WO2021142581A1 - 一种糖苷化合物及其制备方法和应用 - Google Patents

一种糖苷化合物及其制备方法和应用 Download PDF

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WO2021142581A1
WO2021142581A1 PCT/CN2020/071809 CN2020071809W WO2021142581A1 WO 2021142581 A1 WO2021142581 A1 WO 2021142581A1 CN 2020071809 W CN2020071809 W CN 2020071809W WO 2021142581 A1 WO2021142581 A1 WO 2021142581A1
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compound
glycoside compound
glycoside
present
group
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PCT/CN2020/071809
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French (fr)
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程薇颖
程青格
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郑州市御合源生物科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • 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
    • 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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  • the present invention relates to the technical field of chemistry and medicine, in particular to a glycoside analog with anticancer effect, a preparation method thereof and its application in immune anticancer.
  • Alpha-galactoseceramide represented by KRN7000 has shown good anti-tumor activity. Its mechanism of action is mainly to activate NKT cells by forming a ternary complex of presenting cell CD1d protein/KRN7000/NKT cell surface TCP protein. Achieve the secretion of Th1 or Th2 cytokines to achieve immune-driven anti-tumor activity.
  • KRN7000 derivatives developed so far can simultaneously activate Th1 and Th2 cytokines in vivo, but the antagonism between them limits the clinical application of KRN7000. Therefore, designing and synthesizing new glycoside compounds to selectively activate T cells and improve their clinical application potential is an important goal pursued by relevant scientific researchers.
  • the present invention provides a glycoside compound having the structure described in compound 1:
  • the present invention also includes the pharmaceutical use of the aforementioned glycoside compounds for preparing vaccines.
  • the vaccine increases the content of lymphocytes and monocytes in the blood after vaccination.
  • the present invention also includes the use of the above-mentioned glycoside compounds for preparing drugs for inhibiting tumors.
  • said inhibiting tumor includes inhibiting tumor size and/or migration.
  • the present invention also provides a pharmaceutical composition, which includes the glycoside compound and a pharmaceutically acceptable excipient.
  • the present invention also includes the use of the above-mentioned pharmaceutical composition in the preparation of a medicament for stimulating the immune system in a mammal, wherein the glycoside compound is adjusted to administer an effective amount of the pharmaceutical composition to the mammal.
  • the mammal has cancer.
  • the cancer is breast cancer.
  • the present invention also provides a preparation method of the aforementioned glycoside compound, which comprises the following steps:
  • the present invention has the following advantages:
  • the novel glycoside compound of the present invention has the structure shown in compound 1.
  • the invention strengthens the hydrogen bond interaction between the glycoside compound and the receptor protein by introducing multiple hydroxyl groups on the side chain, improves the affinity of the glycoside compound and CD1d, and improves its immune and anti-cancer activity. It can be known from animal experiments that the glycoside compound of the present invention exhibits an efficiency equivalent to that of clinical cyclophosphamide in inhibiting lymphoma, and the combined experiment of cyclophosphamide and the compound has a better tumor-inhibiting effect.
  • the glycoside compound of the present invention can also increase the number of lymphocytes and monocytes in the blood of mice, indicating that the glycoside compound of the present invention can stimulate the immune system of mammals, thereby producing a strong immunosuppressive ability of tumors.
  • the glycoside compound of the present invention can inhibit tumor cell migration, and the intensity of inhibition is directly proportional to the ability to inhibit migration.
  • the glycoside compound shown in compound 1 of the present invention has higher immune and anti-cancer activity, and can inhibit tumor metastasis.
  • the present invention uses chemical methods to synthesize the glycoside compound shown in compound 1 for the first time.
  • the ortho-dihydroxy compound 6 is prepared, and then the target compound 1 is prepared by multi-step reaction of phytosphingosine and the vicinal diol compound 6.
  • the preparation method of the glycoside compound of the present invention has high total yield, easy control of the reaction process, simple conventional processing, and easy mass preparation.
  • Figure 1 is the structural formula of glycoside compound 1.
  • Figure 2 shows the number of lymphocytes in the blood of mice after compound treatment.
  • Figure 3 shows the number of monocytes in the blood of mice after compound treatment.
  • Figure 4 shows the results of the migration of breast cancer model cells 4T1-LG12 to the lungs of mice.
  • Figure 5 shows the inhibitory effect of compound treatment on mouse breast tumors.
  • the present invention provides a new type of glycoside compound, which has the following structure:
  • the present invention enhances the binding ability of glycoside compound and CD1d protein by introducing hydroxyl on the fatty chain, and improves the immunological activity and anti-tumor activity of glycoside compound.
  • Animal experiments show that the glycoside compound of the present invention can increase the content of lymphocytes and monocytes in the blood, and inhibit the size and/or migration of tumors.
  • the glycoside compound of the present invention can be expected to be used in vaccines or to treat diseases such as various cancers, a pharmaceutical composition containing the above-mentioned glycoside compound is also desired. Therefore, the present invention also relates to a pharmaceutical composition containing the aforementioned glycoside compound and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition can be prepared by a method known to those skilled in the art, which is not limited in the present invention. The present invention does not limit the dosage form and administration mode of the pharmaceutical composition, and those skilled in the art make adjustments according to the known pharmaceutical preparation technology and application range.
  • the dosage forms of the pharmaceutical composition of the present invention include, but are not limited to, tablets, pills, lozenges, capsules, elixirs, suspensions, injections, syrups, patches, chewable gels and the like.
  • the excipients in the composition should be selected according to the needs of the type of pharmaceutical dosage form, such as binders, fillers, disintegrants, lubricants in tablets; wine, vinegar, concoctions in Chinese medicine pills, etc.; Preservatives, antioxidants, flavors, fragrances, cosolvents, emulsifiers, solubilizers, osmotic pressure regulators, colorants, etc. in liquid preparations.
