CN103833624A - Protein tyrosine phosphatase 1B (PTP1B) enzyme inhibitor, and preparation method and application thereof - Google Patents
Protein tyrosine phosphatase 1B (PTP1B) enzyme inhibitor, and preparation method and application thereof Download PDFInfo
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- CN103833624A CN103833624A CN201410065148.3A CN201410065148A CN103833624A CN 103833624 A CN103833624 A CN 103833624A CN 201410065148 A CN201410065148 A CN 201410065148A CN 103833624 A CN103833624 A CN 103833624A
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
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Abstract
The present invention relates to a kind of new Protein tyrosine phosphatase 1B(PTP1B) enzyme inhibitor, the PTP1B enzyme inhibitor is 2,2 ', 5,5 ', 6,6 '-hexabromo -3,3 '-bis- -1H- indoles, and structural formula is as follows:
. The present invention also provides the preparation method and applications of the PTP1B enzyme inhibitor. The PTP1B enzyme inhibitor enhances insulin receptor sensibility by the activity of inhibition Protein tyrosine phosphatase 1B, has good therapeutic effect to insulin resistance class diabetes B. The present invention can be applied in the drug of preparation treatment diabetes and/or obesity and its complication.
Description
Technical field
The present invention relates to biomedicine field, be specifically related to a kind of protein-tyrosine phosphide enzyme 1B(PTP1B) enzyme inhibitors and its preparation method and application.
Background technology
Diabetes (Diabetes Mellitus, DM) are a kind of chronic incretion metabolism diseases, and according to international diabetes (IDF) alliance data, wherein diabetes B patient accounts for the more than 90% of total diabetic subject.Be used for the treatment of at present diabetes B (Type 2 Diabetes Mellitus, T2DM) medicine mainly contains biguanides, sulfourea, alpha-glucosidase inhibitor and thiazolidinediones etc., because mostly they are for illness rather than for the design of cause of disease molecular target medicine, thereby there are various drawbacks.
Insulin resistant is the key factor of T2DM morbidity, confirms on evidence arrestin tyrosine phosphide enzyme 1B(Protein tyrosine phosphatase 1B, PTP1B) become the novel method of insulin resistant diabetes B treatment.Protein-tyrosine phosphide enzyme 1B(PTP1B) in Insulin signaling pathway, play important negative regulation effect.Studies confirm that, in insulin sensitivity cell, apply protein-tyrosine phosphide enzyme 1B(PTP1B) inhibitor can make insulin receptor and substrate phosphorylation level thereof raise, promoting glucose transporter transposition and increase the picked-up etc. of glucose, protein-tyrosine phosphide enzyme 1B(PTP1B) inhibitor played the effect of insulin analog and euglycemic agent.Knock out protein-tyrosine phosphide enzyme 1B(PTP1B) gene or suppress protein-tyrosine phosphide enzyme 1B(PTP1B in body by antisense nucleotide (ASO)) expression of albumen and mRNA, not only can significantly improve the susceptibility of tested mouse to Regular Insulin, and can obviously reduce the ill probability of obesity.Gold-stein research shows, protein-tyrosine phosphide enzyme 1B(PTP1B in the insulin target tissue of Patients with Insulin Resistance) and LARPTP expression increase, the expression increase of these two kinds of PTP can be blocked the activation of insulin receptor tyrosine and the signal transduction of Regular Insulin.P387L is protein-tyrosine phosphide enzyme 1B(PTP1B) a kind of missense mutation, Echwald etc. confirm that in diabetes B patient, this gene mutation frequency is 1.4%, and Normal group is only 0.5%, therefore think that this variation is relevant with diabetes B.Adopt protein-tyrosine phosphide enzyme 1B(PTP1B) antisense oligonucleotide processing diabetes type mouse (ob/ob mouse), suppress its protein-tyrosine phosphide enzyme 1B(PTP1B) express, find in liver, fat and skeletal muscle protein-tyrosine phosphide enzyme 1B(PTP1B) down-regulated expression time, it is normal that ob/ob mouse blood sugar recovers, it is normal that the indices relevant with carbohydrate metabolism is all tending towards, Regular Insulin clamp is tested and is shown, liver and the peripheral tissues of diabetic mice strengthen insulin sensitivity.These results confirm protein-tyrosine phosphide enzyme 1B(PTP1B) negative regulation effect in insulin signaling transduction, its activity increases, and may be insulin resistant and an impaired paathogenic factor of insulin receptor signal occur.Therefore, find small molecular protein tyrosine phosphide enzyme 1B(PTP1B) inhibitor become the novel targets for the treatment of T2DM.
