WO2022016755A1 - Conjugué de dérivé de tréhalose et d'antigène glucidique, procédé de préparation correspondant et utilisation associée - Google Patents

Conjugué de dérivé de tréhalose et d'antigène glucidique, procédé de préparation correspondant et utilisation associée Download PDF

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WO2022016755A1
WO2022016755A1 PCT/CN2020/130230 CN2020130230W WO2022016755A1 WO 2022016755 A1 WO2022016755 A1 WO 2022016755A1 CN 2020130230 W CN2020130230 W CN 2020130230W WO 2022016755 A1 WO2022016755 A1 WO 2022016755A1
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compound
conjugate
trehalose
preparation
nhc
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PCT/CN2020/130230
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English (en)
Chinese (zh)
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廖国超
刘中秋
李文伟
练庆海
杨德盈
吴鹏
卢琳琳
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广州中医药大学(广州中医药研究院)
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Publication of WO2022016755A1 publication Critical patent/WO2022016755A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the technical field of chemistry and medicine, in particular to a conjugate of a trehalose derivative and a saccharide antigen and a preparation method and application thereof.
  • TACAs Tumor-associated carbohydrate antigens
  • TACAs tumor-associated carbohydrate antigens
  • TACAs tumor-associated carbohydrate antigens
  • the classic strategy is to conjugate carbohydrate antigens with carrier proteins to enhance their immunogenicity, but glycoprotein vaccines have disadvantages such as uncertain coupling sites, unstable coupling rates, and complex components.
  • the total synthesis strategy of tumor-related carbohydrate antigen vaccines has become one of the new research hotspots; the fully synthetic carbohydrate antigen vaccines have the advantages of clear structure, stable and controllable quality, etc., which are convenient for various immunological and clinical studies.
  • sugar molecules on the surface of various pathogenic bacteria can be used as embedded adjuvants for fully synthesized sugar antigen tumor vaccines, which can not only overcome the shortcomings of the weak immunogenicity of sugar antigens, but also avoid the "epitope" caused by proteins. suppress” effect.
  • Trehalose-6,6-dimycolate (TDM, cord factor) is an important glycolipid component in the cell wall of Mycobacterium tuberculosis, consisting of trehalose and two mycolate chains; this glycolipid can cause inflammatory responses , and has certain cytotoxicity to tumor cells. Studies have shown that the derivatives of trehalose-6,6-dimycolate, Vizantin and TDE, have high immune activity and low toxicity, and can be used as effective adjuvants for vaccine research.
  • the object of the present invention is to provide a conjugate of a trehalose derivative and a carbohydrate antigen.
  • the present invention uses potent immunostimulators trehalose derivatives Vizantin and TDE as built-in adjuvants to conjugate sugar antigens (STn, Tn) respectively to obtain the conjugates, wherein trehalose derivatives can improve the immunogenicity of sugar antigens , the conjugate can induce T cell-mediated humoral immunity, produce high-concentration high-affinity IgG antibody, and achieve the purpose of specifically killing tumor cells.
  • Another object of the present invention is to provide a method for preparing the conjugate of the trehalose derivative and carbohydrate antigen.
  • Another object of the present invention is to provide the application of the conjugate of the trehalose derivative and the saccharide antigen in the preparation of tumor vaccine.
  • Another object of the present invention is to provide the application of the conjugate of the trehalose derivative and the carbohydrate antigen in the preparation of antitumor drugs.
  • X represents a carbohydrate antigen, selected from any one of the carbohydrate antigens in the following formula, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • L represents a linker, selected from the following (CH 2 CH 2 O) a -CH 2 CH 2 -C(O)NH-, (CH 2 CH 2 O) a -, -(OCH 2 CH 2 ) a -NHC(O)-(CH 2 CH 2 O) a -CH 2 CH 2 -C(O)NH-, -NHC(O)-(CH 2 CH 2 O) a -CH 2 CH 2 -(OCH 2 CH 2 ) a -CH 2 CH 2 -C(O)NH-, (CH2) a -C(O)NH-, -NHC(O)-(CH 2 ) a -C(O)NH-, -NHC(O)-(CH 2 ) a Any of , a is any integer from 0 to 20;
  • Y represents a trehalose derivative, selected from any one of the following formulae, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • R 1 and R 2 are each independently selected from hydrogen, -CH 2 -CH(OR 3 )-(CH 2 ) m -CH 3 , -(CH 2 ) m CH 3 or -(CH 2 ) m CHR 3 2 , R 3 is -(CH 2 ) m -CH 3 or -C(O)-(CH 2 ) m -CH 3 , m is an integer selected from 8-26.
  • the L is selected from (CH 2 CH 2 O) a -, -(OCH 2 CH 2 ) a -NHC(O)-(CH 2 CH 2 O) a -CH 2 CH 2 (CH2) a -C(O)NH-, -NHC(O)-(CH 2 ) a Any of , where a is any integer from 0 to 20.
  • the L is selected from (CH 2 CH 2 O) a -, -(OCH 2 CH 2 ) a -NHC(O)-(CH 2 ) a Any of , where a is any integer from 0 to 20.
