CN105949104B - A kind of purposes of the chain diterpene-kind compound of haematinic acid esterification - Google Patents
A kind of purposes of the chain diterpene-kind compound of haematinic acid esterification Download PDFInfo
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- CN105949104B CN105949104B CN201610307937.2A CN201610307937A CN105949104B CN 105949104 B CN105949104 B CN 105949104B CN 201610307937 A CN201610307937 A CN 201610307937A CN 105949104 B CN105949104 B CN 105949104B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/448—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms, e.g. maleimide
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Abstract
The present invention relates to pharmaceutical technology fields, are related to chain Diterpenes noval chemical compound I of haematinic acid esterification that extracting and developing obtains from Chinese Caulerpa racemosa (Forssk) Web V. Bos and preparation method thereof and the application in diabetes, obesity or protein-tyrosine-phosphatase 1B inhibitor.External PTP1B inhibit experiments have shown that, compound for protein tyrosine-phosphatase 1B（PTP1B）It with remarkable inhibiting activity, therefore can be used to prepare PTP1B inhibitor, it can also be used to prepare the drug for the treatment of diabetes, obesity and its complication.
Description
Technical field
The present invention relates to pharmaceutical technology field, relate in particular to a kind of isolated blood red from Chinese Caulerpa racemosa (Forssk) Web V. Bos
The Esterification chain Diterpenes noval chemical compound of element.The invention further relates to the preparation methods of the compound；The invention further relates to the changes
It closes object to can be used to prepare PTP1B inhibitor, it can also be used to prepare the drug for the treatment of diabetes, obesity and its complication.
Background technology
Caulerpa racemosa (Forssk) Web V. Bos Caulerpa racemosaJ.Agardh systems Chlorophyta (Chlorophyta) Chlorophyceae
(Chlorophyceae) Siphonales (Siphonales) Caulerpaceae (Caulerpaceae) caulerpa category (Caulerpa) ocean is planted
Object is distributed mainly on Perenniporia martius marine site, be grown in the rock below intertidal zone, on coral reef or in, low tide band
On sand ground.Also have in China marine site widely distributed, focus primarily upon Dongshan, Fujian, Taiwan, Hainan, Xisha, Coast of Guangdong Province.
Diabetes (diabetes mellitus) are one group clinical comprehensive as caused by h and E factor interaction
Close disease.At present, diabetes are generally divided into two classes, I- patients with type Ⅰ DM (insulin-dependent diabetes mellitus, insulin-
Dependent diabetes mellitus, IDDM) and II- patients with type Ⅰ DM (Non-Insulin Dependent Diabetes Mellitus, non-
Insulin-dependent diabetes mellitus, NIDDM).More than 90% is II- patients with type Ⅰ DM in diabetes.
The characteristics of II- patients with type Ⅰ DM is that insulin sensitive tissues such as skeletal muscle, liver, adipose tissue support insulin action
It is anti-.Protein-tyrosine-phosphatase (PTPases) GAP-associated protein GAP tyrosine phosphatase in insulin action access in statocyte
Effect in change level is increasingly taken seriously, and becomes the new way for the treatment of II- patients with type Ⅰ DM.PTPase includes big nation's cross-film
(receptor type) and intracellular (non-receptor type) enzyme participates in a series of important life processes.At present, PTPase is led in insulin
Receptor or receptor metasomite influence the research of Normal insulin effect in road, be concentrated mainly on LAR-PTPase, SHPTP-2,
PTP1B。
PTP1B is first certified protein-tyrosine-phosphatase (protein tyrosine
Phosphatase), show that PTP1B is acylated by the dephosphorization to insulin receptor by the PTP1B experiments on mice rejected, and then
Very important effect is played in insulin sensitivity and fat metabolic process is adjusted.Thus, it is selective, high activity
PTP1B inhibitor has important value in the treatment of II- patients with type Ⅰ DM, obesity and its complication.
Invention content
The present invention is the chain of the haematinic acid esterification that extraction is isolated from Chinese Caulerpa racemosa (Forssk) Web V. Bos (C.racemesa)
Diterpenes noval chemical compound I.Through pharmacological testing, research shows that, compound for protein tyrosine-phosphatase 1B (PTP1B) has
Remarkable inhibiting activity.
