CN102079692A - Terphenyl compound and preparation method of terphenyl compound and application of terphenyl compound as alpha-glucosidase inhibitor - Google Patents
Terphenyl compound and preparation method of terphenyl compound and application of terphenyl compound as alpha-glucosidase inhibitor Download PDFInfo
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- CN102079692A CN102079692A CN201010518447XA CN201010518447A CN102079692A CN 102079692 A CN102079692 A CN 102079692A CN 201010518447X A CN201010518447X A CN 201010518447XA CN 201010518447 A CN201010518447 A CN 201010518447A CN 102079692 A CN102079692 A CN 102079692A
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Abstract
The invention discloses a kind of terphenyl compounds and preparation method thereof and as the application of alpha-glucosidase restrainer. Shown in the structural formula of terphenyl compounds of the present invention such as formula (I), wherein R is H or OH. Terphenyl compounds of the present invention can be used for preparing alpha-glucosidase restrainer, for preventing and treating type-2 diabetes mellitus.
Description
Technical field
The present invention relates to the medical compounds preparation field, be specifically related to a kind of terphenyl compounds and preparation method thereof and as the application of alpha-glucosidase inhibitor.
Background technology
The threat of disease is particularly serious in the great number of issues that the mankind face, the penicillin that derives from secondary fungus metabolite of exploitation in last century play a part aspect antagonism disease, the maintaining healthy very important.Multiple other pharmaceutical uses such as that the meta-bolites of fungi has is antibiotic, antitumor, immunomodulatory, enzyme inhibition.Thalassiomycetes is because its growing environment has singularity such as high pressure, high salt, anoxic, in order to adapt to this habitat that is different from land, formed unique pathways metabolism, so for the generation of novel structure, the significant all kinds of secondary metabolites of physiologically active provides may.At present, from the marine microorganism that comprises thalassiomycetes, seek the focus that new medicine source has become international and domestic research.
Alpha-glucosidase is that a class can be from the general name of the alpha-glucose-based enzyme of the non-reducing end catalytic hydrolysis that contains α-Pu Taotang glycosidic bond substrate.Alpha-glucosidase is distributed widely in the organism, participates in the biosynthesizing of food digestion, glycoprotein, many bioprocesss such as the synthetic and katabolism of polysaccharide and saccharide complex.Alpha-glucosidase inhibitor is the novel oral antidiabetic drug of a class, its action principle is to suppress the glucuroide of small intestine epimere, the blocking-up carbohydrate breakdown becomes one glucose, undecomposed carbohydrate arrives the middle hypomere of small intestine, slowly absorbed in the blood again, therefore, blood sugar is not concentrated in the upper end absorption of small intestine and blood sugar is sharply increased, and can improve the peak of postprandial blood sugar.Studies confirm that alpha-glucosidase inhibitor can be prevented and treated postprandial hyperglycemia disease and alleviate hyperinsulinemia, can improve sugar tolerance simultaneously.Clinically, alpha-glucosidase inhibitor is used for the treatment of type ii diabetes.
Diabetes are geriatric disease, and along with the Chinese people mouth structure progressively enters aging society, the sickness rate of diabetes constantly rises, and develop new effective medicine, have great social effect.
Summary of the invention
The objective of the invention is to according to the deficiencies in the prior art, a kind of terphenyl compounds that can be used for preparing the alpha-glucosidase inhibitor medicine is provided.
Another purpose of the present invention is to provide the preparation method of above-mentioned terphenyl compounds.
A further object of the invention is to provide the application of above-mentioned terphenyl compounds.
Above-mentioned purpose of the present invention is achieved by the following technical programs:
Its structural formula of a kind of terphenyl compounds is suc as formula shown in (I), and wherein, R is H or OH, when compound 1 is H for R, and when compound 2 is OH for R,
Formula (I).
The preparation method of terphenyl derivative of the present invention comprises the steps:
(1) bacterial strain with the scarlet mould Penicillium of thalassiomycetes chermesinum ZH4-E2 inserts seed culture medium, shaking table is cultivated, (depositary institution of the scarlet mould Penicillium of described thalassiomycetes chermesinum ZH4-E2 is Chinese typical culture collection center to obtain seed culture fluid, the preservation address is a China. Wuhan. and Wuhan University, preserving number is CCTCC M 2010267, and preservation date is on October 15th, 2010);
(2) seed culture fluid is inserted in the fermention medium, leave standstill cultivation;
(3) the tunning filtration is obtained thalline and fermented liquid, fermented liquid obtains medicinal extract through concentrated, extraction, concentrating under reduced pressure, again through chromatographic separation, obtains terphenyl compounds.
As a kind of preferred version, among the above-mentioned preparation method, in the step (1), the component of described seed culture medium is: glucose 40g, peptone 4g, yeast extract paste 4g, sea salt 5g, water 2L.
