CN108715875A - The method of the specific heparin sulfate oligosaccharides of enzyme chemical method composite structure - Google Patents
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Abstract
The invention discloses a kind of methods of the specific heparin sulfate oligosaccharides of enzyme chemical method composite structure；By using substituted benzyl-β-D-Glucose aldehydic acid glucosides as starting material, heparin sulfate derivative is prepared with recombinase using heparin sulfate biosynthesis, catalytic hydrogenation obtains heparin sulfate, wherein the heparin sulfate refers to structure determination and diversified hexuronic acid repeats disaccharide unit with Glucosamine, and structural formula isWherein, R1, R2, R4 are respectively hydrogen or sulfonyl, and R3 is hydrogen, acetyl group or sulfonyl, and n is any integer in 0~6；The synthetic reaction condition is mild, and reaction reagent is easy to get, and yield is high.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical fields, and in particular to a kind of specific heparin sulfate of enzyme chemical method composite structure
The method of oligosaccharides.
Background technology
Heparin sulfate (Heparan sulfate, HS) is linear glutinous polysaccharide, has anticoagulation, antiviral, anti-inflammatory, anti-swollen
The bioactivity such as tumor and regulation and control embryonic development, primary structure repeat disaccharide unit group by hexuronic acid and Glucosamine
At, between Isosorbide-5-Nitrae-glucosides key connection, saccharide residue carries sulfonyl, determines heparin sulfate Space expanding not to some extent
Together, and then different physiological actions is played or cause various disease.Heparin sulfate usually exists in cell surface or cellular matrix, with
Different chain length difference sulfate form exists with core protein conjugated form, and the naturally isolated obtained heparin sulfate that purifies is a kind of
Mixture, and content is few, causes accurately inquire into the biomechanism of heparin sulfate and summarizes its structure-activity relationship, seriously affects
Heparin sulfate scientific research is in progress with medicament research and development.
Through the literature search of existing technologies, the preparation of heparin sulfate there are two main classes method, chemical synthesis and
Enzymology synthetic method, the former is anti-by regional and three-dimensional selection, protection and deprotection of module construction, glycosidic bond etc.
Heparin sulfate should be prepared, however, this method route is long, purifying is difficult, low yield, the heparin sulfate more than six sugared units prepares pole
Has challenge, the synthesis of classical example fondaparinux sodium, 51 step, yield are only 0.053% (heparin class monosaccharide, disaccharides, three in total
The preparation of sugar and pentose, United States Patent (USP), 2017, US20170015695A1).Although in the recent period by reporting that 12 polysulfide heparins synthesize
Report, take 4 heparin sulfate recurring units to be coupled to form, but structure diversity is poor, the scope of application it is small (four glycan iteration close
It at ten disaccharides of heparin class and the distribution research of body radioactivity tagged tissue, communicates naturally, 2013,4 (7), 2016-2024).Enzyme
It is University of North Carolina church mountain branch school professor Liu Jian establishment and the existing synthesis sulfuric acid most approved to learn synthesis of natural heparin sulfate
Heparin method (the uniform low molecular weight heparin of structure with reversible anticoagulant active, natural chemical-biological, 2014,10：248-
250.), but because the p-nitrophenol in starting material p-nitrophenyl β-D-Glucose aldehydic acid exists so that all to obtain structure
It determines and diversified heparin sulfate contains p-nitrophenol label, said on stricti jurise, be not real heparin sulfate, and its is right
Nitrobenzophenone is active on heparin sulfate to be influenced to be unclear, although attempting to remove on heparin sulfate to nitro there are many scientist
Phenyl (p-nitrophenyl in cerium ammonium salt oxicracking enzymology synthesis heparin sulfate, Tet Lett, 2013,54,4471-
4474；By cracking oligosaccharides end position p-nitrophenol to acetylphenyl glycoside forms selective oxidation, Tet Lett,
1996,3343-3344.) it, is easily destroyed reducing end glucuronic acid, is totally produced little effect, it is difficult to promote and apply.To replace benzyl
Base-β-D-Glucose aldehydic acid glycosides is starting material, and enzymology method prepares the required heparin sulfate derivative containing substituted benzyl, hydrogen
Change heparin sulfate is that eaily, phenyl disadvantage can not be taken off by avoiding p-nitrophenyl that from can only restoring nitro, meanwhile, reduction
Shi Wubi increases the amount of catalytic reduction reagents, and the recovery time is too short to be only possible to produce nitro reduzate, and the recovery time is more than 15min
More than, be conducive to heparin sulfate preparation.This research patent replaces p-nitrophenyl with substituted benzyl-β-D-Glucose aldehydic acid glucosides
Base-β-D-Glucose aldehydic acid glucosides is starting material, and the heparin sulfate of various structure determinations is prepared using enzymology method.
