CN109651457A - The compound and its potential application that a kind of alternative induction Th2 immune cell factor generates - Google Patents
The compound and its potential application that a kind of alternative induction Th2 immune cell factor generates Download PDFInfo
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- CN109651457A CN109651457A CN201910086080.XA CN201910086080A CN109651457A CN 109651457 A CN109651457 A CN 109651457A CN 201910086080 A CN201910086080 A CN 201910086080A CN 109651457 A CN109651457 A CN 109651457A
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- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/26—Acyclic or carbocyclic radicals, substituted by hetero rings
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
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- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Transplantation (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Crystallography & Structural Chemistry (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
The present invention relates to the preparation method and applications of the novel glycoside ceramide-analogous with immunoregulatory activity, belong to chemistry and pharmaceutical technology field.We have designed and synthesized compound (R of a kind of saccharide ring by modification based on the structural analysis to receptor, binding molecule docking and means of molecular dynamics simulation technique1Or R2Position introduces tryptophan, glutamate derivatives or para hydroxybenzene propionic acid respectively), bioactivity research shows that this kind of compound has Th2 selectivity, there is the potential for drug.Designed new compound has following main composite character: R1For hydroxyl or pass through the L-Trp derivative of amide condensed reaction forming；R2For hydroxyl, or the Pidolidone derivative or P-hydroxybenzoic acid that pass through amide condensed reaction forming；R3For-OBn, R4For-N3；Or R3For-N3, R4For-OBn；R5It can be SEt, S-iPr, SPh, STol, OC (NH) CCl3Equal substituent groups.
Description
Technical field
The present invention relates to the preparation method and applications of the novel glycoside ceramide-analogous with immunoregulatory activity,
Belong to chemistry and pharmaceutical technology field.
Background technique
Takenori Natori et al. is in 1993 isolated one from the spongy tissue of Okinawa Japan surrounding waters
Serial glycosyl sphingolipid class compound Agelasphins (α-galactosylceramides, α-Galcers), such as
Agelasphins-9b has stronger anticancer activity.Nineteen ninety-five Japan Kyowa Hakko Kirin company is such clear chemical combination
The structure-activity relationship (SAR) of object, has synthesized a series of Agelasphins-9b analogs, and KRN7000 has wide as one of them
The bioactivity such as general antiviral and antitumor, anti-inflammatory and treatment autoimmune disease, efficient immunoregulatory activity is most
To be noticeable, and combine more convenient (without hydroxyl on acyl-fatty chain), it is considered to be optimal time in clinical application
Select drug.
The immunostimulation mechanism of KRN7000 is: α-Galcer with CD1d protein binding, forms CD1d/ α-Galcer first
Binary complex is then identified by the T cell receptor on NKT cell surface, forms CD1d/ α-Galcer/TCR tri compound
Object, and then NKT cell is stimulated to generate a large amount of IFN-γ (cell factor for mediating Th1 cell differentiation), IL-4 (mediation Th2 cell
The cell factor of differentiation) etc. cell factors.But promote to the process non-selectivity a large amount of points of Th1 and Th2 cell factor simultaneously
It secretes and the antagonism of Th1 and Th2 cell factor has seriously undermined its therapeutic effect, affect and developed as therapeutic agent
Process.Therefore, the structure-activity relationship of KRN7000 and its derivative is studied, improving its Th1 and Th2 selectively has important research
And application value.
Structural modification to KRN7000 mainly includes for four glycosidic bond, ceramide side chain, fat chain, glycosyl parts
Modification, some artificial synthesized α-GalCer analogs break up with showing preferable induction NKT cell selective Th1 or
The biological effect of Th2.Currently, having focused largely in its anticancer activity (tool Th1 selectivity to the research of α-Galcer analog
Immune response), but the autoimmune types disease such as non-obese patients with type Ⅰ DM, multiple sclerosis, systemic loupus erythematosus is also serious
The health of the mankind is endangered, therefore, the analog of design synthesis tool Th2 selectivity immune response is of great significance.The study found that
When the half life of CD1d/ α-GalCer/TCR ternary complex, be conducive to the Th2 selectivity for generating immune response.Such as
By shortening acyl-fatty chain or phytosphingosine aliphatic chain chain length, double bond, sulfonyl or three nitrogen are introduced into acyl-fatty chain
Azoles substituted amide key, to two F atoms of amido bond α introducings, 6 " position of glycosyl connects the modification such as armaticity substituent, realizes
NKT cell selective breaks up Th2 cell.