  • the Y is selected from any one of the following formulae, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • R 1 and R 2 are each independently selected from hydrogen, -(CH 2 ) m CH 3 or -(CH 2 ) m CHR 3 2 , and R 3 is -(CH 2 ) m -CH 3 or -C(O )-(CH 2 ) m -CH 3 , m is an integer selected from 8-26.
  • the Y is selected from any one of the following formulae, or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • R 1 and R 2 are each independently selected from hydrogen or -(CH 2 ) m CH 3 , and m is an integer selected from 8-26.
  • the conjugate is selected from any of the following structures or a pharmaceutically acceptable salt, hydrate or solvate thereof:
  • the preparation method of the conjugate of trehalose derivative and saccharide antigen when Y is , the preparation process includes:
  • compound 10 reacts with compound Tn or STn, compound 11 and compound STn respectively under the action of a catalyst to obtain compound 19 or 20, compound 21;
  • the preparation process includes;
  • Compound 22 or 23 are respectively subjected to debenzylation protection reaction to obtain the target product;
  • the catalyst of the debenzylation protection reaction is hydrogen/palladium carbon/palladium hydroxide, hydrogen/palladium carbon or hydrogen/palladium hydroxide, etc., preferably hydrogen/palladium carbon;
  • the solvent used in the reaction is Dichloromethane/methanol/water, dichloromethane, methanol or dichloromethane/methanol, etc.; preferably dichloromethane/methanol/water.
  • the catalyst for the reaction is cuprous iodide/N,N-diisopropylethylamine or cuprous iodide/N,N-diisopropylethylamine/glacial acetic acid, etc.; Cuprous iodide/N,N-diisopropylethylamine is preferred; the reaction solvent is dichloromethane, dichloromethane/methanol or tetrahydrofuran/methanol, etc.; tetrahydrofuran/methanol is preferred.
  • the catalyst for the reaction is an aqueous solution of boron trifluoride ethyl ether or trifluoroacetic acid, etc., preferably boron trifluoride ethyl ether;
  • the solvent for the reaction is acetonitrile, dichloromethane or tetrahydrofuran, etc., preferably acetonitrile.
  • the condensation reagent in the reaction process can be selected from 4-dimethylaminopyridine (DMAP)/1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methyl Iodonium salt (EDC MEI), N,N'-dicyclohexylcarbodiimide (DCC)/4-dimethylaminopyridine (DMAP) or 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (EDC. HCl) / 4- dimethylaminopyridine (DMAP) was the like, preferably DMAP / EDC. HCl.
  • DMAP 4-dimethylaminopyridine
  • EDC MEI 4-dimethylaminopyridine
  • EDC MEI 4-dimethylaminopyridine
  • DCC N,N'-dicyclohexylcarbodiimide
  • DMAP 1-(3-dimethylaminopropyl)-3-e
  • the preparation process of compound 7 is as follows:
  • the catalyst for the reaction is triethylsilane/trifluoromethanesulfonic acid or sodium cyanoborohydride/diethyl ether hydrochloride; the reaction is performed in a solvent such as dichloromethane, methanol or tetrahydrofuran.
  • the catalyst for the reaction is sodium cyanoborohydride/diethyl ether hydrochloride; the reaction is carried out in a solvent dichloromethane.
  • the above-mentioned preparation route of the present invention is short, the reaction conditions are mild, the yield is high, and the operation is convenient, and can be used for industrial preparation.
  • the tumor vaccine or anti-tumor drug is breast cancer, uterine cancer, ovarian cancer, lung cancer, liver cancer, prostate cancer, melanoma, pancreatic cancer, intestinal cancer, renal cell cancer, cellular lymphoma, thyroid cancer , brain cancer, stomach cancer or leukemia vaccines or drugs.
  • the present invention has the following beneficial effects:
  • the present invention uses potent immunostimulators trehalose derivatives Vizantin and TDE as built-in adjuvants to conjugate sugar antigens (STn, Tn) respectively to obtain the conjugates, wherein trehalose derivatives can improve the immunogenicity of sugar antigens , so that the conjugate can induce T cell-mediated humoral immunity, generate high concentration and high affinity IgG antibody, achieve the purpose of specifically killing tumor cells, and can be prepared as a tumor vaccine or an anti-tumor drug for application.
  • FIG. 1 is a graph showing the evaluation of the immune activity of antibodies produced in mice induced by vaccines prepared with conjugates 1, 2, 3 and 4.
  • FIG. 1 is a graph showing the evaluation of the immune activity of antibodies produced in mice induced by vaccines prepared with conjugates 1, 2, 3 and 4.
  • Figure 2 is a graph showing the evaluation of complement-dependent cytotoxicity of antibody serum produced by vaccine-induced mice produced by conjugates 1, 2, 3 and 4 to specifically kill tumor cell MCF-7.
  • test methods used in the following examples are conventional methods unless otherwise specified; the materials, reagents, etc. used are commercially available reagents and materials unless otherwise specified.
  • reaction was carried out at room temperature for 18 h, the reaction solution was cooled to 0 °C, a small amount of methanol solution was dropped to quench the reaction, diluted with ethyl acetate, the mixture was washed with saturated brine, the organic layer was collected, concentrated to obtain the crude product, and purified by silica gel column chromatography to obtain compound 6 as a white solid (14.90 g, 78.4%).