  • the administration mode of the pharmaceutical composition of the present invention includes, but is not limited to, parenteral administration, such as intravenous, intramuscular, intrathecal or subcutaneous injection; rectal administration, transdermal administration, and the like.
  • the present invention also relates to a method of stimulating the immune system in a mammal, the method comprising administering to the mammal an effective amount of the glycoside compound of the present invention.
  • the effective amount of the glycoside compound is administered to the mammal in the form of a pharmaceutical composition.
  • the mammal is a human.
  • the mammal has cancer.
  • the present invention also relates to a preparation method of the aforementioned glycoside compound, which is completed by the following two synthesis steps:
  • the synthetic process reagents with the reaction conditions (a) (i) Dess -Martin reagent, dichloromethane; (ii) C 14 H 27 Ph 3 P + Br - ( tetradecyl quaternary phosphonium salts), LHMDS (lithium hexamethyldisilazide), tetrahydrofuran; (b) AD-Mix- ⁇ , p-methanesulfonamide; (c) 2,2-dimethoxytoluene, tetrahydrofuran; (d) lithium hydroxide, Tetrahydrofuran-methanol-water system.
  • glycoside compound 1 The following synthetic diagram describes the synthetic method for preparing glycoside compound 1:
  • the reagents and conditions in the above synthesis method (a) (i) 6, EDCI (1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride), HOBt (1- Hydroxybenzotriazole), DIPEA (N,N'-diisopropylethylamine), DMF (dimethylformamide); (ii) TBDPSCl (tert-butyldiphenylchlorosilane), pyridine, benzyl Acid chloride; (b) hydrogen fluoride pyridine solution; (c) TMSOTf (trimethylsilyl trifluoromethanesulfonate); (d) methanol solution of sodium methoxide; (e) 4bar H 2 ,Pd(OH) 2 /C ,MeOH/EtOAc.
  • the above method has high total yield, easy control of the reaction process, simple conventional processing, and easy mass preparation of glycoside compound 1.
  • reagents and biological materials used can be purchased from the market and are known reagents and biological materials in the art.
  • Hydrogen fluoride is used to remove the TBDPS group and undergo a glycosylation reaction with the glycosyl donor 10 (available from Carbosynth).
  • the catalyst can be (one of ZnCl 2 , TiCl 4 , TMSOTf, AgOTf, etc.).
  • the product is treated with sodium methoxide to remove the benzoyl Bz, and finally the benzyl Bn is removed by catalytic hydrogenation to obtain the target compound 1.
  • the specific operation process is as follows:
  • Compound 11 a dichloromethane solution containing compounds 9 (208mg, 0.20mmol), 10 (129mg, 0.22mmol) and TMSOTf (20 ⁇ l, 110 ⁇ mol) was reacted at 0°C for 3 hours, triethylamine was reacted comprehensively and subjected to conventional treatment Compound 11 (192 mg, 64%) was obtained as an oil.
  • Compound 1 Compound 11 (148mg, 0.096mmol) was treated with 1M sodium methoxide methanol solution for 5 hours, and then neutralized with acid resin amberlite IR-120 (H+). After the reactant was evaporated to dryness under reduced pressure, a part of the product (62mg, 0.046) mmol) methanol (4mL) and ethyl acetate (1mL) mixed solvent, add the catalyst Pd(OH) 2 /C (20wt% dry basis on carbon, 20mg) and react with H 2 pressure 4bar for 48 hours. The result is obtained after conventional treatment Solid compound 1 (39 mg, 96%).
  • mice Under aseptic conditions, 1 ⁇ 10 7 mouse T-cell lymphoma EL4 cells were inoculated into the armpits of C57BL/6 mice. After 10 days, the tumor tissue was obtained under aseptic conditions, the homogenate was diluted with normal saline and counted to make a tumor cell suspension with a concentration of 1 ⁇ 10 7 cells/mL, and 0.2 mL/mouse was inoculated into the right armpit of the mouse. Before vaccination, the animals were randomly divided into groups of 8 animals.
  • Glycoside compound 1 (denoted as Day-1) was given 1 day before modeling, and cyclophosphamide (CTX) was administered once on the same day as cyclophosphamide (CTX) on the first day after modeling, and then three days later. Administer once. After 2 weeks, the body weight was weighed, the animals were sacrificed, the tumor tissues were stripped, weighed and photographed. Finally, the tumor inhibition rate was calculated, and the intensity of the compound's action was evaluated by the tumor inhibition rate.
  • CTX cyclophosphamide
  • Cyclophosphamide accurately weigh 60 mg of cyclophosphamide, add 20 mL of sterile normal saline to 3 mg/mL, and give each animal 0.4 mL/20 g in the abdominal cavity according to its body weight.
  • Glycoside compound 1 Prepared with DMSO as a stock solution, dilute with normal saline before injection, DMSO does not exceed 0.5%. Available now. Each animal was given 0.2mL/20g orally according to body weight.
  • T/C (%) T/C ⁇ 100%.
  • TGI Tumor growth inhibition rate
  • T tumor weight in the treatment group
  • C tumor weight in the negative control group.
  • T/C(%)>40% is invalid; T/C(%) ⁇ 40%, and statistically processed P ⁇ 0.05 is valid.
  • Glycoside compound 1 shows the same effectiveness as clinical cyclophosphamide in inhibiting lymphoma, and the combined experiment of cyclophosphamide and glycoside compound 1 has better tumor suppressing effect.
  • mice Under aseptic conditions, 1 ⁇ 10 7 mouse T-cell lymphoma EL4 cells were inoculated into the armpits of C57BL/6 mice. After 10 days, the tumor tissue was obtained under aseptic conditions, the homogenate was diluted with normal saline and counted to make a tumor cell suspension with a concentration of 1 ⁇ 10 7 cells/mL, and 0.2 mL/mouse was inoculated into the right armpit of the mouse. The animals were randomly divided into groups before vaccination, with 8 in each group. The treatment was performed according to different compound dosages of 100 ⁇ g/Kg once and 100 ⁇ g/Kg three times.