Therefore, it is an object of the present invention to provide the noval chemical compounds that structural formula is I.
It is a further object to provide the preparation methods of the compound.
The further object of the present invention is to provide the purposes of the compound.Specifically, the compound is preparing egg
Application in the drug of white tyrosine-phosphatase 1B (PTP1B) inhibitor, further prepare treatment diabetes, obesity and
Application in the drug of its complication.
First purpose according to the present invention, the present invention are found that a haematinic acid was esterified from Caulerpa racemosa (Forssk) Web V. Bos for the first time
Chain Diterpenes noval chemical compound I, chemical constitution are as follows：
Second purpose according to the present invention, the present invention provide the preparation method of the compound, it is from Caulerpa racemosa (Forssk) Web V. Bos
In it is isolated, be as follows：
1) extract medicinal extract is prepared
By the Caulerpa racemosa (Forssk) Web V. Bos (C.racemosa) of freezing ethyl alcohol routinely seepage pressure effects, extracting solution is obtained, extracting solution is subtracted
Concentration and recovery ethyl alcohol is pressed, obtains coarse extract；
2) it isolates and purifies
(1) said extracted object is dispersed in water into suspension, suspension is used into petroleum ether, ethyl acetate and positive fourth successively
Alcohol extracts, and the concentration of gained extract liquor respectively obtains petroleum ether extraction medicinal extract, ethyl acetate extraction medicinal extract and n-butanol extraction medicinal extract；
(2) ethyl acetate extract is subjected to silica gel column chromatography, with petroleum ether/acetone gradient elution, is developed the color and merged according to TLC
Similar fraction obtains 5 components (A-E)；Wherein component C, that is, petroleum ether/acetone volume ratio 8:2 and 7:3 elution fractions pass through
Sephadex LH-20 gel filtration chromatographies, are eluted with methylene chloride/methanol, obtain a colorless oil, i.e. Formulas I of the invention
Close object.
In above-mentioned preparation method, in extract medicinal extract step is prepared, the ethyl alcohol used that extracts is 95% ethyl alcohol.
In above-mentioned preparation method, in purification procedures, in the Sephadex LH-20 gel filtration chromatographies
Methylene chloride/methanol wash-out concentration is volume ratio 1:1.
Third purpose according to the present invention, the present invention provides the compounds to prepare protein-tyrosine-phosphatase
1B (PTP1B) inhibitor, diabetes medicament, obesity drug purposes.
The present invention has carried out external PTP1B to the noval chemical compound that resulting structures formula is I and has inhibited experiment, the results showed that the chemical combination
Object has PTP1B apparent inhibitory activity.Therefore, can be used to prepare PTP1B inhibitor, for treat diabetes, obesity and
Its complication.
The chain Diterpenes noval chemical compound I of the haematinic acid esterification of the present invention can be by isolating and purifying to obtain in seaweed；
It can synthesize and obtain through chemical modification method well known to those skilled in the art.
Description of the drawings
Fig. 1：PTP1B inhibitory activity test philosophies.