  • Tetrabutylammonium bromide (6eq); reacted at room temperature for 4h, the reaction solution was cooled to 0°C, slowly added dropwise with a small amount of methanol to quench the reaction, diluted with dichloromethane, rinsed with saturated sodium bicarbonate solution and saturated brine successively, and collected organic The phase was concentrated under reduced pressure, and the purified compound 13 (380.01 mg, 97%) was separated and purified by silica gel column.
  • HEPES hydroxyethylpiperazine ethanethiosulfonic acid
  • mice C57BL/6 mice aged 6-8 weeks were taken and divided into four groups with 6 mice in each group.
  • the immunization test was carried out by subcutaneous injection of mice, and the liposomes 1, 2, and 3 prepared in step (1) were injected on the 1st, 14th, 21st, and 28th days respectively with the scheme of one initial immunization and three boosting immunizations. 4.
  • the injection volume of each mouse is 0.1 mL. Blood is collected on the 0, 27, 35, and 49 days, and 0.1 mL to 0.2 mL of blood is collected from each mouse, placed at 4°C for half an hour, centrifuged at 5000 rpm, and separated. Top layer clearing serum.
  • the blank control group pre-immune serum
  • the vaccine titer was measured using the blood collected on the 35th day.
  • ELISA immunoassay Use 0.1M carbonate buffer (pH 9.6) to prepare Tn-HSA or STn-HSA into a 2.0 ⁇ g/mL solution, add 100 ⁇ L per well to a 96-well plate, and put 4 Incubate overnight at °C; incubate at 37 °C for one hour the next day; wash the plate three times with PBST (PBS+0.05% Tween-20), and add 300 ⁇ L of washing solution to each well. After washing the plate, add blocking buffer (PBST/1% BSA); add 250 ⁇ L to each well; incubate at room temperature for one hour, and wash the plate three times with PBST.
  • PBST blocking buffer
  • the sample serum was diluted with PBS from 1:300 to 1:656100 times according to the half-dilution method; the diluted serum was added to 96-well plate at 100 ⁇ L per well, placed in a 37°C incubator for two hours, and washed. plate three times.
  • 100 ⁇ L of HRP (horseradish peroxidase)-labeled Kappa, IgG, and IgM were added to each well, and incubated at room temperature for one hour; the plate was washed 3 times.
  • Add TMB (3,3',5,5'-tetramethylbenzidine) solution add 100 ⁇ L to each well, and develop color at room temperature for 20 min in the dark.
  • 0.5M H 2 SO 4 solution was added to each well 100 ⁇ L. Absorbance was detected with a microplate reader at dual wavelengths of 450-570 nm.
  • the conjugates 1, 2, 3 and 4 of trehalose derivatives and carbohydrate antigens synthesized in Example 1 of the present invention can all induce high titers without adjuvant.
  • the specific IgG antibody titer produced is more than 2 to 3 times that of IgM, indicating that the covalently conjugated carbohydrate antigen vaccine can induce T cell-mediated humoral immunity; among them, the conjugate vaccine 1 double-linked STn antigen and
  • the titers of IgG antibodies elicited by 2 were slightly higher than those of conjugates 3 and 4, which were single-attached to the antigen, indicating that the more complex the space of the antigen, the more epitopes, had a certain promoting effect on the immune response;
  • the fatty acid chain of trehalose derivatives was Conjugate vaccines 1 and 3 with branched CH(C 9 H 19 ) 2 induced slightly higher antibodies than conjugate vaccines 2 and 4 with fatty acid chain (CH 2 ) 20 CH 2
  • CT-26 cells (mouse colon cancer cells) in logarithmic growth phase were trypsinized, seeded in 96-well plates at 1 ⁇ 10 4 cells per well, cultured overnight at 37°C, and cultured with serum-free 1640 The substrate was washed twice. Take the serum samples of 6 mice in the compound 1 group on 38 days, take 7 ⁇ l of each sample, then mix the serum samples of the 6 mice, and dilute 50 times with serum-free 1640 medium to obtain mouse serum Diluent. The mouse serum dilutions of compound group 2, group 3, group 4 and blank control group were prepared according to the above method.
  • Group 1, Group 2, Group 3, Group 4 and blank control group were set as the maximum enzyme activity control group, sample control group and sample treatment group, each group was made 6 replicate wells in parallel, each well 100 ⁇ l of diluted mouse serum solution was added, and the 96-well plate was incubated at 37° C. for 2 h. After washing the plate twice with serum-free 1640 medium, 100 ⁇ l of rabbit complement serum solution was added to each well of the sample treatment group, 100 ⁇ l of LDH release solution was added to each well of the maximum enzyme activity control group, and 100 ⁇ l of LDH release solution was added to each well of the sample control group. Serum in MEM medium and cultured at 37°C for 1 h.
  • Cell lysis rate (%) (absorbance of sample treatment group-absorbance of sample control group)/(absorbance of maximum enzyme activity control group-absorbance of sample control group) ⁇ 100%.

