,1H),3.69(s,2H),2.78(dt,J＝11.6,7.2Hz,4H),2.64(td,J＝7.0,4.7Hz,4H),1.64(t,J＝7.1Hz,6H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 16.
Embodiment 17: the preparation of compound 17
The preparation method of compound 17 and the preparation method of compound 2 its distinguish and be only, utilize ethylene bromohyrin and reaction of sodium azide to prepare and produce 2-nitrine ethanol.Productive rate when utilizing click chemistry principle to prepare compound 17 is 68.2%.
Warp
1h NMR detects, and the structural characterization of compound 17 is as follows:
1H NMR(400MHz,D
2O)δ8.01(s,1H),7.91(s,1H),7.28(s,1H),5.01(s,2H),4.85(s,2H),4.49(d,J＝10.3Hz,1H),4.44-4.31(m,4H),3.87(s,1H),3.85-3.78(m,4H),3.70(s,2H),3.62(d,J＝9.5Hz,1H),3.59(s,3H).3.35(d,J＝4.9Hz,2H).
The data that nuclear-magnetism detects above describe by analysis and generate target product 17.
Experimental example:
First we carried out the screening of In Vitro Anti tumor cell viability to synthesized compound.
1, test philosophy
Mtt assay full name is 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-Tetrazolium bromide, Chinese chemistry 3-(4 by name, 5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt (trade(brand)name: tetrazolium bromide) is a kind of dyestuff of yellow color.Succinodehydrogenase in viable cell plastosome can make exogenous MTT be reduced to water-insoluble bluish voilet crystallization first a ceremonial jade-ladle, used in libation (Formazan) and be deposited in cell, and dead cell is without this function.First a ceremonial jade-ladle, used in libation in dimethyl sulfoxide (DMSO) (DMSO) energy dissolved cell, measures its absorbance value (also useful 570nm wavelength) with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, can indirectly reflect viable cell quantity.Within the scope of certain cell count, the amount that MTT crystallization is formed is directly proportional to cell count.
2, instrument, reagent, material and given the test agent
Instrument: Bechtop, CO
2incubator, Multi-functional inverted microscope, whizzer, automatic microplate reader, 96 well culture plates.
Reagent: DMEM, 1640 substratum, 10% deactivation calf serum (FBS), PBS lysate, dimethyl sulfoxide (DMSO) (DMSO), three liquid (10%SDS+5% Virahol+12 mMHCl), tetrazolium bromide (MTT).
Material (cell strain): human esophagus cancer EC9706 tumour cell, Gastric Cancer MGC-803 tumour cell, melanin tumour b16 tumour cell.
Given the test agent: (Bergeninum of the present invention is separated to obtain from natural phant Rodgersia podophylla A. Gray, now isolates finished product for the compound 1-17 of the application and Bergeninum.Can reference: Wang Junping, Li Baihua. the assay [J] of Bergeninum in Rodgersia podophylla A. Gray. Chinese patent medicine, 1991,13 (2): 31-32.).
3, experimental technique
Sample preparation: get given the test agent DMSO dissolved compound, ultrasonic dissolution, concentration 100mM/L, gained drug solution can store under-20 DEG C of conditions.
The MTT experiment of attached cell: attached cell comprises human esophagus cancer EC9706 tumour cell, Gastric Cancer MGC-803 tumour cell, melanin tumour b16 tumour cell.
Collect logarithmic phase cell, suspend with complete DMEM substratum, and to adjust concentration of cell suspension be 3 × 10
4/ mL, inoculates 96 porocyte culture plates, 100 μ L/ holes.Put 37 DEG C, 5%CO
2incubator cultivates 24 hours, supernatant discarded, adds fresh complete DMEM substratum, 90 μ L/ holes, and adds different concns drug solution to be measured, 10 μ L/ holes, and each concentration establishes 3 multiple holes; Blank well adds DMEM substratum 10 μ L/ hole; This bottom outlet adds not celliferous substratum 100 μ L/ hole.Put 37 DEG C, 5%CO
2hatch 48 hours.Every hole adds 100 μ L MTT solution (0.5mg/mL, incomplete DMEM substratum preparation), continues to put incubator and hatches 4h.Stop after 4h cultivating, supernatant discarded, every hole adds 150 μ L dimethyl sulfoxide (DMSO), puts low-speed oscillation 5min on shaking table, crystallisate is fully dissolved.The light absorption value in each hole is measured at enzyme-linked immunosorbent assay instrument 570nm place.
4, experimental data method of calculation
Experimentally result, calculates the whole ICs quite close with regular method by point slope method principle
50relevant data.
Fundamental formular:
1.IC
50:IC
50＝Log
-1[X
m-i×(∑p–0.5)+i/4×(1-P
m-P
n)]
2. containing the LD of 0% and 100% mortality ratio
50:
IC
50＝Log
-1[X
m-i×(∑p–0.5)]
X in formula
mfor most high mortality P
mthe dosage logarithmic value of group, i is group distance, P
mfor most high mortality, P
nfor minimum mortality, n is number of animals in each group.
