CN112920239B - Preparation and application of alpha-glucosidase induced release NO donor - Google Patents
Preparation and application of alpha-glucosidase induced release NO donor Download PDFInfo
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- CN112920239B CN112920239B CN201911235057.9A CN201911235057A CN112920239B CN 112920239 B CN112920239 B CN 112920239B CN 201911235057 A CN201911235057 A CN 201911235057A CN 112920239 B CN112920239 B CN 112920239B
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- C—CHEMISTRY; METALLURGY
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- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
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- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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Abstract
The invention relates to an alpha-glucosidase induced release NO donor. Alpha-glucosidase widely exists on small intestine mucosa, catalyzes alpha-1.4-glycosidic bond hydrolysis, and plays an important role in the process of food digestion and absorption. Aiming at the tissue distribution characteristics of the alpha-glucosidase, a glucose fragment is connected with an NO donor (NONONOate) in an alpha glycosidic bond mode based on a prodrug principle, and the NO donor released by induction of the alpha-glucosidase is synthesized into novel small molecules and high molecules. In view of the activity of NO, the NO donor released by the induction of alpha-glucosidase is applied to a pharmaceutical excipient and used as a drug absorption enhancer to improve the absorption of the drug in the small intestine; in addition, it is also used as an anti-inflammatory agent, and the therapeutic effect on enteritis and ulcer caused by the non-steroidal anti-inflammatory agent is studied.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to preparation and application of an alpha-glucosidase induced release NO donor.
Background
Endogenous Nitric Oxide (NO) is precisely produced from L-arginine by three enzymes, inducible Nitric Oxide Synthase (iNOS), endothelial nitric oxide synthase (eNOS) and neurogenic nitric oxide synthase (nNOS), and is involved in numerous biological processes. In view of the above-mentioned functions of endogenous NO, further studies have found that exogenous NO has many potential medical applications, such as improving cardiac function, lowering blood pressure, anticancer, anti-inflammatory, etc. Because of the great medical potential of NO, many types of NO donors have been developed.
The biological function of NO is closely related to its concentration and site of production: high concentrations of NO have inflammatory and cell-damaging effects, in contrast to low concentrations of NO which have anti-inflammatory and cytoprotective effects. In addition, systemic NO donor has the side effects of increasing heart rate, lowering blood pressure and the like. The development of intelligently responsive NO donors targeted to focal tissue on-demand has therefore become a hotspot of research in this field.
Disclosure of Invention
In order to solve the technical problems, the invention provides preparation and application of an alpha-glucosidase induced release NO donor.
The technical scheme adopted by the invention is as follows: alpha-glucosidase induces the release of NO donor, to which the glucose fragment is linked by self-resolution.
Preferably, the compound is self-resolved into a compound having the structure of formula 1;
R 2 is halogen, nitro, C1-6 alkyl or phenyl; preferably halogen, nitro or C1-6 alkyl.
Preferably, the NO donor is a micromolecular NO donor, and the synthesized micromolecular alpha-glucosidase induced release NO donor is a compound with the structure as formula 2;
R 1 is H or OH;
R 2 is halogen, nitro, C1-6 alkyl or phenyl; preferably halogen, nitro or C1-6 alkyl;
R 3 、R 4 is an alkyl or cycloalkyl radical;
preferably, the small molecular NO donor is a compound with a structure shown in formula 3,
preferably, the NO donor is a high molecular NO donor, and the synthesized high molecular alpha-glucosidase induced release NO donor is a compound with a structure shown in formula 4;
R 1 is H or OH;
R 2 is halogen, nitro, C1-6 alkyl or phenyl; preferably halogen, nitro or C1-6 alkyl;
the Polymer is PAMA, chitosan, hyaluronic acid or cyclodextrin; preferably chitosan or PAMA.
Alpha-glucosidase induces release of NO donor intermediate, linked by glucose fragment and self-resolution chain;
preferably, the compound has a structure shown in formula 5;
R 1 is H or OH;
R 2 is halogen, nitro, C1-6 alkyl or phenyl; preferably halogen, nitro or C1-6 alkyl.
A method for preparing an alpha-glucosidase induced release NO donor comprises the following specific steps:
connecting glucose and a self-decomposition chain to obtain an alpha-glucosidase induced release NO donor intermediate;
modifying the tail end of the NO donor intermediate induced and released by alpha-glucosidase through an initiator;
and step three, connecting the modified alpha-glucosidase induced release NO donor intermediate with an NO donor, and then removing a protecting group through sodium methoxide to obtain the alpha-glucosidase induced release NO donor.