Invention content
It is an object of the invention to overcome above-mentioned the shortcomings of the prior art, a kind of enzyme chemical method synthesis sulfuric acid liver is provided
The method of plain oligosaccharides, taps the latent power applied to heparin sulfate biological function and structure-activity relationship inquires into research.Specifically take substitution benzyl
Base glucuronic acid is starting material, and the sulfuric acid of recombinase preparation structure determination is related to by a series of heparin sulfate biosynthesis
Heparin, structure-activity relationship and corresponding biological effect mechanism to explore heparin sulfate provide tool molecule or probe.
Heparin sulfate of the present invention is hexuronic acid and Glucosamine repeats disaccharide unit, between by Isosorbide-5-Nitrae-glucosides
Key, saccharide residue carry sulfonyl in various degree, and the enzymatic synthesis reaction condition is mild, and reaction reagent is easy to get, the structure of synthesis
It determines and diversified heparin sulfate can be as the tool molecule or probe studied its biological function with inquire into its structure-activity relationship.
The purpose of the present invention is be achieved through the following technical solutions：
The present invention relates to a kind of heparin sulfate, structural formula is shown in formula I：
Wherein, R1, R2, R4 are respectively hydrogen or sulfonyl (SO3 -),
R3 is hydrogen, acetyl group (Ac-) or sulfonyl (SO3 -), n is any integer in 0~6.
The invention further relates to a kind of enzymology synthetic methods of the heparin sulfate of the present invention, with substituted benzyl-β-D- grapes
GlycuronideIt is closed under the action of heparin sulfate biosynthesis recombinase for starting material
At the repetition disaccharide unit heparin sulfate derivative containing substituted benzyl
Wherein, R5 is-NO3Or-OCH3；Through Pd/C catalytic hydrogenation debenzylations, the heparin sulfate is made.
Preferably, the heparin sulfate biosynthesis is selected from pmSH with recombinase2,KfiA,NST,NDST C5-Epi,2-
OST,6-OST,3-OST。
Preferably, described method includes following steps：
S1, at 30 DEG C~37 DEG C, using substituted benzyl-β-D-Glucose aldehydic acid glucosides as starting material, in HS polymerases
The sources Heparosan synthase-2 Pasteurella multocida (pmSH2) or KfiA catalysis under, with UDP- activate second
Acylamino- glucose (UDP-Glc NAc) or UDP- activation trifluoroacetamido glucose (UDP-Glc NTFA), UDP- activation
Glucuronic acid (UDP-GlcA) alternation response extends；According to target structural requirement again, through N- sulphonyl based transferases (N-
Deacetylase/N-sulfotransferase, NDST), 2-O- sulphonyl transferases (2-O-sulfotransferase, 2-
OST)、C5Isomerase (C5-epimerase,C5- Epi), 6-O- sulphonyl transferases (6-O-sulfotransferase, 6-
OST), one or more of 3-O- sulphonyl transferase (3-O-sulfotransferase, 3-OST) is catalyzed, and is contained described in preparation
The repetition disaccharide unit heparin sulfate derivative of substituted benzyl；
S2, under hydrogen protection, dissolves in water by the repetition disaccharide unit heparin sulfate derivative containing substituted benzyl
In, with 10%Pd/C catalytic hydrogenations or oxidizing, 15min-60min is stirred at 30 DEG C~37 DEG C, is filtered, organic solvent extraction
It takes, centrifugal concentrating water layer is to get the heparin sulfate.
Preferably, in the step S2, the hydrogen source that 10%Pd/C catalytic hydrogenations use is hydrogen or ammonium formate, catalytic amount
10wt%~50wt%；Oxidant selects one or both of dichloro dinitrile benzoquinones (DDQ), sodium perchlorate.
Preferably, in the step S2, the organic solvent is ethyl acetate, dichloromethane or chloroform etc.
The invention further relates to a kind of biological functions of heparin sulfate of present invention heparin sulfate in as research life body
And the purposes in the tool small molecule or probe of structure-activity relationship.
Cause extremely because of heparin sulfate in preparation prevention or treatment the invention further relates to a kind of heparin sulfate of the present invention
Purposes in disease medicament.
Compared with prior art, the present invention has the advantages that：
1, the method for the present invention is not necessarily to as chemical synthesis is by protecting and being deprotected tedious steps, consider region and spatial configuration
The problems such as selection, directly has characteristic preparation structure clearly and diversified heparin sulfate by enzymatic, and reaction condition is mild,
Route is short, and yield is high.