  • dosing refers to the intraperitoneal injection of the compound on the first day after modeling, and the dose of administration is 100 ⁇ g/Kg; three dosing refers to the administration once a day before modeling, and cyclophosphine on the first day after modeling.
  • the amide dose 10 mg/Kg was administered once on the same day, and the compound was injected separately three days later, each time the compound was administered 100 ⁇ g/Kg, and a total of 300 ⁇ g/Kg was administered.
  • the venous blood of the mice was taken to complete the blood test. The test results are shown in Figure 2 and Figure 3.
  • LYM is the number of lymphocytes
  • MON is the number of monocytes.
  • CTX+K 100 It means that cyclophosphamide is used in combination with commercially available KRN7000 compound. The dosage of KRN7000 is 100 ⁇ g/Kg.
  • K represents the commercially available KRN7000 compound;
  • O is the reference compound ⁇ -GalCer donated by an external unit (document: K. Seino et al., Cancer Sci. 2006, 97, 807-812).
  • S1" and “S2” are both glycoside compound 1 prepared in Example 1. In order to pursue the objectivity of the experimental results, we prepared two samples for activity studies.
  • glycoside compound 1 single agent of the present invention can increase the lymphocytes in the blood of mice, and can also significantly increase the monocytes in the blood. It shows that glycoside compound 1 has a strong immunosuppressive ability of tumor.
  • Mouse lung metastasis model 4T1-LG12 cells (labeled by exogenous luciferase gene) (2 ⁇ 10 4 cells/mouse) were injected into mice through the tail vein, and the model was successfully constructed after 2-3 weeks.
  • the dosage of the experimental group is: the normal dose group of cyclophosphamide (10mg/Kg), the normal dose group of cyclophosphamide (10mg/Kg) combined administration once group (the definition is the same as before), the normal dose group of cyclophosphamide (10mg/Kg) Kg) combined administration three times group, cyclophosphamide high-dose group (60mg/Kg).
  • the IVIS spectral imaging system was used to detect the biofluorescence in the lungs to monitor the growth of metastatic tumors.
  • the biofluorescence signal intensity can be monitored gradually, indicating that 4T1-LG12 cells rapidly localize in the lungs and form metastatic lesions.
  • the intensity of the biofluorescence signal of the mice in the experimental administration group was inhibited, indicating that the migration of 4T1-LG12 tumor cells to the lungs was inhibited, and the intensity of inhibition was proportional to the ability to inhibit migration (Figure 4).
  • Mouse orthotopic breast cancer model The PBS solution of 4T1-LG12 cells (labeled by exogenous luciferase gene) and Matrigel (1:1) were configured to form a cell suspension (1 ⁇ 10 4 cells/mouse). Shave the mouse's abdominal hair clean and wipe it with alcohol for disinfection; use ophthalmological scissors to cut an "L"-shaped wound next to the fourth pair of breast fat pads in the mouse, and use a 50 ⁇ L micro syringe to inject 10 ⁇ L of 4T1-LG12 cell suspension into the mouse fourth It is administered under the breast fat pad and after successful modeling.