In the world to protein-tyrosine phosphide enzyme 1B(PTP1B) research of inhibitor is few, mainly contain following a few class: (1), peptide class: the peptide class substrate of phosphorous acidifying tyrosine residues (pTyr) and protein-tyrosine phosphide enzyme 1B(PTP1B) there is higher affinity, but its chemistry and biologically stable are poor; (2), naphthoquinones class Naphthnoquinone: the activity of carrying out inhibitory enzyme by modifying the avtive spot of PTPase; (3), thiazolidinediones Azolidinediones: improve the control of blood sugar by increasing the insulin sensitivity of target organ, mainly comprise ciglitazone, troglitazone and rosiglitazone, but due to serious hepatotoxicity, ciglitazone withdraws from from market; (4), Benzo[b] naphthol[2,3-d] furans and thiophenes class: with benzbromarone (PTP1B inhibitor, IC
50=26 μ M) design synthetic serial Benzo[b for lead compound] naphthol [2,3-d] furans and thiophenes compounds, in Mice Body, show good hypoglycemic activity, but to finally become treatment diabetes medicament and also need to overcome a lot of obstacles, as high in electronegativity, permeability of cell membrane is poor and select specificity poor etc., above factor all makes the one-tenth property of medicine of these inhibitor reduce.Therefore, safe and effective, the reasonable price of market in urgent need and the ofhypoglycemic medicine can long-term safety taken.
In order to solve the safe and reliable protein-tyrosine phosphide enzyme 1B(PTP1B of current shortage) problem of inhibitor, the invention provides a kind of novel protein-tyrosine phosphide enzyme 1B(PTP1B) inhibitor, this inhibitor is by the activity of arrestin tyrosine Phospholipid hydrolase 1B, strengthen insulin receptor susceptibility, can be used in the medicine of preparation treatment insulin resistant class diabetes B and/or obesity and complication thereof.
For achieving the above object, the technical solution used in the present invention is as follows:
A kind of PTP1B enzyme inhibitors, described PTP1B enzyme inhibitors is 2,2 ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles, its structural formula of compound is as follows:
2,2 ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles (1), 3', 5', 6,6'-tetrabromobisphenol, 4-dimethyl diphenyl ether (2).
The present invention also provides a kind of preparation method of PTP1B enzyme inhibitors, and described preparation method operates as follows:
1. after marine alga sample collecting, air-dry and pulverizing, with 95% ethanol soaking at room temperature extraction 3 times, each 3-5 days, after extracting solution merges, evaporate to dryness ethanol obtains crude extract, and runic thing is suspended in distilled water, be extracted with ethyl acetate, acetic acid ethyl acetate extract concentrating under reduced pressure obtains brownish black medicinal extract;
2. brownish black medicinal extract is carried out to normal phase silica gel column chromatography separation, with petrol ether/ethyl acetate gradient elution, the volume ratio that wherein petrol ether/ethyl acetate gradient elution adopts is respectively 100:1,50:1,20:1,15:1,10:1,5:1 and 1:1;
By the similar part of thin-layer chromatography combining data detection composition, finally obtain 6 polar fractions, be labeled as respectively corresponding to different petrol ether/ethyl acetate volume ratios: I, II, III, IV, V and VI;
3. be that petrol ether/ethyl acetate volume ratio is the polar portion of 20:1 wash-out gained by III part, after sephadex LH-20 chromatographic separation, obtain 4 subfractions by the similar part of thin-layer chromatography combining data detection composition, the 1st subfraction after silica gel column chromatography separates through sephadex LH-20 chromatogram repeatedly wash-out obtain 2,2 ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles is PTP1B enzyme inhibitors.