2, the method for the present invention retains to have to prepare isolates and purifies monitoring advantage fragrance label needed for heparin sulfate, meanwhile,
Can under conditions of pd/C hydrogenating catalytics or the oxidizing cracking such as DDQ slough fragrant label to prepare various structures specific
Heparin sulfate, the debenzylation methods mild condition, compatible with other protecting groups and heparin sulfate, the time is short, and yield is high.
Description of the drawings
Upon reading the detailed description of non-limiting embodiments with reference to the following drawings, other feature of the invention,
Objects and advantages will become more apparent upon：
Fig. 1 is that the enzyme chemical method of the present invention synthesizes the route map of heparin sulfate oligosaccharides；
Fig. 2 is the illustrative schemes figure to prepare heparin sulfate as raw material to nitrobenzyl glucuronic acid.
Specific implementation mode
It elaborates below to the embodiment of the present invention：The present embodiment is carried out lower based on the technical solution of the present invention
Implement, to be to prepare heparin sulfate representativeness knot to nitrobenzyl-monosaccharide or heparin sulfate disaccharides or heparin sulfate trisaccharide glucosides
Structure gives detailed embodiment and specific operating process, but the protection domain invented is not limited to following embodiments.
Embodiment
The present invention enzyme chemical method synthesis heparin sulfate oligosaccharides route as shown in Figure 1, the present embodiment illustrative schemes figure
As shown in Fig. 2, specifically comprising the following steps：
1, to the synthesis of nitrobenzyl-β-D-Glucose aldehydic acid glucosides 1
The iodine of 41.6 grams of silver carbonates (151.2mmoL), 11.6 grams of (75.6mmoL) p nitrobenzyl alcohols, catalytic amount is distinguished
80mL dichloromethane is dissolved in, is addedMolecular sieve stirs 10mins, dissolved with 20 gram 2,3,4- tri--O- acetyl group-α-D- bromines
20 milliliters of dichloromethane of generation-glucuronate (50.4mmoL) are slowly added into, and drop finishes, with masking foil encapsulation reaction 24 hours,
Ethyl acetate dilution, diatomite filtering, filtrate decompression concentration, crude product silica gel column purification, with the preparation of 95% ethyl alcohol recrystallization is added
22.1 grams to 2,3,4-O- acetyl group-β of nitrobenzyl-D-Glucose aldehydic acid glucosides methyl white solid, yield 93.4%.1H
NMR(400MHz,CDCl3)δ:8.18 (d, J=8Hz, 2H), 7.45 (d, J=8Hz, 2H), 5.26 (t, J=4Hz, 2H), 5.10
(t, J=8,4Hz, 1H), 5.02 (t, J=16Hz, 1H), 4.68 (t, J=16,12Hz, 2H), 4.06 (d, J=4Hz, 1H),
3.73(s,3H),2.03(s,3H),2.01(s,6H).13C NMR(100MHz,CDCl3)δ:169.97,169.34,169.15,
167.08,147.41,144.16,127.58,123.62,99.94,72.57,71.76,71.09,69.64,69.20,52.92,
20.43.
By 14.8 grams to nitrobenzyl 2,3,4-O- acetyl group-β-D-Glucose aldehydic acid glucosides methyl (30mmol) solution without
In water beetle alcoholic solution, 3.6 grams of lithium hydroxides (150mmoL) are added, are stirred at room temperature 4 hours, TLC monitoring process, Dowex 50WX
Resin, which is added, neutralizes excess base, and filtering is concentrated under reduced pressure to nitrobenzyl-β-D-Glucose aldehydic acid, 7.4 grams are obtained with ethyl alcohol recrystallization
The solid of white plates, yield 75%.
1H NMR(400MHz,DMSO-d6)δ:8.22 (d, J=8Hz, 2H), 7.72 (d, J=8Hz, 2H), 6.85 (s,
1H), 5.23 (t, J=4Hz, 2H), 5.00 (t, J=8Hz, 2H), 4.74 (d, J=12Hz, 1H), 4.31 (d, J=8, Hz,
1H),3.17-3.07(m,3H).