  • the mode of administration is the tail vertebra injection of mice, and the dosage is: the normal dose group of cyclophosphamide (10mg/Kg) combined with glycoside compound 1 administration three times group (A), the high dose group of cyclophosphamide (60mg/Kg) ( B). After 16 days, the experimental mice were weighed, the mice were sacrificed, the tumor tissue was stripped, and the tumor proliferation effect was observed.

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Abstract

本发明涉及化学与医药技术领域，公开一种具有高活性免疫抗癌作用的糖苷类似物，通过在侧链上引入多个羟基，加强糖苷化合物与受体蛋白间的氢键相互作用，提高糖苷化合物与CD1d的亲和力，提高其免疫抗癌活性。本发明还公开了其制备方法及其在免疫抗癌中的应用。动物实验表明，本发明的糖苷化合物能够增加血液中的淋巴细胞和单核细胞含量，抑制肿瘤的大小和/或迁移。

Description

一种糖苷化合物及其制备方法和应用 技术领域
本发明涉及化学与医药技术领域，尤其涉及一种具有抗癌作用的糖苷类似物、其制备方法及其在免疫抗癌中的应用。
背景技术
以KRN7000为代表的α-半乳糖神经酰胺已经表现出较好的抗肿瘤活性，其作用机理主要是通过形成呈递细胞CD1d蛋白/KRN7000/NKT细胞表面TCP蛋白的三元复合物来激活NKT细胞，达到分泌Th1或Th2类细胞因子以实现免疫驱动下的抗肿瘤活性。
目前研发出的许多KRN7000衍生物能在生物体内同时激活Th1和Th2类细胞因子，但它们之间的拮抗作用又限制了KRN7000的临床应用。因此，设计合成新型糖苷类化合物以达到选择性激活T细胞、提高其临床应用的潜力，是相关科研工作者追求的重要目标。
发明内容
我们基于呈递细胞CD1d蛋白/KRN7000/NKT细胞表面TCP蛋白三元复合物蛋白结晶结构的分析，发现在糖苷化合物与蛋白相互作用的区域内，除了疏水基团外，还有大量的亲水基团，为此，针对已发表化合物活性较差的不足，我们通过在脂肪链上引入羟基以增强它和CD1d蛋白的结合能力，期望这样的改变能改善新化合物的免疫作用机制。
本发明的技术方案如下：
本发明提供了一种糖苷化合物，具有化合物1所述结构：
Figure PCTCN2020071809-appb-000001
本发明还包括上述糖苷化合物用于制备疫苗的药物用途。
优选的，所述疫苗在接种后，增加血液中的淋巴细胞和单核细胞含量。
本发明还包括上述糖苷化合物用于制备抑制肿瘤的药物用途。
优选的，所述抑制肿瘤包括抑制肿瘤的大小和/或迁移。
本发明还提供了一种药物组合物，包括上述糖苷化合物和药学上可接受的赋形剂。
本发明还包括上述药物组合物在制备在哺乳动物中刺激免疫系统的药物的用途，其中调整所述糖苷化合物，以向哺乳动物给药有效量的药物组合物。
优选的，所述哺乳动物患有癌症。
进一步优选的，所述癌症为乳腺癌。
本发明还提供了上述糖苷化合物的制备方法，包括以下步骤：
(1)从化合物2出发，通过Dess-Martin氧化伯羟基成醛，再通过Wittig反应延长碳链到设计的含有不饱和双键的碳链长度，得到化合物3；对化合物3中的双键进行Sharpless双羟基化，接着通过与苯甲醛的缩合反应得到化合物6；
Figure PCTCN2020071809-appb-000002
(2)植物鞘氨醇与化合物6在缩合剂存在条件下，通过胺基与羧基的酰胺化反应，向其产物中先加入叔丁基二苯基氯硅烷，然后再加入苯甲酰氯，区分开伯羟基和两个仲羟基形成化合物8，用氟化氢脱出TBDPS基团，并与糖基供体10发生糖基化反应，产物经甲醇钠处理脱除苯甲酰基Bz，最后催化氢化脱除苄基Bn，得到目标化合物1，即为权利要求1所述糖苷化合物；
Figure PCTCN2020071809-appb-000003
现有技术相比，本发明具有以下优点：
本发明的新型糖苷化合物，具有化合物1所示结构。本发明通过在侧链上引入多个羟基，加强糖苷化合物与受体蛋白间的氢键相互作用，提高糖苷化合物与CD1d的亲和力，提高其免疫抗癌活性。通过动物实验可知，本发明的糖苷化合物表现出与临床环磷酰胺相当的抑制淋巴瘤的效率，联合实验环磷酰胺与化合物的抑瘤效果更好。本发明的糖苷化合物还能增加小鼠血液中的淋巴细胞及单核细胞的数量，说明本发明糖苷化合物可以刺激哺乳动物的免疫系统，进而产生强烈的免疫抑制肿瘤的能力。通过小鼠肺转移模型实验，表明本发明的糖苷化合物能够抑制肿瘤细胞的迁移，抑制强度与抑制迁移的能力成正比。相对于已知KRN7000类似物而言，本发明化合物1所示的糖苷化合物具有更高的免疫抗癌活性，且能抑制肿瘤的转移。
本发明首次利用化学方法合成了化合物1所示糖苷化合物。从已知化合物2出发制备邻二羟基化合物6，再通过植物鞘氨醇与邻二醇化合物6经过多步反应制备得到目标化合物1。本发明糖苷化合物的制备方法总产率高、反应过程容易控制、常规处理简单、易于大量制备。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前 提下，还可以根据这些附图获得其他的附图。
图1为糖苷化合物1的结构式。
图2为化合物处理后小鼠血相的淋巴细胞数。
图3为化合物处理后小鼠血相的单核细胞数。
图4为乳腺癌模型细胞4T1-LG12向小鼠肺部迁移的结果。
图5为化合物处理对小鼠乳腺肿瘤的抑制效果。
具体实施方式
下面对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明为了改善已发表的KRN7000及其衍生物活性较差的不足，提供了一种新型的糖苷化合物，该化合物具有以下结构：
Figure PCTCN2020071809-appb-000004
本发明通过在脂肪链上引入羟基，增强了糖苷化合物和CD1d蛋白的结合能力，提高了糖苷化合物的免疫活性和抗肿瘤活性。动物实验表明，本发明的糖苷化合物能够增加血液中的淋巴细胞和单核细胞含量，抑制肿瘤的大小和/或迁移。
由于本发明的糖苷化合物可预期用于疫苗或用于治疗例如各种癌症的病症，还期望含有上述糖苷化合物的药物组合物。因此本发明还涉及含有上述糖苷化合物和药学上可接受的赋形剂的药物组合物。该药物组合物可使用本领域技术人员所公知的方法制备，本发明对此不做限定。本发明对该药物组合物的剂型及给药方式均不做限定，本领域技术人员根据已知药物制作技术及应用范围做出调整。本发明药物组合物剂型包括但不限于片剂、丸剂、锭剂、胶囊、酏剂、悬浮剂、注射剂、糖浆、贴片、可咀嚼胶体等。组合物中的赋形剂根据药物剂型种类的需求选择合适的赋形剂，如片剂中的黏合剂、填充剂、崩解剂、润滑剂；中药丸剂中的酒、醋、药汁等；液体制剂中的防腐剂、抗氧剂、 矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等。本发明药物组合物的给药方式包括但不限于肠胃外给药，如通过静脉内、肌内、鞘内或皮下注射给药；直肠给药、经皮给药等。