Takashi Yamamura seminar (does not change α-GalCer glycosyl part, shortens acyl in the OCH of synthesis in 2001
Base aliphatic chain and phytosphingosine aliphatic chain) break up Th2 cell with can induce NKT cell selective, but it induces mechanism still not
Clear, they guess to may be to affect hydrophilic area gala because the binding force of OCH and CD1d weaken compared with α-GalCer
The orientation of sugar, and then influence the interaction between galactolipin hydrophilic area and TCR.Bioactivity research discovery to OCH,
OCH can be effectively prevented and treated mice with experimental autoimmune encephalomyelitis, and not generate mouse over the course for the treatment of
Quick property shock；In addition, OCH can also increase the quantity of NKT cell in liver.But it induces people NKT cell to generate immune ring
The Th2 answered is selectively not obvious.
Chi-Huey Wong seminar in 2006 propose: may have factors affect Th1 and Th2 cell because
The release of son, the stability of CD1d/ α-GalCer are one of reason.Unstable CD1d/ α-GalCer can shorten thin to NKT
The stimulation time of born of the same parents is conducive to the immune response for generating tool Th2 selectivity, and correspondingly, stable CD1d/ α-GalCer can be with
Extend the stimulation time to NKT cell, is conducive to the immune response for generating tool Th1 selectivity.But the stabilization of α-GalCer/TCR
The selectivity how property or the stability of CD1d- α-GalCer/TCR influence Th1/Th2 not yet has been reported that.
Summary of the invention:
The present invention is based on the structural analysis to receptor, binding molecule docking and means of molecular dynamics simulation technique are designed and are closed
At a kind of α-GalCer analog, that is, passes through the glycosyl and its fat chain part to α-GalCer while being modified to obtain
NKT cell selective can be effectively induced to break up Th2 cell.We are modified (4 ", 6 " positions on the basis of OCH, to its saccharide ring
Tryptophan, glutamate derivatives or P-hydroxybenzoic acid, calculated result is introduced respectively to show to increase the binding force with TCR),
Obtain the a-GalCer analog with Th2 selectivity.
Invention also provides a kind of synthetic method of novel alpha-GalCer analog, compound has following structure spy
Point:
(1) work as R1=OH,When, it is HU_ZHAO_2018-1. by the Compound nomenclature
(2) work as R1=OH,When, it is HU_ZHAO_2018-2. by the Compound nomenclature
(3) whenR2It is HU_ZHAO_2018-3. by the Compound nomenclature when=OH
The preparation method of novel alpha-GalCer analog, it is characterised in that this method includes the following steps:
The specific synthesis step of above-mentioned route are as follows:
(1) D-MANNOSE successively protects adjacent hydroxyl, the different head position hydroxyl of benzyl protection to obtain intermediate 2 through acetonylidene；
(2) intermediate 2 obtains aldehyde through 5,6 acetonylidene protecting groups of periodic acid selective ablation, after through sodium borohydride also
Original obtains intermediate 3；
(3) intermediate 3 removes benzyl through catalytic hydrogenation, obtains intermediate 4；
(4) intermediate 4 reacts to obtain intermediate 5 with tert-butyl chloro-silicane；
(5) intermediate 5 obtains intermediate 6 through Witting Reaction；
(6) intermediate 6 first obtains reduzate through catalytic hydrogen reduction double bond, after obtained through Mitsnobu Reaction
To intermediate 7；
(7) intermediate 7 first obtains reduzate through Staudinger Reaction, after through amide condensed obtain centre
Body 8；
(8) intermediate 8 obtains intermediate 9 under the action of hydrofluoric acid pyridine complex or tetrabutyl ammonium fluoride；
(9) receptor 9 reacts to obtain coupled product 11 with donor 10 under the effect of the catalyst；
(10) intermediate 11 obtains reduzate through Staudinger Reaction, later with amino acid derivativges or right
Hydroxybenzoic acid derivative obtains intermediate 12 through amide condensed；Condensation reagent can choose 2- (7- azo benzotriazole)-
N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate
(EDCI)/I-hydroxybenzotriazole (HOBt), 1- n-propyl phosphoric anhydride (T3P) etc.
(11) intermediate 12 obtains α-GalCer analog through deprotection.Wherein, the step of intermediate 11 to intermediate 13
Sequence can be adjusted according to the design feature of different target molecule.
The advantages of route is: reaction condition is mild, easy to operate, can be used in preparation of industrialization.Synthetic route can
It is used to prepare different types of α-GalCer analog.