Wherein, described step 1. in when evaporate to dryness ethanol temperature lower than 45 ℃.
Wherein, 2. the silica gel size of silicagel column is between 160-200 order for described step, and the sherwood oil temperature of petrol ether/ethyl acetate is between 60-90 ℃.
Wherein, described step 2. silica gel column chromatography elutriant used be sherwood oil: acetone=30:1 by volume.
Wherein, described step 3. sephadex LH-20 chromatography eluant elutriant used be sherwood oil by volume: chloroform: methyl alcohol=5:5:1.
Wherein, described marine alga is that marine red alga is like knurl concave crown algae.
The present invention also provides a kind of application of PTP1B enzyme inhibitors, described PTP1B enzyme inhibitors 2,2 ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles, as protein-tyrosine phosphatase 1B inhibitor, is applied in the medicine of preparation treatment diabetes and/or obesity and complication thereof.
We are from marine alga, especially marine red alga like in knurl concave crown algae, find 2,2 ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles shows good protein-tyrosine phosphide enzyme 1B(PTP1B) enzyme inhibition activity.
Compound 2,2 involved in the present invention ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles be from marine red alga like the new compound of finding knurl concave crown algae, its chemical structure novelty, not yet finds bibliographical information up to now.2,2 ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles is small molecules organic compound, is easy to preparation and industrial applications.Compound of the present invention is to protein-tyrosine phosphide enzyme 1B(PTP1B) enzyme has good restraining effect, in the treatment of diabetes and obesity, has important value.
Accompanying drawing explanation
Fig. 1 is that the present invention prepares extraction separation process figure;
Fig. 2 is relevant (HMBC) schematic diagram of compound heteronuclear remote chemical of the present invention displacement.
Embodiment
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment are only not used in and limit the scope of the invention for the present invention is described.In addition should be understood that, after having read content of the present invention, those skilled in the art can make various changes or modifications the present invention, these equivalent form of values fall within limited range of the present invention equally.
The present invention implements through the following steps:
Marine red alga picks up from Chinese Sanya, Hainan marine site like knurl concave crown algae, air-dry and the pulverizing (dry weight 1.1 kg) in cool place place, with 95% ethanol soaking at room temperature extraction 3 times, each ethanol 3L that uses, each 3-5 days that soaks, after merging, extracting solution obtains crude extract through Rotary Evaporators (the B ü CHI R-3 of company model) evaporate to dryness ethanol (temperature is lower than 45 ℃), runic thing is suspended in 1L distilled water, with isopyknic ethyl acetate extraction three times, acetic acid ethyl acetate extract obtains brownish black medicinal extract 28.5 g through Rotary Evaporators (bath temperature is 40 ℃) concentrating under reduced pressure after merging.Brownish black medicinal extract is carried out to purification on normal-phase silica gel (Qingdao Marine Chemical Co., Ltd., 160-200 order, silica gel consumption 300 g) column chromatography separates, so that sherwood oil (60-90 ℃)/(volume ratio is respectively 100:1 to ethyl acetate gradient elution, 50:1,20:1,15:1,10:1,5:1 and 1:1), receive by 100ml/ part, by the similar part of thin-layer chromatography combining data detection composition, finally obtain 6 polar fractions, be labeled as respectively I, II, III, IV, V and VI according to the volume ratio of petrol ether/ethyl acetate elutriant.
III part [from sherwood oil: ethyl acetate (20:1) wash-out part] is through sephadex LH-20(hydroxypropyl dextrane gel) (eluent is sherwood oil to chromatogram: chloroform: methyl alcohol, volume ratio 5:5:1) separate after obtain 4 subfractions, the 1st subfraction of this III part is that subfraction IIIa obtains the compound containing a small amount of impurity after silica gel column chromatography (eluent is sherwood oil: acetone volume ratio 30:1) separates, this compound is passed through to sephadex LH-20(hydroxypropyl dextrane gel again) (eluent is sherwood oil to chromatogram: chloroform: methyl alcohol, volume ratio 5:5:1) separate and obtain compound (9.3 mg) after purifying.Through Spectrum Analysis (comprising infrared spectra, mass spectrum, proton nmr spectra and carbon spectrum etc.), determine that this compound is: 2,2 ', 5,5 ', 6,6 '-hexabromo-3,3 '-bi-1H-indole (English), 2,2 ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles (Chinese).