Activity Results is as follows:
Can see from above anti-tumor activity result, compound of the present invention all has significant cancer cell suppression activity, especially compound 4,5,7,9,11,12,13 pairs of EC9706 cells have good restraining effect, compound 5,15 pairs of MGC803 cells have strong restraining effect, compound 5,7,9 pairs of restraining effect that B16 cell has had.Compound of the present invention can be applied in the treatment metabolic trouble relevant to malignant tumour.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (9)
1. a derivative for Bergeninum, is characterized in that, has following structure,
Wherein, R
1for the one in phenyl ring, different phenyl, pyridine, the different pyridyl that replaces or the aliphatic chain replaced.
2. the derivative of Bergeninum according to claim 1, is characterized in that, R
1for at least one hydrogen atom on phenyl ring, phenyl ring is by CH
3-O-,-CN ,-NO
2, halogen or C1-C4 alkyl phenyl, pyridine, at least one hydrogen atom of the replacing pyridyl, ester group, the alkyl of C1-C5 or the aliphatic chain of hydroxyl that are optionally substituted by halogen in one.
3. the derivative of Bergeninum according to claim 1 and 2, is characterized in that, R
1for
-CH
2cH (CH
3)
2,-CH
2cH
2cH
2cH
2cH
3,-COOCH
3,-CH
2cOOCH
3, CH
2cH
2cOOCH
2cH
3or-CH
2one in OH.
4. the preparation method of bergenin derivative described in any one of claim 1-3, is characterized in that, the preparation method of compound 1 comprises the following steps:
(1) by Bergeninum, KI and K
2cO
3join in N-Methyl pyrrolidone reaction solvent, wherein, Bergeninum in molar ratio: KI:K
2cO
3for 1:(2 ~ 5): (2 ~ 5), are stirred to and dissolve completely, add 3-propargyl bromide, in molar ratio 3-propargyl bromide: Bergeninum is (2 ~ 5): 1, and under room temperature to 100 DEG C condition, reaction is to transforming completely;
(2) in the reaction system of step (1) gained, add ethyl acetate and distilled water extracts to obtain organic phase, the water washing of described organic phase saturated common salt, then uses anhydrous Na SO
4powder for drying;
(3) by step (2) products therefrom after filtration, concentrated, with silica gel column chromatography separating purification, during purifying, volume ratio is that the sherwood oil of 5:1 ~ 1:1 and the mixing solutions of ethyl acetate carry out wash-out, and namely concentrate eluant obtains compound 1.
5. the preparation method of bergenin derivative according to claim 4, is characterized in that, the one in step (1) described solvent selected from acetone, DMF or NMP.
6. the preparation method of the bergenin derivative according to any one of claim 4 or 5, is characterized in that, further comprising the steps of:
Compound 1 and triazo-compound is added, in molar ratio compound 1: triazo-compound is 1:(2 ~ 5 in reaction vessel), then add CuSO
45H
2o and sodium ascorbate, by weight compound 1:CuSO
45H
2o: sodium ascorbate is (0.1 ~ 0.2): (0.1 ~ 0.2): 1, finally adds THF and the H that volume ratio is 1:1 ~ 1:5
2the mixed solvent of O or volume ratio are t-BuOH and the H of 1:1 ~ 1:5
2the mixed solvent of O, makes sample fully dissolve, and carries out 1,3-Dipolar Cycloaddition under room temperature to 100 DEG C condition, namely obtains the bergenin derivative representated by formula I after reaction 0.5 ~ 5h.
7. the preparation method of bergenin derivative according to claim 6, is characterized in that, the preparation method of described triazo-compound comprises the following steps:
(1) in reaction vessel, add halogenated compound and sodiumazide, in molar ratio halogenated compound: sodiumazide is 1:1 ~ 1:5, then add DMF and sample is fully dissolved, under 25 ~ 100 DEG C of conditions, react 0.5 ~ 12h;
(2) reaction terminates to add ether in backward reaction solution and distilled water extracts, and organic phase saturated common salt water washing, separates organic phase, use anhydrous Na SO
4drying, filters, concentrates and obtain triazo-compound.
8. the preparation method of bergenin derivative according to claim 7, it is characterized in that, described halogenated compound be selected from cylite, 4-methyl benzyl chloride, 4-ethyl benzyl chloride, 4-tertiary butyl benzyl chloride, to methoxyl group benzyl chloride, to fluorobenzyl chloride, to the one in cyano group benzyl chloride, p-nitrobenzyl chloride, CCMP, 2-chloromethylpyridine, 1-bromo iso-pentane, bromohexane, methyl bromoacetate, 3-methyl bromide c, 4-bromobutyrate or ethylene bromohyrin.
9. the application of bergenin derivative in cancer therapy drug described in any one of claim 1-3.
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| CN114716450A (en) * | 2022-05-12 | 2022-07-08 | 中国药科大学 | Bergenin derivative and preparation method and application thereof |
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