Specific embodiment:
The embodiment of the present invention (by taking HU_ZHAO_2018-1 as above as an example) presented below:
The synthesis of compound 2:
At room temperature, mannose (1eqv) is dissolved in acetone soln, is added the iodine of catalytic amount, react at room temperature 5h, with full
It is quenched, is evaporated with hypo solution, ethyl acetate and water extraction, dry organic phase are concentrated to give crude product, crude product are dissolved in
It in tetrahydrofuran solution, sequentially adds solid potassium hydroxide (1.8eqv), crown ether -6 18- of catalytic amount, cylite (1.1eqv),
30min is reacted at room temperature, saturated ammonium chloride solution quenching reaction, ethyl acetate and water extraction, dry organic phase, concentration, column is added
Chromatography obtains intermediate 2, and two step gross production rates are 80%.
The synthesis of compound 3:
Compound 2 (1eqv) is dissolved with ethyl acetate, under condition of ice bath be added periodic acid (1.5eqv), 5min move back to
30min is reacted under room temperature, is concentrated, is dissolved with methylene chloride, filters, filtrate is concentrated, is dissolved with dehydrated alcohol, and boron is added
Sodium hydride (1.5eqv) reacts at room temperature 1h, and reaction solution is cooled to 0 DEG C, acetone is added, and stirs 10min, concentration, methylene chloride
It is extracted with water, dry organic phase, concentration, column chromatography obtains intermediate 3, and two step successive reaction gross production rates are 68%.
The synthesis of compound 4:
At room temperature, intermediate 3 is dissolved in methanol, Pd (OH) is added thereto2- C, glacial acetic acid, by system in H2
It reacts overnight, filters under (4.5atm), filtrate concentration, column chromatography obtains intermediate 4, yield 88%.
The synthesis of compound 5:
Intermediate 4 (1eqv) is dissolved with methylene chloride, sequentially adds imidazoles (2.5eqv), tert-butyl diphenyl chlorosilane
(1.2eqv) reacts at room temperature 3h, concentration, ethyl acetate and water extraction, and dry organic phase is concentrated, and column chromatography obtains intermediate 5.
Yield is 90%.
The synthesis of compound 6:
Intermediate 5 (1eqv) is added in flask a, dry tetrahydrofuran solution is added, it is double to delay addition under condition of ice bath
Trimethyl silicon substrate amido lithium (1eqv)；Normal-butyl tri-phenyl-phosphorus bromide (3eqv) is added in flask b, dry tetrahydro furan is added
It mutters solution, delays under condition of ice bath and lithium hexamethyldisilazide (3eqv) is added, by the reaction solution in above-mentioned a, b flask in ice bath
Reaction solution in b flask is added a flask, reacts 6h, saturated ammonium chloride solution, acetic acid second are added into system by lower reaction 1h
Ester and water extraction, dry organic phase, concentration, column chromatography obtain intermediate 6.Yield is 78%.
The synthesis of compound 7:
Intermediate 6 (1eqv) is dissolved in ethyl acetate, is added Pd (OH)2- C, hydrogenation reaction 30min, filter, and filtrate is dense
Contracting, obtains reduzate crude product, is dissolved with dry tetrahydrofuran solution, sequentially adds triphenylphosphine (2.2eqv) under ice bath, even
Nitrogen dioctyl phthalate diisopropyl ester (2.2eqv) is slowly added to diphenyl phosphate azide (2.2eq v), 5min is moved back after stirring 5min
It to room temperature sustained response 3h, is concentrated under reduced pressure, ethyl acetate and water extraction, dry organic phase, concentration, column chromatography obtains intermediate 7.
Yield is 88%.
The synthesis of compound 8:
Intermediate 7 (1eqv) is dissolved in pyridine/water (v/v=10/1), is added triphenylphosphine (2eqv), is reacted at 40 DEG C
5h, concentration, ethyl acetate and water extraction, dry organic phase are concentrated to get reduzate, by itself and lignoceric acid (1.3eqv)
It is dissolved in DMF, is sequentially added under ice bath triethylamine (2eqv), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine hydrochloric acid
Salt (1.5eqv), I-hydroxybenzotriazole (1.5eqv), overnight, concentration, ethyl acetate and water extraction, drying have for reaction at room temperature
Machine phase, concentration, column chromatography obtain intermediate 8.Two step successive reaction gross production rates are 58%.