Abstract

La présente invention relève du domaine technique de la chimie et des médicaments. L'invention concerne un conjugué de dérivé de tréhalose et d'antigène glucidique, un procédé de préparation correspondant et une utilisation associée. Le conjugué selon la présente invention est obtenu en utilisant du tréhalose en tant qu'adjuvant incorporé et en couplant le tréhalose avec un antigène glucidique associé à une tumeur (STn ou Tn) exprimé de manière anormale sur la surface d'une cellule tumorale. Le conjugué présente les avantages d'être transparent dans la structure, simple et pratique dans le procédé de synthèse, stable et pouvant être contrôlé concernant la qualité de produit, et analogues, et en particulier, un vaccin peut surmonter le défaut d'immunogénicité faible de l'antigène glucidique et peut induire la génération d'un anticorps IgG spécifique à haute affinité, de telle sorte que l'effet antitumoral de destruction de cellules tumorales de manière ciblée est obtenu.
PCT/CN2020/130230 2020-07-20 2020-11-19 Conjugué de dérivé de tréhalose et d'antigène glucidique, procédé de préparation correspondant et utilisation associée WO2022016755A1 (fr)

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CN111875649B (zh) * 2020-07-20 2021-12-17 广州中医药大学(广州中医药研究院) 一种海藻糖衍生物与糖抗原的缀合物及其制备方法与应用

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CN111875649A (zh) * 2020-07-20 2020-11-03 广州中医药大学(广州中医药研究院) 一种海藻糖衍生物与糖抗原的缀合物及其制备方法与应用

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