Fig. 2：Hydrogen spectrum (the deuterated reagent of Compounds of structural formula I：CDCl3)。
Fig. 3：Hydrogen spectrum (the deuterated reagent of Compounds of structural formula I：pyridine-d5)。
Fig. 4：Carbon spectrum (the deuterated reagent of Compounds of structural formula I：CDCl3)。
Fig. 5：Carbon spectrum (the deuterated reagent of Compounds of structural formula I：pyridine-d5)。
Fig. 6：COSY spectrum (the deuterated reagents of Compounds of structural formula I：CDCl3)。
Fig. 7：Hsqc spectrum (the deuterated reagent of Compounds of structural formula I：CDCl3)。
Fig. 8：HMBC spectrum (the deuterated reagents of Compounds of structural formula I：CDCl3)。
Specific embodiment
(Arabic numerals in structural formula are chemistry to the chemical structural formula of signified compound I in examples below
The mark of carbon atom in structure)：
Embodiment 1
The preparation of Compounds of structural formula I
1. prepare Caulerpa racemosa (Forssk) Web V. Bos extract medicinal extract
(1) extracting solution is prepared
Chinese Caulerpa racemosa (Forssk) Web V. Bos (C.racemosa) (it is coastal the to pick up from Zhanjiang) 5kg (dry weight) of freezing is used into 30L respectively
95% ethanol percolation extracts three times, and each diacolation 1 day merges extracting solution；
(2) extract medicinal extract is prepared
Recycling ethyl alcohol is concentrated under reduced pressure in temperature≤45 DEG C for said extracted liquid, obtains coarse extract 350g；
2. it isolates and purifies
1) said extracted object medicinal extract is dispersed in water into suspension, by suspension successively with petroleum ether (1.5L), acetic acid
Ethyl ester (1.5L) and n-butanol (1L) extract three times respectively, and the reduced pressure of gained extract liquor respectively obtains petroleum ether extraction medicinal extract
(38g), ethyl acetate extraction medicinal extract (160g) and n-butanol extraction medicinal extract (120g)；
2) ethyl acetate extract is subjected to silica gel column chromatography, with petroleum ether/acetone gradient elution；The concentration of gradient elution with
This is volume ratio 100:0、95:5、85:15、80:20、70:30 and 50:50, similar fraction is merged according to TLC colour developings and obtains 5
Component (A-E)；
3) component C, that is, petroleum ether/acetone volume ratio 8:2 and 7:3 elution fractions through Sephadex LH-20 gel filtration chromatographies,
With methylene chloride/methanol volume ratio 1:1 elution obtains a colorless oil, i.e. compound of formula I of the invention, is identified as new
Compound.
3. Structural Identification
Fig. 2：Hydrogen spectrum (the deuterated reagent of Compounds of structural formula I：CDCl3)；
Fig. 3：Hydrogen spectrum (the deuterated reagent of Compounds of structural formula I：pyridine-d5)；
Fig. 4：Carbon spectrum (the deuterated reagent of Compounds of structural formula I：CDCl3)；
Fig. 5：Carbon spectrum (the deuterated reagent of Compounds of structural formula I：pyridine-d5)；
Fig. 6：COSY spectrum (the deuterated reagents of Compounds of structural formula I：CDCl3)；
Fig. 7：Hsqc spectrum (the deuterated reagent of Compounds of structural formula I：CDCl3)；
Fig. 8：HMBC spectrum (the deuterated reagents of Compounds of structural formula I：CDCl3)。
Routinely through the various moderns spectral technique such as NMR, HRESIMS, UV, IR and optically-active, it is determined that the chemistry of compound I
Structure, physicochemical property are as follows：
White powder, molecular formula C28H47NO4；
Specific rotatory power [α20 D–22.0(c 0.23,CHCl3)；
Ultraviolet spectra UV (MeOH) λmax(logε)221(4.28),238(3.80)nm；
Infrared spectrum IR (KBr) νmax:3258,2854,1739,1723,1715,1421,1292,1221,1026,903,
829cm–1；
(the calcd for C of high resolution mass spectrum HRESIMS m/z 484.342528H47NO4Na,484.3403)；
Nuclear magnetic resonance spectroscopy1H NMR (400MHz) and carbon-13 nmr spectra13C NMR (100MHz) data are shown in Table one
Compound I described in table one1H and13C NMR
Embodiment 2
The test of PTP1B inhibitory activity：
Test philosophy：See Fig. 1.Using molecular biology method people's source protein tyrosine phosphatase is expressed in E. coli system
Esterase 1B (hPTP1B) catalyst structure domain, it is purified after hPTP1B recombinant proteins can hydrolyze substrate p-nitrophenyl phosphoric acid (p-
Nitrophenyl phosphate, pNPP) phosphatide key, obtain yellow soluble product p-nitrophenol (p-
Nitrophenol), which has very strong light absorption at 410nm, therefore can directly detect the change of light absorption at 410nm
The activity change and compound of change and observation enzyme are to the inhibition situation of enzymatic activity.
The live body system of standard：10mM Tris.Cl tri- (methylol) aminomethane hydrochloride), pH 7.6,10mM
PNPP, 2%DMSO, 100nM hPTP1B.