As a kind of preferred version, among the above-mentioned preparation method, in the step (1), the component of described seed culture medium is: glucose 40g, peptone 4g, yeast extract paste 4g, sea salt 5g, water 2L.
As a kind of preferred version, among the above-mentioned preparation method, the component of fermention medium is described in the step (2): glucose 2200g, peptone 200g, yeast extract paste 200g, sea salt 250g, water 100L.
As a kind of preferred version, among the above-mentioned preparation method, the time of leaving standstill cultivation described in the step (2) is 30 days, and the temperature that leaves standstill cultivation is 28 ℃.
As a kind of preferred version, among the above-mentioned preparation method, concentrated solution described in the step (3) extraction is to be 1: 1 ethyl acetate extraction with volume ratio; Described medicinal extract separates with silica gel column chromatography, uses ethyl acetate-sherwood oil gradient elution of 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 100% respectively.
As a kind of preferred version, among the above-mentioned preparation method, partly separation obtains R to described 40% ethyl acetate-sherwood oil wash-out through preparation HPLC
1Be OH, R
2Terphenyl compounds (compound 1) for H; The chromatographic column of preparation HPLC is the ODS post, and moving phase is that volume ratio is 1: 1 a methanol-water, and the detection wavelength is 254nm; 50% ethyl acetate-sherwood oil wash-out part obtains R through recrystallization repeatedly
1Be H, R
2Terphenyl compounds (compound 2) for H.
Terphenyl compounds of the present invention has restraining effect to acetylcholinesterase, can be used for preparing alpha-glucosidase inhibitor, therefore can be used for preventing and treating type ii diabetes.
Compared with prior art, the present invention has following beneficial effect:
Terphenyl compounds of the present invention can be used for preventing and treating type ii diabetes.
Description of drawings
Fig. 1 is the single crystal structure figure of compound 1.
Embodiment
Further explain the present invention below in conjunction with embodiment, but embodiment does not do any type of qualification to the present invention.
Embodiment 1
Compound 1 of the present invention and 2 can separate obtaining from the fermented liquid of the scarlet mould Penicillium of thalassiomycetes chermesinumZH4-E2.The scarlet mould Penicillium of thalassiomycetes chermesinumZH4-E2 separates to obtain from the stem of Guangdong Zhanjiang sea area mangrove Kandelia candel.Concrete steps are as follows:
1. seed culture:
(1) preparation seed culture medium: glucose 40g, peptone 4g, yeast extract paste 4g, sea salt 5g, tap water 2000mL, average mark are loaded on 8 500mL Erlenmeyer flasks, and 121 ℃ went out 25 minutes.
(2) cultivation of seed: the bacterial strain of the scarlet mould Penicillium of thalassiomycetes chermesinum ZH4-E2 is inserted seed culture medium, under 28 ℃ temperature, puts on the shaking table with the rotating speed of 150rpm, cultivate 60 hours must seed culture fluid.
2. fermentation culture:
(1) preparation fermention medium: glucose 2200g, peptone 200g, yeast extract paste 200g, sea salt 250g, tap water 100L, 121 ℃ went out 25 minutes.
(2) fermentation culture:
In super clean bench, seed liquor 5mL access is equipped with in the Erlenmeyer flask of fermention medium, leaves standstill in 28 ℃ and cultivated 30 days.
3. extraction separation:
Fermented product filter thalline and fermented liquid, fermented liquid is concentrated into 20L being lower than under 50 ℃, the concentrated solution volume ratio is 1: 1 a ethyl acetate extraction, acetic acid ethyl acetate extract gets medicinal extract 24.5g being lower than 50 ℃ of following concentrating under reduced pressure.This medicinal extract separates through silica gel column chromatography, uses 5%, 10% respectively, 20%, 30%, 40%, 50%, 60%, 70%, 100% ethyl acetate-sherwood oil gradient elution, wherein partly separation obtains compound 1 (12mg) to 40% ethyl acetate-sherwood oil wash-out through preparation HPLC, the chromatographic column of preparation HPLC is the ODS post, and moving phase is methanol-water (1: 1), and the detection wavelength is 254nm; 50% ethyl acetate-sherwood oil wash-out part obtains compound 2 (18mg) through recrystallization repeatedly.
Embodiment 2
Compound among the embodiment 1 is carried out the structural analysis test, obtains following physico-chemical property data:
Compound 1: white crystal, fusing point＞300 ℃ (thermometer is not proofreaied and correct), EI-MS (m/z): 324[M]
+HR-EI-MS (m/z): 324.0990[M]
+(theoretical value 324.0992).