Preferably, the initiator in step one is BPO or AIBN.
Wherein, when the NO donor is a polymer NO donor, the method also comprises the following steps:
step four, connecting the alpha-glucosidase induced release NO donor to a small molecular compound with a modifiable functional group through click reaction;
step five; connecting an alpha-glucosidase induced release NO donor to a high molecular material;
preferably, the modifiable functional group in the fourth step is-COOH or-NH 2 ；
Preferably, in the fifth step, the polymer material is chitosan or PAMAM.
The application of alpha-glucosidase induced release NO donor as a pharmaceutical adjuvant in promoting drug absorption;
preferably, the drug is a P-glycoprotein (P-gp) substrate drug.
Application of alpha-glucosidase induced release NO donor in preparation of medicine for inhibiting intestinal inflammation caused by non-steroidal anti-inflammatory drugs.
The invention has the advantages and positive effects that: the scheme firstly provides an NO donor responding to alpha-glucosidase, NO can promote the absorption of the medicine by instantly opening the Tight Junction (TJ) of epithelial cells, the oral availability of the medicine is improved, and the NO donor is a novel medicine absorbent; the NO donor responded by the alpha-glucosidase can realize small intestine targeted supply of NO and intelligent response; the association of the NSAID with the NO donor protects the gastrointestinal tract from the damage caused by the NSAID.
Drawings
FIG. 1 is a graph of the time course of co-administration of alpha-glucosidase induced release of NO donor drug with anticancer drug doxorubicin in example 3 of the present invention;
FIG. 2 is a graph showing the co-administration of an alpha-glucosidase induced release NO donor drug and a paclitaxel anticancer drug in example 3 of the present invention;
FIG. 3 is a graph showing the co-administration of the NO donor drug and the camptothecin anticancer drug induced by α -glucosidase in example 3 of the present invention;
FIG. 4 is a nuclear magnetic spectrum of chitosan-grafted NO polymer (CS-NO) in example 4 of the present invention;
FIG. 5 shows the case of the control group in example 4 of the present invention in which villi in the small intestine were damaged;
FIG. 6 shows the case of the damaged villi of the small intestine after the administration of the mixture of CS-NO and chitosan at a ratio of 20% in example 4 of the present invention;
FIG. 7 shows the case of the damaged villi of the small intestine after administration of a mixture of CS-NO and chitosan in an added ratio of 50% in example 4 of the present invention.
Detailed Description
Alpha-glucosidase widely exists on small intestinal mucosa, catalyzes alpha-1.4-glycosidic bond hydrolysis, plays an important role in the process of food digestion and absorption, and aims at the tissue distribution characteristics of the alpha-glucosidase, and based on the prodrug principle, a glucose fragment is connected with a NO donor (NONONOATE) in an alpha-glycosidic bond mode, so that the NO donor responding to the alpha-glucosidase is synthesized for the first time.
Firstly, alpha-glucose and autolysis are connected to obtain an alpha-glucosidase induced release NO donor intermediate, the tail end of the alpha-glucosidase induced release NO donor intermediate is modified through an initiator BOP, the modified alpha-glucosidase induced release NO donor intermediate is connected with a NO donor to obtain a basic alpha-glucosidase induced release NO donor, and then the basic alpha-glucosidase induced release NO donor is modified through sodium methoxide to obtain an alpha-glucosidase induced release NO donor. Alpha glucose and self-decomposition chain of the structure formula 1 are connected to form an alpha-glucosidase induced release NO donor intermediate of the structure formula 5, the connected NO donor can be a micromolecule donor or a macromolecule donor of the structure formula 3, and the micromolecule alpha-glucosidase induced release NO donor of the structure formula 2 and the macromolecule alpha-glucosidase induced release NO donor of the structure formula 4 are obtained by respectively synthesizing the connected NO donor and the alpha-glucosidase induced release NO donor intermediate.
Wherein R is 1 Is H or OH; r is 2 Is halogen, nitro, C1-6 alkyl or phenyl; preferably halogen, nitro or C1-6 alkyl; r 3 、R 4 Is alkanyl or cycloalkyl; the Polymer is PAMA, chitosan, hyaluronic acid or cyclodextrin; preferably chitosan or PAMA.