Observation index：Dynamic measures wavelength as the light absorption at 410nm, and the time is 3 minutes, and kinetic curve level-one is anti-
Activity index of the slope answered as enzyme.
Test method：Protein-tyrosine-phosphatase PTP1B for screening is from expression in escherichia coli and purifies
Gst fusion protein.Using ultraviolet suitable substrates p-nitrophenyl phosphoric acid (pNPP), suppression of the observation various concentration to the activity of recombinase
It makes and uses, with the medicinal effects of preliminary assessment compound.Sample is dissolved in DMSO before use and is made into debita spissitudo, 3 times dilute, and 7
A dilution sets three wells, and 2 μ L samples solution is taken to add in 96 orifice plates, then add in 88 μ L assay mix (assay
Buffer, pNPP, H2O), 10 μ L PTP1B are added.It is at 410nm that 96 orifice plates are placed in dynamic detection wavelength on VERSAmax
Absorbance value is detected, the time is 3 minutes.
The judge and explanation of experimental result：
The selection result is compound concentration when being 20 μ g/ml to the percent inhibition of enzymatic activity, when inhibiting rate is higher than 50%,
Routinely screening (by detected diluted chemical compound of the inhibiting rate higher than 50% into different concentration, is carried out according to above-mentioned test method
Reaction, all experiments are respectively provided with multiple holes) obtain IC50, the IC of positive control sodium vanadate50It is 2 μM.
Experimental result：Formula Compound I is to the IC of PTP1B enzyme inhibition activities50It is 2.3 μM.
Experiment conclusion：Pass through molecular biology test, it can be seen that compound I is to protein-tyrosine esterase 1B (PTP1B)
With preferable inhibitory activity.Therefore, the compound of the present invention I can be used for preparing the medicine of diabetes, obesity and its complication
In object, common pharmaceutic adjuvant can also be further added in order to improve performance and is easily produced the medicament forms being more easily accepted by.
Claims (1)
1. structural formula is application of the compound of I in protein-tyrosine-phosphatase 1B inhibitor is prepared, structural formula is the change of I
Object is closed, chemical structural formula is as follows：
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| CN201610307937.2A CN105949104B (en) | 2014-11-03 | 2014-11-03 | A kind of purposes of the chain diterpene-kind compound of haematinic acid esterification |
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| CN201410608113.XA CN104557658B (en) | 2014-11-03 | 2014-11-03 | The chain diterpene-kind compound of a kind of haematinic acid esterification and preparation and purposes |
| CN201610307937.2A CN105949104B (en) | 2014-11-03 | 2014-11-03 | A kind of purposes of the chain diterpene-kind compound of haematinic acid esterification |
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| CN108484542B (en) * | 2018-05-16 | 2021-10-08 | 浙江医药高等专科学校 | Methylene butyrolactone diterpenoid compound with hypoglycemic activity and preparation method and application thereof |
| CN108896520B (en) * | 2018-06-13 | 2021-01-01 | 南昌大学 | Ratiometric fluorescence detection of As (V) based on the principle of inhibition of acid phosphatase Activity |
| CN111302942B (en) * | 2020-04-09 | 2022-03-01 | 中国热带农业科学院热带生物技术研究所 | Compound with PTP1B inhibitory activity and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101288676A (en) * | 2007-04-17 | 2008-10-22 | 暨南大学 | New application of hexadecanoyl-sulfonic-glycerol-glucose ester and its preparation method |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101288676A (en) * | 2007-04-17 | 2008-10-22 | 暨南大学 | New application of hexadecanoyl-sulfonic-glycerol-glucose ester and its preparation method |
Non-Patent Citations (2)
| Title |
|---|
| 中国南海总状旅藻(Caulerpa racemosa) 的次生代谢产物;毛水春，等;《第九届全国天然有机化学学术会议论文集》;20121108;142 * |
| 中国南海总状蕨藻的脂肪酸类化学成分和生物活性研究;刘定权，等;《中国海洋药物》;20131231;第32卷(第6期);13-20 * |
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| CN105949104A (en) | 2016-09-21 |
| CN104557658B (en) | 2016-08-17 |
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