本发明还涉及在哺乳动物中刺激免疫系统的方法，所述方法包括向哺乳动物给药有效量的本发明糖苷化合物。在一个实施方案中，有效量的糖苷化合物以药物组合物的形式给药到哺乳动物。在一个实施方案中，哺乳动物为人。在一个实施方案中，哺乳动物患有癌症。
本发明还涉及上述糖苷化合物的制备方法，通过以下两个合成步骤完成：
(1)制备邻二羟基化合物6：
以下合成图描述了制备邻二羟基化合物6的合成方法：
Figure PCTCN2020071809-appb-000005
其中，上述合成方法中的试剂与反应条件：(a)(i)Dess-Martin试剂，二氯甲烷；(ii)C 14H 27Ph 3P +Br -(十四烷基季磷盐)，LHMDS(六甲基二硅基氨基锂),四氢呋喃；(b)AD-Mix-β,对甲磺酰胺；(c)2,2-二甲氧基甲苯,四氢呋喃；(d)氢氧化锂，四氢呋喃-甲醇-水体系。
(2)制备糖苷化合物1：
以下合成图描述了制备糖苷化合物1的合成方法：
Figure PCTCN2020071809-appb-000006
其中，上述合成方法中的试剂与条件：(a)(i)6,EDCI(1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐)，HOBt(1-羟基苯并三唑)，DIPEA(N,N'-二异丙基乙胺)，DMF(二甲基甲酰胺)；(ii)TBDPSCl(叔丁基二苯基氯硅烷),吡啶，苯甲酰氯；(b)氟化氢吡啶溶液；(c)TMSOTf(三甲基硅基三氟甲磺酸酯)；(d)甲醇钠的甲醇溶液；(e)4bar H 2,Pd(OH) 2/C,MeOH/EtOAc。
上述方法总产率高、反应过程容易控制、常规处理简单、易于糖苷化合物1的大量制备。
以上所述的具体实施方式，对本发明的目的、技术方案和有益效果进行了进一步详细说明，所应理解的是，以上所述仅为本发明的具体实施方式而已，并不用于限定本发明的保护范围，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
以下提供本发明的实施例，其中所用试剂及生物材料均可以从市场常规购买获得，为本领域中的已知试剂和生物材料。
以下实施例中所述的“常规操作”是指本领域技术人员根据本领域中的常识对产物进行有机溶剂萃取、减压浓缩、柱色谱分离这一套标准的常规处理流程，在无特殊说明的情况下，本领域技术人员均能够通过常规操作完成并得到目标产物。
实施例1
糖苷化合物1的制备
Figure PCTCN2020071809-appb-000007
1、制备邻二羟基化合物6：
Figure PCTCN2020071809-appb-000008
我们从已知的化合物2出发，通过Dess-Martin氧化伯羟基成醛，再通过Wittig反应延长碳链到设计的含有不饱和双键的碳链长度，这个双键正好是设计的双羟基的位置，对该双键进行Sharpless双羟基化，接着通过与苯甲醛的缩合反应完成已保护好的羧酸化合物6。具体操作过程如下：
化合物3：向溶于二氯甲烷(10mL)的化合物2(311mg,1.35mmol)在零度下加入Dess-Martin试剂(746mg,1.76mmol)，反应6小时，反应常规处理后加入到事先预冷至-78℃的C 14H 29Ph 3P +Br -(800mg,1.48mmol)四氢呋喃溶液中，然后慢慢加入LHMDS(2.5M in THF,0.59ml,1.48mmol)继续反应30分钟，反应液常规处理后得到油状化合物3(309mg)。
1H NMR(400MHz,CDCl 3)δ5.41–5.29(m,2H),3.66(s,3H),2.30(t,J＝7.6Hz,2H),2.05–1.93(m,4H),1.60(td,J＝7.3,4.6Hz,2H),1.26(m,36H),0.92–0.83(m,3H)ppm； 13C NMR(100MHz,CDCl3)δ174.5,130.1,130.0,51.6,51.6,34.3,32.1,29.9,29.9,29.8,29.7,29.7,29.6,29.5,29.5,29.5,29.4,29.3,27.4,25.1,22.9,14.3ppm；HRMS(ESI):m/z calcd for C 27H 52O 2Na[M+Na] +431.3860,found 431.3874.
化合物4：向预冷至0℃的AD-Mix-β(2.81g)水/叔丁醇(V/V 1:1)溶液加入CH 3SO 2NH 2(186mg,1.96mmol)和化合物3(800mg,1.96mmol)，继续反应32小时。反应液常规处理后得到白色固体4(676mg,78％)，熔点111.2℃；
1H NMR(400MHz,CDCl 3)δ3.67(s,3H),3.60(t,J＝5.3Hz,2H),2.30(t,J＝7.5Hz,2H),1.73(d,J＝17.1Hz,2H),1.61(q,J＝7.3Hz,2H),1.53–1.48(m,6H),1.46–1.22(m,34H),0.90–0.86(m,3H)ppm； 13C NMR(100MHz,CDCl 3)δ174.5,74.9,74.8,51.6,34.3,32.1,31.4,31.4,29.8,29.8,29.8,29.8,29.8,29.7,29.6,29.5,29.5,29.4,29.3,26.2,26.2,25.1,22.8,14.3ppm；HRMS(ESI):m/z calcd for C 27H 54O 4Na[M+Na] +465.3914,found 465.3927.
化合物5：将2,2-二甲氧基甲苯(344mg,2.26mmol)和对甲苯磺酸(10mg,0.06mmol)加入到含有化合物4(500mg,1.13mmol)的四氢呋喃(20mL)溶剂中，在40℃下反应4小时。常规处理反应液之后得到油状化合物5(552mg,92％)。
1H NMR(400MHz,CDCl 3)δ7.50–7.45(m,2H),7.40–7.33(m,3H),5.77(s,1H),4.14–4.09(m,2H),3.66(s,3H),2.30(t,J＝7.5Hz,2H),1.66–1.53(m,6H),1.52–1.44(m,2H),1.42–1.22(m,34H),0.92–0.83(m,3H)ppm； 13C NMR(100MHz,CDCl 3)δ174.5,138.3,129.3,128.4,127.0,103.2,79.5,79.4,51.6,34.3,32.1,30.1,29.8,29.8,29.8,29.8,29.7,29.7,29.6,29.5,29.4,29.3,26.5,25.1,22.8,14.3ppm；HRMS(ESI):m/z calcd for C 34H 58O 4Na[M+Na] +553.4227,found 553.4239.