NO can promote the drug absorption by instantaneously opening the Tight Junction (TJ) of epithelial cells, improves the oral availability of the drug and is a novel drug absorption promoting agent. Research shows that the non-steroidal anti-inflammatory drug is connected with the NO donor to protect the gastrointestinal tract from being damaged by the non-steroidal anti-inflammatory drug, and the NO has the function of protecting the gastrointestinal tract mucosa. Based on the activity of NO, the scheme further researches the alpha-glucosidase induced release NO donor obtained by synthesis as a pharmaceutical adjuvant for improving the absorption of the drug in the small intestine and an anti-inflammatory drug for researching the treatment effect of the alpha-glucosidase induced release NO donor on enteritis and ulcer caused by non-steroidal anti-inflammatory drugs.
The preparation and application of the alpha-glucosidase induced release NO donor according to the present invention are further illustrated by the following examples, but the following examples are for the purpose of making the skilled person more understand the present invention or making some insubstantial modifications and adjustments according to the present invention, but the examples are not intended to limit the scope of the claimed technical solution, and are included in but not included in all the claimed scope.
Example 1: the synthesis method of the small molecular alpha-glucosidase induced release NO donor has the following synthetic route:
the method comprises the following steps: dissolving a compound a (1.0 eq.) and a compound b (2 eq.) with a structure shown in a formula 1 in dry DCM, and adding BF under the protection of argon 3 .Et 2 Heating and refluxing O (3 eq.) at 45 ℃ for reaction for 48 hours; after the reaction is finished, adding a proper amount of saturated NaHCO 3 Quenching reaction, extracting, drying and passingAfter filtering and spin-drying, separating and purifying the crude product by silica gel column chromatography to obtain a target compound c, namely the compound with the structure shown in the formula 5, wherein the compound c is yellow oily matter, and the yield is 40-60%.
Step two: dissolve compound c (1.0 eq.), NBS (1.5 eq.), and initiator BPO (0.1 eq.) in CCl 4 And heating and refluxing at 78 ℃ for 6h under the protection of argon. After the reaction is finished, cooling, filtering and spin-drying the filtrate to obtain a crude product, and separating and purifying the crude product by silica gel column chromatography to obtain a target compound d with the yield of 60-75%.
Step three: dissolving compound d (1.0 eq.), NONOATES (2.0 eq.) and KI (0.3 eq.) in dry DMF under ice bath, and continuing stirring reaction for 24h under ice bath; TLC detection reaction shows that water quenching reaction is added after the reaction is finished, ethyl acetate is adopted for extraction for 3 times, the combined organic phase is respectively washed once by saturated NaCl aqueous solution and water, a crude product is obtained after drying, filtering and spin-drying, and a target compound e, namely a basic alpha-glucosidase induced release NO donor, is obtained through silica gel column chromatography separation and purification, wherein the yield is 35% -55%;
dissolving the compound e in dry methanol, adding a catalytic amount of sodium methoxide while stirring, stirring at room temperature for 1h, performing TLC detection reaction to show that the raw materials disappear, performing spin-drying, and performing silica gel column chromatography separation and purification on the obtained crude product to obtain a target compound f, which is a yellow solid and has the yield of 55-57.4%.
The results of mass spectrometry analysis of the intermediate products obtained by the preparation according to the method of example 1 and the final products obtained by the preparation of different types of starting compounds are as follows, confirming that the target compound f can be obtained by the above-mentioned preparation scheme.