Compound 2: white crystal, fusing point 248-250 ℃ (thermometer is not proofreaied and correct), EI-MS (m/z): 340[M]
+, HR-EI-MS (m/z): 340.0944[M]
+(theoretical value 340.0941).
Compound 1 and 2 NMR data see Table 1.
Table 1 compound 1 and 2 NMR data (125MHz/400MHz, TMS, ppm)
Monocrystalline to compound 1 carries out monocrystalline-X diffraction analysis, records the crystalline structure and the data of compound 1:
Accompanying drawing 1 is the single crystal structure figure of compound 1.
The monocrystalline data of following compound 1:
Identification?code 1
Empirical?formula C15H14O6
Formula?weight 290.26
Temperature 110(2)K
Wavelength 0.71073A
Crystal?system，space?group Monoclinic，P2(1)/n
Unit?cell?dimensions a＝8.2622(17)A alpha＝90deg.
b＝12.062(2)A beta＝106.141(3)deg.
c＝13.212(3)A gamma＝90deg.
Volume 1264.8(4)A^3
Z，Calculated?density 4，1.524Mg/m^3
Absorption?coefficient 0.119mm^-1
F(000) 608
Crystal?size 0.46x0.45x0.21mm
Theta?range?for?data?collection 2.33?to?27.00deg.
Limiting?indices -10＜＝h＜＝9，-14＜＝k＜＝15，-16＜＝1＜＝16
Reflections?collected/unique 7414/2746[R(int)＝0.0198]
Completeness?to?theta＝27.00 99.5％
Absorption?correction None
Refinement?method Full-matrix?least-squares?on?F^2
Data/restraints/parameters 2746/0/190
Goodness-of-fit?on?F^2 1.053
Final?R?indices[I＞2sigma(I)] R1＝0.0415，wR2＝0.1145
R?indices(all?data) R1＝0.0528，wR2＝0.1242
Largest?diff.peak?and?hole 0.394?and-0.314e.A^-3
Embodiment 3
Compound among the embodiment 11,2 is carried out alpha-glucosidase suppresses experiment:
Adopting p-NP-alpha-glucosaccharase (pNPG) is substrate, carries out in 0.01M phosphoric acid buffer (pH7.0).PNPG is a p-NP by the alpha-glucosidase enzymolysis, measures the variation of its absorbancy with ultraviolet-visible spectrophotometer at 410nm wavelength place and calculates the activity of enzyme.Sample and positive control (genistein) all are made into DMSO solution (being 20 μ mol/mL), and enzyme and substrate are made into suitable concentration solution with the 0.01M phosphoric acid buffer, and 1mL initial reaction system includes the 0.8unit enzyme, 0.2 μ mol substrate, 10 μ L DMSO.Get an amount of enzyme liquid, add the DMSO solution of blank DMSO solution or sample, mixing left standstill 20 minutes, added substrate, mixing, the changing value of the absorbancy of system in 1min is detected at 410nm wavelength place immediately.Calculate enzymic activity with following formula: inhibiting rate (%)=[(B-S)/B] * 100%, wherein B is the absorbancy changing value when adding blank DMSO, S is the absorbancy changing value of sample.Measure the sample of 5 concentration, draw dosage-inhibiting rate curve, draw its IC
50Value.Each sample replication three times, the result represents with mean value ± standard deviation.
The result records this compound 1 and 2 pairs of alpha-glucosidases are inhibited, its IC
50Be respectively 0.90 ± 0.02 μ M and 4.91 ± 0.11 μ M.
Claims (10)
1. a terphenyl compounds is characterized in that structural formula suc as formula shown in (I), and wherein, R is H or OH,
Formula (I).
2. the preparation method of the described terphenyl compounds of claim 1 is characterized in that comprising the steps:
(1) bacterial strain with the scarlet mould Penicillium of thalassiomycetes chermesinum ZH4-E2 inserts seed culture medium, and shaking table is cultivated, and obtains seed culture fluid;
(2) seed culture fluid is inserted in the fermention medium, leave standstill cultivation;
(3) the tunning filtration is obtained thalline and fermented liquid, fermented liquid obtains medicinal extract through concentrated, extraction, concentrating under reduced pressure, again through chromatographic separation, obtains terphenyl compounds;
Wherein, the depositary institution of the scarlet mould Penicillium of described thalassiomycetes chermesinum ZH4-E2 is Chinese typical culture collection center C CTCC, and preserving number is CCTCC M 2010267, and preservation date is on October 15th, 2010.
3. according to the preparation method of the described terphenyl compounds of claim 2, it is characterized in that the component of described seed culture medium is in the step (1): glucose 40g, peptone 4g, yeast extract paste 4g, sea salt 5g, water 2L.
4. according to the preparation method of the described terphenyl compounds of claim 2, it is characterized in that in the step (1) that it is under 28 ℃ that described shaking table is cultivated, shaking speed 150rpm, incubation time are 60h.