化合物6：向含有化合物5(600mg,1.13mmol)的THF,H 2O和MeOH(V/V/V 1:1:1,24毫升)混合溶剂中加入LiOH·H 2O(95mg,2.26mmol)并让反应过夜，然后调反应液的pH至3-4(HCl.aq,1N)，常规处理后得到油状化合物6(549mg,94％)。
1H NMR(400MHz,CDCl 3)δ7.52–7.43(m,2H),7.42–7.32(m,3H),5.78(s,1H),4.16–4.08(m,2H),2.34(t,J＝7.5Hz,2H),1.66–1.53(m,6H),1.52–1.44(m,2H),1.39–1.22(m,34H),0.92–0.84(m,3H)ppm； 13C NMR(100MHz,CDCl 3)δ179.4,138.3,129.3,128.4,127.0,103.2,79.5,79.4,34.1,32.1,30.1,29.8,29.8,29.8,29.8,29.8,29.7,29.6,29.5,29.5,29.4,29.2,26.5,24.8,22.8,14.3ppm；HRMS(ESI):m/z calcd for C 33H 55O 4[M-H] -515.4106,found 515.4111.
2、制备糖苷化合物1：
Figure PCTCN2020071809-appb-000009
植物鞘氨醇7与新的邻二醇化合物6在缩合剂存在条件下，通过胺基与羧基的酰胺化反应，向其产物中先加入叔丁基二苯基氯硅烷TBDPSCl，然后再加入苯甲酰氯，这样可以区分开伯羟基和两个仲羟基形成化合物8。用氟化氢脱出TBDPS基团，并与糖基供体10(Carbosynth公司有售)发生糖基化反应，催化剂可以是(ZnCl 2、TiCl 4、TMSOTf、AgOTf等中的一种)。产物经甲醇钠处理脱除了苯甲酰基Bz，最后催化氢化脱除苄基Bn而得到目标化合物1。具体操作过程如下：
化合物9：向化合物6(800mg,1.55mmol)的二甲基甲酰胺(10.0mL)溶液中加入HOBt(230mg,1.71mmol),EDCI(328mg 1.71mmol)和二异丙基乙胺(0.6ml,3.56mmol)。反应30分钟后，加入植物鞘氨醇(492mg,1.55mmol)和二异丙基乙胺(0.6ml,3.56mmol)，继续搅拌3小时，反应液蒸干后溶于吡啶(30mL)，加入TBDPSCl(0.48mL,1.86mmol)，反应18小时后，加入苯甲酰氯(0.71ml,6.20mmol)并继续反应12小时。反应液经常规处理后得到油状化合物8(1.29g)。化合物8(500mg,0.40mmol)经HF的吡啶盐与二氯甲烷中处理5小时后，硅胶柱分离得到油状化合物9(395mg,97％)。
1H NMR(400MHz,CDCl 3)δ8.09–8.02(m,2H),7.97–7.92(m,2H),7.67–7.60(m,1H),7.49(tt,J＝9.3,7.2Hz,5H),7.40–7.32(m,5H),6.39(d,J＝9.2Hz,1H),5.77(s,1H),5.42–5.33(m,2H),4.39(tt,J＝9.3,2.6Hz,1H),4.20–4.07(m,2H),3.64(qd,J＝12.3,2.6Hz,2H),2.83(s,1H),2.36–2.23(m,2H),2.02(q,J＝8.6,7.4Hz,2H),1.73–1.52(m,6H),1.51–1.42(m,2H),1.40–1.20(m,58H),0.88(t,J＝6.6Hz,6H)ppm； 13C NMR(100MHz,CDCl 3)δ173.4,167.3,166.4,138.3,134.0,133.2,130.1,130.0,129.8,129.3,129.2,128.8,128.8,128.5,128.4,127.0,126.3,103.2,101.6,79.4,79.4,78.9,77.4,74.1,73.9,61.7,50.1,37.0,32.1,30.1,30.1,29.9,29.8,29.8,29.8,29.8,29.7,29.7,29.6,29.5,29.5,29.5,29.5,28.6, 26.5,26.5,26.0,25.9,22.8,14.3ppm；HRMS(ESI):m/z calcd for C 65H 101NO 8Na[M+Na] +1046.7419,found 1046.7413.
化合物11：含有化合物9(208mg,0.20mmol)、10(129mg,0.22mmol)和TMSOTf(20μl,110μmol)的二氯甲烷溶液在0℃下反应3小时，三乙胺综合反应并经过常规处理后得到油状化合物11(192mg,64％)。
1H NMR(400MHz,CDCl 3)δ8.07–7.99(m,2H),7.95–7.88(m,2H),7.63–7.56(m,1H),7.48(dq,J＝17.0,7.5Hz,5H),7.39–7.31(m,9H),7.31–7.17(m,16H),6.87(d,J＝9.6Hz,1H),5.77(s,1H),5.67(dd,J＝9.8,2.8Hz,1H),5.41(dt,J＝7.5,3.4Hz,1H),4.86(d,J＝11.5Hz,1H),4.76–4.70(m,2H),4.64(dd,J＝12.1,6.0Hz,3H),4.59–4.49(m,3H),4.41(d,J＝12.1Hz,1H),4.19–4.07(m,3H),4.08–3.97(m,2H),3.90–3.78(m,2H),3.60(dd,J＝12.0,2.6Hz,1H),3.51(dd,J＝9.5,7.2Hz,1H),3.29(dd,J＝9.5,5.4Hz,1H),2.14(t,J＝8.1Hz,2H),1.88(d,J＝6.2Hz,2H),1.67–1.53(m,6H),1.43–1.14(m,60H),0.87(td,J＝6.9,2.2Hz,6H)ppm； 13C NMR(100MHz,CDCl 3)δ173.3,166.1,165.3,138.9,138.5,138.5,138.3,137.8,133.4,133.0,130.3,130.1,129.9,129.9,129.3,128.8,128.7,128.5,128.5,128.4,128.3,128.3,128.3,128.1,128.1,127.9,127.8,127.8,127.7,127.6,127.0,126.3,103.2,101.6,100.6,79.4,79.4,78.9,78.8,77.4,76.7,75.0,74.8,73.9,73.6,73.4,73.4,72.5,70.9,70.5,69.3,48.8,36.8,32.1,30.1,30.1,29.9,29.9,29.8,29.8,29.8,29.8,29.8,29.7,29.7,29.6,29.6,29.5,29.5,28.9,28.7,26.6,26.5,25.8,25.8,22.8,14.3ppm；MALDI-TOF MS:m/z calcd for C 99H 135NO 13Na[M+Na] +1569.0,found 1569.1.