Compound c: 1 HNMR(CDCl 3 ,400MHz)δ6.99(d,J＝8.4Hz,1H),6.98(s,1H),6.93(dd,J＝8.0,2.0Hz,1H),5.70(apparent t,J＝10.0Hz,1H),5.61(d,J＝3.6Hz,1H),5.17(apparent t,J＝10.0Hz,1H),5.05(dd,J＝10.0,3.6Hz,1H),4.28(dd,J＝12.4,4.8Hz),4.20-4.16(m,1H),4.09(dd,J＝12.4,2.0Hz,1H),2.27(s,3H),2.26(s,3H),2.08(s,3H),2.06(s,3H),2.05(s,3H).2.05(s,3H)； 13 CNMR(CDCl 3 ,100MHz)δ170.6,170.2,170.1,169.7,152.6,132.4,131.7,127.5,127.3,114.8,95.2,70.6,70.2,68.4,67.9,61.7,20.8,20.7,20.6,20.5,16.0(one carbon less due to overlap)
compound f 1 : 1 HNMR(MeOD,400MHz)δ7.20(d,J＝8.4Hz,1H),7.07(d,J＝1.6Hz,1H),6.94(d,J＝8.0,2.0Hz,1H),5.46(d,J＝3.6Hz,1H),5.12(s,2H),3.88(apparent t,J＝9.2Hz,1H),3.85(s,1H),3.83-3.78(m,1H),3.74-3.66(m,2H),3.54(dd,J＝10.0,3.6Hz,1H),3.50-3.46(m,4H),3.42(apparent t,J＝9.2Hz,1H),3.31-3.29(m,4H)； 13 CNMR(MeOD,100MHz)δ151.9,147.8,132.7,122.7,119.5,114.3,100.7,76.1,75.0,74.7,73.6,71.4,62.3,56.6,52.0,23.7；HRMS(ESI,positive)m/z calcd for C18H27N3NaO9[M+Na] + :452.1640,found 452.1687
Compound f 2 : 1 HNMR(MeOD,400MHz)δ7.87(d,J＝2.4Hz,1H),7.59(d,J＝8.4Hz,1H),7.51(dd,J＝8.4,2.4Hz,1H),5.60(d,J＝3.6Hz,1H),5.49(s,2H),3.84(apparent t,J＝9.6Hz,1H),3.75(d,J＝12.0,2.4Hz,1H),3.67(dd,J＝12.0,5.2Hz,1H),3.62-3.57(m,2H),3.50-3.46(m,4H),3.42(apparent t,J＝10.0Hz,1H),1.94-1.91(m,4H)； 13 CNMR(MeOD,100MHz)δ158.6,150.0,132.4,126.6,123.2,114.2,99.6,75.0,74.8,73.1,72.1,71.3,62.3,51.9,23.7；HRMS(ESI,positive)m/zcalcd for C17H24N4NaO10[M+Na] + :422.1534,found 422.1577
Compound f 3 : 1 HNMR(MeOD,400MHz)δ7.35(dd,J＝7.6,1.2Hz,1H),7.30(td,J＝7.2,1.2Hz,1H),7.26(dd,J＝8.0,0.8Hz,1H),7.01(td,J＝7.2,1.2Hz,1H),5.58(d,J＝3.6Hz,1H),5.41(d,J＝12.0Hz,1H),5.26(d,J＝12.4Hz,1H),3.89(apparent t,J＝9.2Hz,1H),3.72-3.63(m,3H),3.59(dd,J＝9.6,3.2Hz,1H),3.50-3.46(m,4H),3.42(apparent t,J＝9.2Hz,1H),3.34(s,1H),1.94-1.90(m,4H)； 13 CNMR(MeOD,100MHz)δ156.5,131.6,131.2,126.7,123.1,116.1,98.8,75.1,74.7,73.5,71.9,71.6,62.3,52.0,23.7；HRMS(ESI,positive)m/z calcd for C17H24FN3NaO8[M+Na] + :467.1385,found 467.1428；
Compound f 4 : 1 HNMR(MeOD,400MHz)δ7.28(dd,J＝8.8,4.4Hz,1H),7.11(dd,J＝8.8,3.2Hz,1H),7.03(td,J＝8.8,3.2Hz,1H),5.49(s,1H),5.48(d,J＝3.6Hz,1H),5.37(d,J＝13.2Hz,1H),5.28(d,J＝12.8Hz,1H),3.86(apparent t,J＝9.2Hz,1H),3.73-3.63(m,3H),3.58(dd,J＝9.6,3.6Hz,1H),3.52-3.48(m,4H),3.40(apparent t,J＝8.8Hz,1H),1.95-1.91(m,4H)； 13 CNMR(MeOD,100MHz)δ159.22(d,J＝238),152.47,129.11(d,J＝7Hz),118.11(d,J＝8Hz),117.25(d,J＝24Hz),116.76(d,J＝23Hz),99.76,74.95,74.83,73.43,71.56,71.01,62.40,51.99,23.70；HRMS(ESI,positive)m/z calcd for C17H25N3NaO8[M+Na] + :440.1440,found 440.1479
Compound f 5 : 1 HNMR(MeOD,400MHz)δ7.17-7.14(m,2H),7.11(dd,J＝8.4,2.0Hz,1H),5.51(d,J＝3.6Hz,1H),5.48(s,1H),5.37(d,J＝12.0Hz,1H),5.23(d,J＝12.0Hz,1H),3.88(apparent t,J＝9.6Hz,1H),3.73-3.63(m,3H),3.57(dd,J＝9.6,3.6Hz,1H),3.51-3.47(m,4H),3.41(apparent t,J＝9.2Hz,1H),2.28(s,3H),1.94-1.91(m,4H)； 13 CNMR(MeOD,100MHz)δ156.9,135.2,134.7,134.0,128.9,118.8,101.5,77.6,77.1,76.1,74.4,74.1,64.8,54.5,26.2,23.1；HRMS(ESI,positive)m/z calcdfor C18H27N3NaO8[M+Na] + :436.1690,found 436.1735
Compound f 6 : 1 HNMR(MeOD,400MHz)δ7.23-7.17(m,3H),5.53(d,J＝3.6Hz,1H),5.07(s,2H),3.90(apparent t,J＝9.6Hz,1H),3.71-3.58(m,4H),3.49-3.30(m,5H),2.29(s,3H),1.94-1.91(m,4H)； 13 CNMR(MeOD,100MHz)δ156.8,132.6,130.8,129.1,128.8,98.9,76.2,75.0,74.6,73.4,71.6,62.4,52.0,23.6,16.5；HRMS(ESI,positive)m/z calcd for C18H27N3NaO8[M+Na] + :436.1690,found 436.1737
Example 2: the synthesis method of the NO donor released by the induction of the macromolecular alpha-glucosidase comprises the following synthetic route:
the method comprises the following steps: dissolving a compound a (1.0 eq.) and a compound b (2 eq.) with a structure shown in a formula 1 in dry DCM, and adding BF under the protection of argon 3 .Et 2 Heating and refluxing O (3 eq.) at 45 ℃ for reaction for 48 hours; adding a proper amount of saturated NaHCO after the reaction is finished 3 Quenching reaction, extracting, drying, filtering and spin-drying, and separating and purifying the crude product by silica gel column chromatography to obtain a target compound c, namely the compound with the structure shown as the formula 5, wherein the compound c is yellow oily matter, and the yield is 40-60%.
Step two: dissolve compound c (1.0 eq.), NBS (1.5 eq.), and initiator BPO (0.1 eq.) in CCl 4 And heating and refluxing at 78 ℃ for 6h under the protection of argon. After the reaction is finished, cooling, filtering and spin-drying the filtrate to obtain a crude product, and separating and purifying the crude product by silica gel column chromatography to obtain a target compound d with the yield of 60-75%.
Step three: dissolving compound d (1.0 eq.), NONOATES (2.0 eq.) and KI (0.3 eq.) in dry DMF under ice bath, and continuing stirring reaction for 24h under ice bath; TLC detection reaction shows that water quenching reaction is added after the reaction is finished, ethyl acetate is adopted for extraction for 3 times, the combined organic phase is respectively washed once by saturated NaCl aqueous solution and water, a crude product is obtained after drying, filtering and spin-drying, and a target compound g is obtained after silica gel column chromatography separation and purification;
dissolving the compound g in dry methanol, adding a catalytic amount of sodium methoxide while stirring, stirring at room temperature for 1h, performing TLC detection reaction to show that the raw materials disappear, performing spin drying, and performing silica gel column chromatography separation and purification on the obtained crude product to obtain an alpha-glucosidase induced release NO donor h, wherein the yield of the two steps is 31%.
Step four; reacting the compound h with hexynoic acid in CuSO 4 5H2O and ascorbic acid are catalyzed to carry out 'click' reaction, and white solid i is obtained after purification by reverse phase silica gel column chromatography, and the yield is 60%.
Step five; dissolving chitosan by using 2N HCl aqueous solution, adjusting the pH value to 5-6 by using 1N NaOH solution, adding chitosan, condensing agents EDC (1.5 eq.) and NHS (2 eq.), stirring for reacting for 24 hours, dialyzing unreacted micromolecules, and freeze-drying to obtain white spongy solid, namely chitosan grafted NO donor (CS-NO).
Example 3: effect of NO Donor drugs on oral absorption of P-gp substrate drugs
The alpha-glucosidase induced release NO donor medicament prepared in the example 1 or 2 and adriamycin, paclitaxel and camptothecin anticancer drugs are simultaneously infused into a mouse, a blank comparison experiment is carried out, and the influence of the alpha-glucosidase induced release NO donor on the oral availability of the medicament is researched through an ICR mouse pharmacokinetic experiment. The results are shown in fig. 1-3, and indicate that the NO donor drug can remarkably increase the bioavailability of adriamycin and the effective time of adriamycin; paclitaxel and camptothecin may have too low oral bioavailability and the NO donor has little effect on the oral bioavailability of both drugs.