5. according to the preparation method of the described terphenyl compounds of claim 2, it is characterized in that the component of fermention medium described in the step (2) is: glucose 2200g, peptone 200g, yeast extract paste 200g, sea salt 250g, water 100L.
6. according to the preparation method of the described terphenyl compounds of claim 2, the time that it is characterized in that leaving standstill described in the step (2) cultivation is 30 days, and the temperature that leaves standstill cultivation is 28 ℃.
7. according to the preparation method of the described terphenyl compounds of claim 2, it is characterized in that the extraction of concentrated solution described in the step (3) is is 1: 1 ethyl acetate extraction with volume ratio; Described medicinal extract separates with silica gel column chromatography, uses ethyl acetate-sherwood oil gradient elution of 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 100% respectively.
8. according to the preparation method of the described terphenyl compounds of claim 7, it is characterized in that partly separation obtains R to described 40% ethyl acetate-sherwood oil wash-out through preparation HPLC
1Be OH, R
2Terphenyl compounds for H; The chromatographic column of preparation HPLC is the ODS post, and moving phase is that volume ratio is 1: 1 a methanol-water, and the detection wavelength is 254nm; 50% ethyl acetate-sherwood oil wash-out part obtains R through recrystallization repeatedly
1Be H, R
2Terphenyl compounds for H.
9. the application of the described terphenyl compounds of claim 1 in the preparation alpha-glucosidase inhibitor.
10. according to the application of the described terphenyl compounds of claim 9, it is characterized in that described acetylcholinesterase depressant is used to prevent and treat type ii diabetes.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102126934A (en) * | 2011-01-13 | 2011-07-20 | 山东大学 | Paraterphenyl derivative and application thereof to preparation of antitumor medicaments |
| CN103804392A (en) * | 2014-02-19 | 2014-05-21 | 中国科学院微生物研究所 | Two terphenylzidioxazine derivatives and applications thereof |
| CN105175241A (en) * | 2015-08-28 | 2015-12-23 | 浙江工业大学 | Terphenyl compound and preparation method therefor and application thereof |
| CN115246803A (en) * | 2021-04-25 | 2022-10-28 | 中国科学院南海海洋研究所 | Terphenyl compounds and application thereof in preparation of anti-herpes virus medicines |
Citations (3)
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|---|---|---|---|---|
| US3254562A (en) * | 1961-10-26 | 1966-06-07 | Polaroid Corp | Process for polarizing ultraviolet light utilizing oriented, polyphenyl stained film |
| CN101376655A (en) * | 2008-10-11 | 2009-03-04 | 中国海洋大学 | Penicillazine derivative, and preparation and use thereof |
| WO2009112461A1 (en) * | 2008-03-11 | 2009-09-17 | Neurosearch A/S | Novel triaryl derivatives useful as modulators of nicotinic acetylcholine receptors |
-
2010
- 2010-10-22 CN CN201010518447.XA patent/CN102079692B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3254562A (en) * | 1961-10-26 | 1966-06-07 | Polaroid Corp | Process for polarizing ultraviolet light utilizing oriented, polyphenyl stained film |
| WO2009112461A1 (en) * | 2008-03-11 | 2009-09-17 | Neurosearch A/S | Novel triaryl derivatives useful as modulators of nicotinic acetylcholine receptors |
| CN101376655A (en) * | 2008-10-11 | 2009-03-04 | 中国海洋大学 | Penicillazine derivative, and preparation and use thereof |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102126934A (en) * | 2011-01-13 | 2011-07-20 | 山东大学 | Paraterphenyl derivative and application thereof to preparation of antitumor medicaments |
| WO2012094788A1 (en) * | 2011-01-13 | 2012-07-19 | 山东大学 | Paraterphenyl derivative and use thereof for preparing antitumor medicaments |
| CN102126934B (en) * | 2011-01-13 | 2013-05-15 | 山东大学 | Paraterphenyl derivative and application thereof in preparation of antitumor medicaments |
| CN103804392A (en) * | 2014-02-19 | 2014-05-21 | 中国科学院微生物研究所 | Two terphenylzidioxazine derivatives and applications thereof |
| CN105175241A (en) * | 2015-08-28 | 2015-12-23 | 浙江工业大学 | Terphenyl compound and preparation method therefor and application thereof |
| CN115246803A (en) * | 2021-04-25 | 2022-10-28 | 中国科学院南海海洋研究所 | Terphenyl compounds and application thereof in preparation of anti-herpes virus medicines |
| CN115246803B (en) * | 2021-04-25 | 2023-11-14 | 中国科学院南海海洋研究所 | Terphenyl compounds and application thereof in preparation of anti-herpesvirus drugs |
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