化合物1：化合物11(148mg,0.096mmol)用1M的甲醇钠甲醇溶液处理5小时，再用酸性树脂amberlite IR-120(H+)中和，反应物减压蒸干后取部分产品(62mg,0.046mmol)甲醇(4mL)和乙酸乙酯(1mL)混合溶剂中，加入催化剂Pd(OH) 2/C(20wt％dry basis on carbon,20mg)与H 2压力4bar下反应48小时，常规处理后得到固体化合物1(39mg,96％)。
1H NMR(400MHz,Pyridine-d 5)δ8.46(d,J＝8.6Hz,1H),5.58(d,J＝3.9Hz,1H),5.28(d,J＝6.9Hz,1H),5.11–4.87(m,8H)4.72–4.63(m,2H),4.56(dd,J＝3.4,1.2Hz,1H),4.52(dd,J＝6.6,5.4Hz,1H),4.46–4.37(m,4H),4.32(d,J＝4.7Hz,2H),4.03–3.96(m,2H),2.44(t,J＝7.5Hz,2H),2.08–1.98(m,1H),2.02(m,J＝11.6,7.6,4.7Hz,2H),1.90(d,J＝11.7Hz,4H),1.81(q,J＝7.6Hz,2H),1.66(ddd,J＝11.4,5.9,2.8Hz,3H),1.50–1.16(m,56H),0.91–0.84(m,6H)ppm； 13C NMR(100MHz,Pyridine-d 5)δ173.7,101.9,77.2,75.7,73.4,72.9,72.0,71.4,70.7,69.0,63.1,51.9,37.2,34.8,34.0,32.5,30.8,30.7,30.5,30.4,30.3,30.2,30.1,30.0,27.2,26.9,26.8,23.3,14.7ppm；HRMS(ESI):m/z calcd for C 50H 99NO 11Na[M+Na] +912.7110,found 912.7124.
实施例2
糖苷化合物1对淋巴瘤的抑制率评价
生物实验
无菌条件下将1×10 7个小鼠T细胞淋巴瘤EL4细胞接种到C57BL/6小鼠腋下。10天后，无菌条件下获取肿瘤组织，匀浆用生理盐水稀释后计数制成浓度为1×10 7个/mL肿瘤细胞悬液，于小鼠右侧腋下接种0.2mL/只。接种前动物随机分组，每组8只，造模前1天给予糖苷化合物1(记为Day-1)，造模后第1天与环磷酰胺(CTX)同一天给药一次，三天后再给药一次。2周后称量体重，处死动物，剥取肿瘤组织，称重并进行拍照。最后计算肿瘤抑制率，以肿瘤抑制率评价化合物作用强度。
药物配制
(1)环磷酰胺：精确称取60mg环磷酰胺，加入20mL无菌生理盐水至3mg/mL，每只动物按体重腹腔给予0.4mL/20g。
(2)糖苷化合物1：用DMSO配置为储液，注射前用生理盐水稀释，DMSO不超过0.5％。现用现配。每只动物按体重口服给予0.2mL/20g。
计算方法
相对肿瘤增殖率T/C(％)：T/C％＝T/C×100％。
肿瘤增殖抑制率TGI(％)：TGI＝(1-T/C)×100。
其中：T：治疗组肿瘤重量；C：阴性对照组肿瘤重量。
评价标准：T/C(％)>40％为无效；T/C(％)≤40％，并经统计学处理P<0.05为有效。
表1.化合物对小鼠T细胞淋巴瘤EL4生长的作用
Figure PCTCN2020071809-appb-000010
NA:不适用，与溶剂组比， ***p<0.001.
结论：糖苷化合物1表现出与临床环磷酰胺相当的抑制淋巴瘤的效率，联合实验环磷酰胺与糖苷化合物1的抑瘤效果更好。
实施例3
糖苷化合物1对小鼠免疫效果评价
无菌条件下将1×10 7个小鼠T细胞淋巴瘤EL4细胞接种到C57BL/6小鼠腋下。10天后，无菌条件下获取肿瘤组织，匀浆用生理盐水稀释后计数制成浓度为1×10 7个/mL肿瘤细胞悬液，于小鼠右侧腋下接种0.2mL/只。接种前动物随机分组，每组8只。分别按照100μg/Kg给药一次和100μg/Kg给药三次的不同化合物用量进行处理。给药一次指的是在造模后第1天腹腔注射化合物，给药剂量为100μg/Kg；给药三次指的是在造模前1天给药一次，造模后第1天与环磷酰胺(剂量为10mg/Kg)同一天给药一次，三天后再单独注射化合物一次，每次化合物给药100μg/Kg，共给药300μg/Kg。造模后第16天取小鼠静脉血完成血液检测，检测结果见图2和图3。
图2和图3中，LYM是淋巴细胞数，MON是单核细胞数。“CTX+K 100”:表示环磷酰胺与市售KRN7000化合物联合用药，KRN7000用量为100μg/Kg。“K”代表市售KRN7000化合物；“O”是外单位赠送的对照化合物α-GalCer(文献：K.Seino等，Cancer Sci.2006,97,807-812)。“S1”和“S2”均为实施例1中制备的糖苷化合物1，为了追求实验结果的客观性，我们制备了两个样品来做活性研究。
通过图2和图3可以看出，本发明的糖苷化合物1单药可增加小鼠血液中的淋巴细胞，还可显著增加血液中的单核细胞。说明糖苷化合物1具有强烈的免疫抑制肿瘤的能力。
实施例4
糖苷化合物1对肿瘤肺迁移的抑制能力评价