Example 4: application of alpha-glucosidase induced release NO donor in preparation of medicine for inhibiting intestinal inflammation caused by non-steroidal anti-inflammatory drugs
The nuclear magnetic spectrum of the chitosan grafted NO donor (CS-NO) is shown in FIG. 4. The mice for test are subjected to modeling by oral gavage of a non-steroidal anti-inflammatory drug indometacin and are divided into three groups, a control group is administered with chitosan, and two experimental groups are respectively administered with a mixture of CS-NO and chitosan with the addition ratio of 20% and a mixture of CS-NO and chitosan with the addition ratio of 50%. As shown in FIGS. 5 to 7, the control group (FIG. 5) administered with chitosan had severely damaged villi, the experimental group administered with 20% CS-NO added had significantly reduced symptoms (FIG. 6), and the protective effect on the damaged villi was more significant as the addition rate was increased to 50% CS-NO (FIG. 7). The experiments show that the NO donor medicine can obviously relieve the small intestine injury caused by the non-steroidal anti-inflammatory drug and recover the mucosal barrier function in the small intestine, and the NO donor has dose dependence on the protection effect on the small intestine injury.
The embodiments of the present invention have been described in detail, but the description is only for the preferred embodiments of the present invention and should not be construed as limiting the scope of the present invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.
Claims (8)
1. Alpha-glucosidase-induced release of NO donor characterized by: the glucose fragment is linked to the NO donor by self-resolution; the NO donor is a small molecular NO donor or a high molecular NO donor, and the NO donor is a compound with a structure shown in a formula 1 through self-decomposition;
R 2 is halogen, nitro or C1-6 alkyl;
when the NO donor is a micromolecular NO donor, the synthesized micromolecular alpha-glucosidase induced release NO donor is a compound with the structure as formula 2;
R 1 is H or OH;
R 3 、R 4 is a ringAn alkyl group;
when the NO donor is a high-molecular NO donor, the synthesized high-molecular alpha-glucosidase induced release NO donor is a compound with the structure shown in formula 4;
R 1 is H or OH;
the Polymer is chitosan or PAMA.
2. The alpha-glucosidase induced release of NO donor of claim 1, characterized in that: the micromolecular NO donor is a compound with a structure shown in a formula 3,
3. A method of preparing an alpha-glucosidase induced release NO donor as claimed in claim 1 or 2, characterized in that: the method comprises the following specific steps:
the method comprises the following steps: connecting glucose with a self-melting chain to obtain an alpha-glucosidase induced release NO donor intermediate;
step two: modifying the tail end of the NO donor intermediate induced and released by alpha-glucosidase through an initiator; the initiator is BPO or AIBN;
step three: connecting the modified alpha-glucosidase induced release NO donor intermediate with a NO donor, and then removing a protecting group through sodium methoxide to obtain an alpha-glucosidase induced release NO donor;
when the NO donor is a macromolecule NO donor, the method further comprises the following steps:
step four: connecting an alpha-glucosidase induced release NO donor to a small molecule compound with a modifiable functional group through a click reaction;
step five: and (3) connecting the alpha-glucosidase induced release NO donor to the high molecular material.
4. The method of claim 3 for the induced release of NO donors by alpha-glucosidase, wherein: the modifiable functional group in the step four is-COOH or-NH 2 。
5. The method of claim 3 for the induced release of NO donors by alpha-glucosidase, wherein: and in the fifth step, the high molecular material is chitosan or PAMAM.
6. Alpha-glucosidase induced release of NO donor intermediates, characterized in that: the compound of claim 3-5, prepared by step one, wherein the glucose fragment is linked to a self-immolative linker having the structure of formula 5;
R 1 is H or OH;
R 2 is halogen, nitro or C1-6 alkyl.
7. The use of an alpha-glucosidase induced-release NO donor as a pharmaceutical excipient in promoting drug absorption according to claim 1 or 2, wherein: the medicine is P glycoprotein (P-gp) substrate medicine.
8. Use of an alpha-glucosidase induced release of NO donor as defined in claim 1 or 2 for the manufacture of a medicament for inhibiting gut inflammation induced by non-steroidal anti-inflammatory drugs.
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