2, nitrobenzyl heparin sulfate disaccharides 2a is synthesized
329mg is dissolved in 20mL Tris (25mM, pH 7.2) to nitrobenzyl-β-D-Glucose aldehydic acid glucosides (1mmoL)
In buffer solution, then a concentration of 5mM of manganese chloride in reaction solution it is poly- to be separately added into 1.25mmoL UDP-GlcN Ac and 1.05mg
Synthase pmHS2, overnight, Poly II-HPLC monitor reaction process, C18 chromatographic columns (1.5 × 70cm, Biotage, 0 for 30 DEG C of reactions
~100% methanol aqueous solution (containing 0.1% trifluoroacetic acid) is used as mobile phase, flow velocity 2mL/min) disaccharides is purified to obtain, centrifugation is dense
Contract dry 505.4mg white powders, yield 95%.1H NMR(600MHz,H2O):8.09 (d, J=6.0Hz, 2H), 7.48
(d, J=6.0Hz, 2H), 5.23 (d, J=3.0Hz, 1H), 4.85 (d, J=12.0Hz, 1H), 4.75 (d, J=12.0Hz,
1H), 4.50 (d, J=6.0Hz, 1H), 3.95 (d, J=12.0Hz, 1H), 3.79 (dd, J=6.0,6.0Hz, 1H), 3.73-
3.70 (m, 2H), 3.65-3.56 (m, 3H), 3.50-3.42 (m, 2H), 3.32-3.30 (m, 1H), 1.93 (s, 3H) .ESI-MS
(negative ion mode), m/z:C21H28N2O14,[M-1]-Calculated value 531.15, measured value 531.75.
3, nitrobenzyl heparin sulfate trisaccharide 2b is synthesized
329mg is dissolved in 20mL Tris (25mM, pH7.2) to nitrobenzyl base-β-D-Glucose aldehydic acid glycosides (1mmoL)
In buffer solution, then a concentration of 5mM of manganese chloride in reaction solution is separately added into 1.25mmoL UDP-GlcNAc and 1.05mg polymerizations
Enzyme pmHS2,30 DEG C of reactions are stayed overnight, Poly II-HPLC monitoring reaction process, C18 chromatographic columns (1.5 × 70cm, Biotage, 0~
100% methanol aqueous solution (containing 0.1% trifluoroacetic acid) is used as mobile phase, flow velocity 2mL/min) purify to obtain disaccharides, centrifugal concentrating
Dry white powder is directly dissolved in 20mL and contains 5mM manganese chloride Tris buffer solutions (25mM, pH 7.2), is successively added
The UDP-GlcA of 1.25mmoL and polymerase pmHS2,37 DEG C of reactions overnight, (such as two glucose monitors and purify after C18 column purifications
Method) trisaccharide, centrifugal concentrating it is dry 625.4mg white powders, yield 88.1%.1H NMR(600MHz,H2O):8.08
(d, J=4Hz, 2H), 7.48 (d, J=4Hz, 2H), 5.21 (d, J=3.0Hz, 1H), 4.84 (d, J=12.0Hz, 2H), 4.74
(d, J=12.0Hz, 1H), 4.49 (dd, J=6.0,6.0Hz, 2H), 3.95 (dd, J=8.0,3.6Hz, 1H), 3.81-3.78
(m, 2H), 3.72-3.66 (m, 3H), 3.65-3.55 (m, 3H), 3.53-3.41 (m, 2H), 3.30-3.25 (m, 2H), 1.92
(s, 3H) (is calculated) with p-nitrophenyl-β-D-Glucose aldehydic acid glycosides.ESI-MS (negative ion mode), m/z:C27H36N2O20,
[M-1]-, calculated value 707.18, measured value 707.75.
4, the synthesis of glucuronic acid (3a)
329mg is dissolved in dual distilled water nitrobenzyl-β-D-Glucose aldehydic acid glucosides (1mmoL, 1), is added
40mg 10%Pd/C, are passed through hydrogen catalytic, take off to nitre benzyl, diatomite filtering, ethyl acetate extraction, water layer centrifugal concentrating obtains
194mg compound 3a, yield 100%.
1C NMR(100MHz,D2O):174.2,96.6,75.1,74.5,73.6,71.3.ESI-MS (negative ion mode),
m/z:C6H10O7, calculated value 193.04, measured value 193.04.52
5, the synthesis of heparin sulfate disaccharides 3b
53.2mg is dissolved in dual distilled water nitrobenzyl heparin sulfate disaccharides (0.1mmoL, 2a), is added
10mg10%Pd/C is passed through hydrogen catalytic, takes off to nitre benzyl, diatomite filtering, ethyl acetate extraction, water layer centrifugal concentrating obtains
38.4mg heparin sulfate disaccharides 3b, yield 96.%.ESI-MS (negative ion mode), m/z:Calculated value C14H23NO12,[M-
1]-, calculated value 396.11, measured value 396.47.