小鼠肺转移模型：将4T1-LG12细胞(被外源荧光素酶基因标记)(2×10 4cells/mouse)通过尾静脉注射入小鼠体内，2-3周后模型成功构建。实验组给药量为：环磷酰胺正常剂量组(10mg/Kg)、环磷酰胺正常剂量组(10mg/Kg)联合给药一次组(定义同前)、环磷酰胺正常剂量组(10mg/Kg)联合给药三次组、环磷酰胺高剂量组(60mg/Kg)。
上述荷瘤小鼠经腹腔内注射100μL D-萤光素(15mg/mL)后，使用IVIS光谱成像系统检测肺中的生物荧光来监测转移性肿瘤的生长。随着时间的推移，在未经处理的组的小鼠肺部可以监测到生物荧光信号强度逐渐增强，表明4T1-LG12细胞快速定位于肺 中并形成转移性病变。但实验给药组小鼠生物荧光信号强度被抑制，表明4T1-LG12肿瘤细胞向肺部的迁移被抑制，抑制强度与抑制迁移的能力成正比(图4)。
图4结果显示：与空白对照组相比(未经治疗的小鼠)，临床药物环磷酰胺正常剂量组(10mg/Kg)以及正常剂量与1次糖苷化合物1的联合用药组表现出显著减轻乳腺癌向小鼠肺部转移的能力，小鼠的肺肿瘤结节数分别减少了38％和56％。相比之下，环磷酰胺正常剂量组(10mg/Kg)与3次糖苷化合物1的联合用药组小鼠肺中肿瘤结节数更进一步减少到65％。虽然大剂量化疗组(环磷酰胺60mg/Kg)中小鼠肺中肿瘤结节数减小幅度最大(89％)，但从环磷酰胺临床数据来看，减少化疗药物环磷酰胺的使用量可以极大改进病人的生存质量，表现出本发明糖苷化合物1的优越性。
实施例5
糖苷化合物1对乳腺肿瘤的抑制能力评价
小鼠原位乳腺癌模型：将4T1-LG12细胞(被外源荧光素酶基因标记)的PBS溶液与Matrigel基质胶(1:1)配置成细胞悬液(1×10 4cells/mouse)。将小鼠腹部毛发剃干净，并擦拭酒精消毒；使用眼科剪在小鼠第四对乳腺脂肪垫旁边剪“L”型创口，使用50μL微量注射器将10μL 4T1-LG12细胞悬液注入小鼠第四对乳腺脂肪垫下，造模成功后给药。给药方式为小鼠尾椎注射，给药量为：环磷酰胺正常剂量组(10mg/Kg)联合糖苷化合物1给药三次组(A)、环磷酰胺高剂量组(60mg/Kg)(B)。16天后，给实验小鼠称量体重，处死小鼠，剥取肿瘤组织，并观察肿瘤增殖效果。
实验结果表明：环磷酰胺联合给药三次组的乳腺肿瘤大小与高剂量组环磷酰胺组相当，表现出相同的抑制原位肿瘤生长的能力(图5)，但可大大降低化疗药的使用量，减轻实验对象的治疗痛苦，改善其生存质量。
以上所述的具体实施方式，对本发明的目的、技术方案和有益效果进行了进一步详细说明，所应理解的是，以上所述仅为本发明的具体实施方式而已，并不用于限定本发明的保护范围，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种糖苷化合物，具有化合物1所述结构：
    Figure PCTCN2020071809-appb-100001
  2. 权利要求1所述糖苷化合物用于制备疫苗的药物用途。
  3. 根据权利要求2所述的用途，所述疫苗在接种后，增加血液中的淋巴细胞和单核细胞含量。
  4. 权利要求1所述糖苷化合物用于制备抑制肿瘤的药物用途。
  5. 根据权利要求4所述的用途，所述抑制肿瘤包括抑制肿瘤的大小和/或迁移。
  6. 一种药物组合物，包括权利要求1所述糖苷化合物和药学上可接受的赋形剂。
  7. 权利要求6所述药物组合物在制备在哺乳动物中刺激免疫系统的药物的用途，其中调整所述糖苷化合物，以向哺乳动物给药有效量的药物组合物。
  8. 根据权利要求7所述的用途，所述哺乳动物患有癌症。
  9. 根据权利要求8所述的用途，所述癌症为乳腺癌。
  10. 权利要求1所述糖苷化合物的制备方法，包括以下步骤：
    (1)从化合物2出发，通过Dess-Martin氧化伯羟基成醛，再通过Wittig反应延长碳链到设计的含有不饱和双键的碳链长度，得到化合物3；对化合物3中的双键进行Sharpless双羟基化，接着通过与苯甲醛的缩合反应得到化合物6；
    Figure PCTCN2020071809-appb-100002
    (2)植物鞘氨醇与化合物6在缩合剂存在条件下，通过胺基与羧基的酰胺化反应，向其产物中先加入叔丁基二苯基氯硅烷，然后再加入苯甲酰氯，区分开伯羟基和两个仲羟基形成化合物8，用氟化氢脱出TBDPS基团，并与糖基供体10发生糖基化反应，产物经甲醇钠处理脱除苯甲酰基Bz，最后催化氢化脱除苄基Bn，得到目标化合物1，即为权利要求1所述糖苷化合物；
    Figure PCTCN2020071809-appb-100003
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CN103748103A (zh) * 2011-01-05 2014-04-23 台湾大学 制备鞘糖脂的方法及其应用
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CN103748103A (zh) * 2011-01-05 2014-04-23 台湾大学 制备鞘糖脂的方法及其应用
CN105461681A (zh) * 2014-09-05 2016-04-06 中国科学院生态环境研究中心 具有抗肿瘤活性的krn7000类似物及合成方法
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