Above-claimed cpd has following physico-chemical property:
2,2 ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles, amorphous powder, is soluble in chloroform; Infrared spectra IR (Potassium Bromide KBr): 3432,1611,1508,1433,1417,1249,1109,798.Mass spectrum EI-MS:
m/z710 (8)/709 (28)/707 (73)/705 (100)/703 (73)/701 (28)/699 (8) [M]
+; 626 (10)/628 (8) (M-Br); 545 (18)/547 (11) (M-2B); 226 (15). high resolution mass spectrum HR-EI-MS:
m/z(705.5561 [M]
+, C
16h
6 79br
3 81br
3n
2; Calcd.705.5570). proton nmr spectra
1h-NMR and carbon spectrum
13c-NMR is in table 1.Fig. 2 is shown in by relevant (HMBC) schematic diagram of heteronuclear remote chemical displacement.
In the present embodiment, instrument is as follows:
Infrared spectrometer: Nicolet impact 400 type Fourier transformation infrared spectrometers
Nuclear magnetic resonance analyser: BrukerAvance-500 MHz nuclear magnetic resonance analyser
Mass spectrograph: Autospec Ultima-Tof mass spectrograph
Table 1 proton nmr spectra of the present invention
1h NMR (500 MHz) and carbon spectrum
13c NMR (125 MHz) data (solvent/deuterochloroform CDCl
3, δ/ppm, J/Hz)
Embodiment 2, Protein tyrosine phosphatase 1B suppresses determination of activity
In experiment, material noun used is explained: DMSO is dimethyl sulfoxide (DMSO), pNPP is 4-NPP, and hGST-PTP1B is the PTP 1B of human glutathione S-transferase-tagged protein tyrosine phosphatase 1B mankind gsh-s-transferring enzyme mark.
Testing compound is mixed with respectively to the need testing solution of 5 μ g/mL, 20 μ g/mL with DMSO, get (the 50 mM Tris-HCl of survey live body system that 2 μ L need testing solutions join respectively standard, pH 6.5,2 mM pNPP, 2% DMSO, 30 nM hGST-PTP1B), negative control: DMSO, positive control: sodium vanadate, temperature of reaction is 30 ℃, dynamic measurement wavelength is the photoabsorption at 405 nm places, and times 3 min is calculated as follows compound protein-tyrosine phosphide enzyme 1B(PTP1B) enzyme activity inhibiting rate.Inhibiting rate=(experimental group A value-negative control group A value)/(control group A value-negative control group A) × 100%, the results are shown in Table 2.
Table 2 protein-tyrosine Phospholipid hydrolase 1B inhibiting rate (%)
Result shows, the compounds of this invention can suppress the activity of PTP1B in the time that concentration is 5 μ g/mL, and inhibiting rate can reach 82.1%, therefore the present invention shows significant restraining effect to protein-tyrosine Phospholipid hydrolase 1B, there is good anti-diabetes B potential applicability in clinical practice.
Compound 2,2 disclosed in this invention ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles be from marine red alga like the new compound of finding knurl concave crown algae, its chemical structure novelty, is easy to preparation and industrial applications.The present invention is to protein-tyrosine phosphide enzyme 1B(PTP1B) enzyme has good restraining effect, in the treatment of diabetes and obesity, has important value.
Be more than the description to the embodiment of the present invention, by the above-mentioned explanation to the disclosed embodiments, make professional and technical personnel in the field can realize or use the present invention.To be apparent for those skilled in the art to the multiple modification of these embodiment, General Principle as defined herein can, in the situation that not departing from the spirit or scope of the present invention, realize in other embodiments.Therefore, the present invention will can not be restricted to these embodiment shown in this article, but will meet the widest scope consistent with principle disclosed herein and features of novelty.