6, the synthesis of heparin sulfate trisaccharide 3c
70.8mg is dissolved in dual distilled water nitrobenzyl heparin sulfate trisaccharide (0.1mmoL, 2b), is added
10mg10%Pd/C is passed through hydrogen catalytic, takes off to nitre benzyl, diatomite filtering, ethyl acetate extraction, water layer centrifugal concentrating obtains
55.4mg heparin sulfate trisaccharide 3c, yield 96.9%.ESI-MS (negative ion mode), m/z:Calculated value C20H31NO18[M-
1]-, calculated value 572.14, measured value 572.36.
Specific embodiments of the present invention are described above.It is to be appreciated that the invention is not limited in above-mentioned
Particular implementation, those skilled in the art can make various deformations or amendments within the scope of the claims, this not shadow
Ring the substantive content of the present invention.
Claims (8)
1. a kind of heparin sulfate, structural formula are shown in formula I：
Wherein, R1, R2, R4 are respectively hydrogen or sulfonyl, and R3 is
Hydrogen, acetyl group or sulfonyl, n are any integer in 0~6.
2. a kind of enzymology synthetic method of heparin sulfate as described in claim 1, which is characterized in that with substituted benzyl-β-
D-Glucose aldehydic acid glycosidesFor starting material, in the effect of heparin sulfate biosynthesis recombinase
Under, synthesize the repetition disaccharide unit heparin sulfate derivative containing substituted benzyl
Wherein, R5 is-NO2Or-OCH3；Through Pd/C catalytic hydrogenation debenzylations, the heparin sulfate is made.
3. the enzymology synthetic method of heparin sulfate according to claim 2, which is characterized in that the heparin sulfate biology
Synthesis is selected from pmSH with recombinase2,KfiA,NST,NDST C5-Epi,2-OST,6-OST,3-OST。
4. heparin sulfate enzymology synthetic method according to claim 2, which is characterized in that the method includes walking as follows
Suddenly：
S1, at 30 DEG C~37 DEG C, using substituted benzyl-β-D-Glucose aldehydic acid glucosides as starting material, in pmSH2Or KfiA is urged
Under change, activates acetylglucosamine with UDP- or UDP- activation trifluoroacetamidos glucose, UDP- activate glucuronic acid
Alternation response extends；According to target structural requirement again, through N- sulphonyl based transferase, 2-O- sulphonyl transferase, C5Isomerase, 6-O-
One or more of sulphonyl transferase, 3-O- sulphonyl transferases are catalyzed, and prepare the repetition disaccharides list containing substituted benzyl
Position heparin sulfate derivative；
S2, under hydrogen protection, the repetition disaccharide unit heparin sulfate derivative containing substituted benzyl is dissolved in water, is used
10%Pd/C catalytic hydrogenations are oxidizing, and 15min-60min is stirred at 30 DEG C~37 DEG C, filtering, organic solvent extraction, from
The heart concentrates water layer to get the heparin sulfate.
5. heparin sulfate enzymology synthetic method according to claim 4, which is characterized in that in the step S2,10%
The hydrogen source that Pd/C catalytic hydrogenations use is hydrogen or ammonium formate, catalytic amount 10wt%~50wt%；Oxidant selects dichloro dintrile
One or both of base benzoquinones, sodium perchlorate.
6. heparin sulfate enzymology synthetic method according to claim 4, which is characterized in that described in the step S2
Organic solvent is ethyl acetate, dichloromethane or chloroform etc..
7. the biological function and structure effect of a kind of heparin sulfate as described in claim 1 heparin sulfate in as research life body
Purposes in the tool small molecule or probe of relationship.
8. a kind of heparin sulfate as described in claim 1 is preparing prevention or is treating the disease medicine caused extremely by heparin sulfate
Purposes in object.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023280235A1 (en) * | 2021-07-07 | 2023-01-12 | 山东大学 | Heparin molecule containing at binding sequence and continuous 2-o-glucuronic acid residue, and preparation method therefor and use thereof |
| WO2024046048A1 (en) * | 2022-09-01 | 2024-03-07 | 山东大学 | Anticoagulant heparin-derived oligosaccharide biphenyl dimer, and preparation method therefor and use thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023280235A1 (en) * | 2021-07-07 | 2023-01-12 | 山东大学 | Heparin molecule containing at binding sequence and continuous 2-o-glucuronic acid residue, and preparation method therefor and use thereof |
| WO2024046048A1 (en) * | 2022-09-01 | 2024-03-07 | 山东大学 | Anticoagulant heparin-derived oligosaccharide biphenyl dimer, and preparation method therefor and use thereof |
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