The synthesis of compound 9:
Intermediate 8 (1eqv) is dissolved into tetrahydrofuran, is added TBAF (2eqv), after reaction 1 hour, saturation chlorine is added
Change aqueous ammonium, ethyl acetate and water extraction, dry organic phase is concentrated, and column chromatography obtains intermediate 9, yield 96%.
The synthesis of compound 11:
N2Under protection, intermediate 9 (1eqv) is added into flask, is dissolved with methylene chloride, is addedMolecular sieve, at 0 DEG C
It sequentially adds N- N-iodosuccinimide (1.5eq), trifluoromethanesulfonic acid trimethyl silicone grease (0.5eqv), until after clear solution, with
Constant pressure funnel delays the donor 10 for being dissolved in methylene chloride in instillation system, and 3h is reacted at 0 DEG C, and saturated sodium thiosulfate is added
Solution and saturated sodium bicarbonate solution quenching reaction filter, extraction, dry organic phase, concentration, and column chromatography obtains intermediate 11,
Yield is 40%.
The synthesis of compound 12:
Intermediate 11 (1eqv) is dissolved in pyridine/water mixed solvent, is added triphenylphosphine (2eqv), was reacted at 30 DEG C
Night, concentration, ethyl acetate and water extraction, dry organic phase are concentrated to get reduzate, by itself and tryptophan derivative (2eqv)
It is dissolved in DMF, is sequentially added under ice bath triethylamine (2eqv), 1- ethyl-(3- dimethylaminopropyl) phosphinylidyne diimine hydrochloric acid
Salt (1.5eqv), I-hydroxybenzotriazole (1.5eqv), overnight, concentration, ethyl acetate and water extraction, drying are organic for room temperature reaction
Phase, concentration, column chromatography obtain intermediate 12.Two step successive reaction gross production rates are 90%.
The synthesis of compound 13:
Intermediate 12 is dissolved in THF/MeOH in the mixed solvent, HCl (3M) is added thereto, reacts 12h, Xiang Ti at room temperature
Pd (OH) is added in system2- C, hydrogenation reaction 5h, the hydrochloric acid in basic resin and in system, filter, and filtrate concentration, column chromatography obtains
To target molecule 13, two-step reaction yield is 58%.
Claims (5)
1. the compound with inducing T cell selectively secretion Th2 para-immunity cell factor, structure feature are as follows:
(1) work as R1=OH,When, it is HU_ZHAO_2018-1 by the Compound nomenclature；
(2) work as R1=OH,When, it is HU_ZHAO_2018-2 by the Compound nomenclature；
(3) whenR2It is HU_ZHAO_2018-3 by the Compound nomenclature when=OH.
2. compound according to claim 1, R1When for hydroxyl, R2To pass through the Pidolidone of amide condensed reaction forming or right
Hydroxy phenylpropionic acid (HU_ZHAO_2018-1 and HU_ZHAO_2018-2)；Work as R2When for hydroxyl, R1To be connected by amide condensed reaction
The L-Trp derivative (HU_ZHAO_2018-3) connect.
3. the combination drug component part that the compound in claim 1 is used as treatment autoimmune disease.
4. compound according to claim 1, preparation is characterized in that:
Wherein, R1For hydroxyl or pass through the L-Trp derivative of amide condensed reaction forming；R2For hydroxyl, or passes through amide and contract
Close the Pidolidone derivative or para hydroxybenzene propionic acid of reaction forming；R3For-OBn, R4For-N3；Or R3For-N3, R4For-OBn；
R5It can be SEt, S-iPr, SPh, STol, OC (NH) CCl3Equal substituent groups；Work as R5When for SEt, SPh, STol, catalyst can be three
Fluorine methanesulfonic acid, boron trifluoride ether, trifluoromethanesulfonic acid trimethyl silicone grease, trifluoromethanesulfonic acid triethyl group silicone grease, tert-butyl diformazan silicon
Base triflate etc.；Work as R5For OC (NH) CCl3When, catalyst can be boron trifluoride ether, trifluoromethanesulfonic acid trimethyl silicane
The custom catalysts such as rouge, trifluoromethanesulfonic acid triethyl group silicone grease, tert-butyl dimethyl silyl triflate；Solvent can be dichloro
The organic solvents such as methane, ether, tetrahydrofuran, toluene.
5. this is that we survey its bioactivity for the compound that such alternative induction Th2 immune cell factor generates
Test result data:
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| CN114805454B (en) * | 2021-01-21 | 2023-07-18 | 中国科学院生态环境研究中心 | Alpha-galactose ceramide compound, and preparation method and application thereof |
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