Claims (8)
1. a PTP1B enzyme inhibitors, is characterized in that, described PTP1B enzyme inhibitors is 2,2 ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles, its chemical structural formula is as follows:
.
2. a preparation method for PTP1B enzyme inhibitors, is characterized in that, described preparation method comprises the steps:
1. after marine alga sample collecting, air-dry and pulverizing, with 95% ethanol soaking at room temperature extraction 3 times, each 3-5 days, after extracting solution merges, evaporate to dryness ethanol obtains crude extract, and runic thing is suspended in distilled water, be extracted with ethyl acetate, acetic acid ethyl acetate extract concentrating under reduced pressure obtains brownish black medicinal extract;
2. brownish black medicinal extract is carried out to normal phase silica gel column chromatography separation, with petrol ether/ethyl acetate gradient elution, the volume ratio that wherein petrol ether/ethyl acetate gradient elution adopts is respectively 100:1,50:1,20:1,15:1,10:1,5:1 and 1:1;
By the similar part of thin-layer chromatography combining data detection composition, finally obtain 6 polar fractions, be labeled as respectively corresponding to different petrol ether/ethyl acetate volume ratios: I, II, III, IV, V and VI;
3. be that petrol ether/ethyl acetate volume ratio is the polar portion of 20:1 wash-out gained by III part, after sephadex LH-20 chromatographic separation, obtain 4 subfractions by the similar part of thin-layer chromatography combining data detection composition, the 1st subfraction after silica gel column chromatography separates through sephadex LH-20 chromatogram repeatedly wash-out obtain 2,2 ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles is PTP1B enzyme inhibitors.
3. the preparation method of PTP1B enzyme inhibitors according to claim 2, is characterized in that, described step 1. in when evaporate to dryness ethanol temperature lower than 45 ℃.
4. the preparation method of PTP1B enzyme inhibitors according to claim 2, is characterized in that, 2. the silica gel size of silicagel column is between 160-200 order for described step, and the sherwood oil temperature of petrol ether/ethyl acetate is between 60-90 ℃.
5. the preparation method of PTP1B enzyme inhibitors according to claim 2, is characterized in that, described step 3. sephadex LH-20 chromatography eluant elutriant used is sherwood oil by volume: chloroform: methyl alcohol=5:5:1.
6. the preparation method of PTP1B enzyme inhibitors according to claim 2, is characterized in that, described step 3. silica gel column chromatography to separate elutriant used be sherwood oil: acetone=30:1 by volume.
7. according to the preparation method of the arbitrary described PTP1B enzyme inhibitors of claim 2 ~ 6, it is characterized in that, described marine alga is that marine red alga is like knurl concave crown algae.
8. the application of a PTP1B enzyme inhibitors, it is characterized in that, described PTP1B enzyme inhibitors 2,2 ', 5,5 ', 6,6 '-hexabromo-3,3 '-bis--1H-indoles, as protein-tyrosine phosphatase 1B inhibitor, is applied in the medicine of preparation treatment diabetes and/or obesity and complication thereof.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669516A (en) * | 2016-03-09 | 2016-06-15 | 中山大学 | Preparation method of 3,3'-bisindole compounds |
| CN113461532A (en) * | 2021-07-05 | 2021-10-01 | 南昌大学 | Black mulberry extract A with blood sugar reducing effect, and preparation method and application thereof |
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2014
- 2014-02-26 CN CN201410065148.3A patent/CN103833624A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105669516A (en) * | 2016-03-09 | 2016-06-15 | 中山大学 | Preparation method of 3,3'-bisindole compounds |
| CN105669516B (en) * | 2016-03-09 | 2018-08-03 | 中山大学 | A kind of preparation method of 3,3 '-bis-benzazolyl compounds |
| CN113461532A (en) * | 2021-07-05 | 2021-10-01 | 南昌大学 | Black mulberry extract A with blood sugar reducing effect, and preparation method and application thereof |
| CN113461532B (en) * | 2021-07-05 | 2023-05-02 | 南昌大学 | Black Sang Su A with blood sugar reducing effect and preparation method and application thereof |
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Application publication date: 20140604 |