Glycoside analogue, and preparation method and application thereof

A technology of compounds and glycosides, which is applied in the fields of chemistry and medicine, can solve the problems of poor activity of compounds, and achieve the effects of simple conventional treatment, high yield, and easy control of the reaction process

Inactive Publication Date: 2020-05-08
ZHENGZHOU YUHEYUAN BIOTECHNOLOGY CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] Based on the analysis of the crystallographic structure of the TCP protein ternary complex on the surface of the presenting cell CD1d protein / KRN7000 / NKT cells, we found that in the region where the glycoside compound interacts with the protein, there are a large number of hydrophilic groups in addition to the hydrophobic groups , therefore, aiming at the poor activity of the published compounds, we introduced a hydroxyl group on the aliphatic chain to enhance its ability to bind to the CD1d protein, expecting such a change to improve the immune mechanism of the new compound

Method used

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  • Glycoside analogue, and preparation method and application thereof
  • Glycoside analogue, and preparation method and application thereof
  • Glycoside analogue, and preparation method and application thereof

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preparation example Construction

[0035] The present invention also relates to the preparation method of the above-mentioned glycoside compound, which is completed through the following two synthesis steps:

[0036] (1) Preparation of o-dihydroxy compound 6:

[0037] The following synthetic scheme describes the synthetic method for the preparation of the ortho-dihydroxy compound 6:

[0038]

[0039] Wherein, reagent and reaction condition in the above-mentioned synthetic method: (a) (i) Dess-Martin reagent, dichloromethane; (ii) C 14 h 27 Ph 3 P + Br - (tetradecyl quaternary phosphonium salt), LHMDS (lithium hexamethyldisilazide), tetrahydrofuran; (b) AD-Mix-β, p-methanesulfonamide; (c) 2,2-dimethoxytoluene , tetrahydrofuran; (d) lithium hydroxide, tetrahydrofuran - methanol - water system.

[0040] (2) Preparation of glycoside compound 1:

[0041] The following synthetic scheme describes the synthetic method for the preparation of glycoside compound 1:

[0042]

[0043] Among them, the reagents ...

Embodiment 1

[0049] Preparation of Glycoside Compound 1

[0050]

[0051] 1. Preparation of o-dihydroxy compound 6:

[0052]

[0053] Starting from the known compound 2, we oxidized the primary hydroxyl group to form an aldehyde through Dess-Martin, and then extended the carbon chain to the designed carbon chain length containing an unsaturated double bond through the Wittig reaction. This double bond is exactly the position of the designed double hydroxyl group. , the double bond was subjected to Sharpless dihydroxylation, followed by condensation reaction with benzaldehyde to complete the protected carboxylic acid compound 6. The specific operation process is as follows:

[0054] Compound 3: Add Dess-Martin reagent (746mg, 1.76mmol) to compound 2 (311mg, 1.35mmol) dissolved in dichloromethane (10mL) at zero temperature, and react for 6 hours. -78°C 14 h 29 Ph 3 P + Br - (800mg, 1.48mmol) tetrahydrofuran solution, and then slowly added LHMDS (2.5M in THF, 0.59ml, 1.48mmol) to...

Embodiment 2

[0072] Evaluation of Inhibition Rate of Glycoside Compound 1 on Lymphoma

[0073] Biological experiments

[0074] Aseptically place 1 x 10 7 Mouse T-cell lymphoma EL4 cells were inoculated into the axilla of C57BL / 6 mice. After 10 days, the tumor tissue was obtained under sterile conditions, and the homogenate was diluted with normal saline and counted to make a concentration of 1×10 7 cells / mL tumor cell suspension, inoculate 0.2 mL / mouse in the right armpit of mice. Animals were randomly divided into groups before inoculation, with 8 animals in each group. Glycoside compound 1 (denoted as Day-1) was administered one day before modeling, 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 measured, the animals were sacrificed, the tumor tissues were stripped, weighed and photographed. Finally, the tumor inhibition rate was calculated, and the effect str...

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Abstract

The invention relates to the technical fields of chemistry and medicine, and discloses a glycoside analogue with a high-activity immune anticancer effect. According to the invention, a plurality of hydroxyl groups are introduced into a side chain, so the hydrogen bond interaction between a glycoside compound and receptor protein is enhanced; the affinity of the glycoside compound and CD1d is improved; and the immune anticancer activity of the glycoside compound is improved. The invention also discloses a preparation method for the glycoside analogue and an application of the glycoside analoguein immunization and anticancer. Animal experiment results show that the glycoside compound provided by the invention can increase the contents of lymphocytes and monocytes in blood and inhibit the size and/or migration of tumors.

Description

technical field [0001] The invention relates to the technical fields of chemistry and medicine, in particular to a glycoside analogue with anticancer effect, its preparation method and its application in immune anticancer. Background technique [0002] α-Galactosylceramide represented by KRN7000 has shown good anti-tumor activity, and its mechanism of action is mainly to activate NKT cells by forming a ternary complex of presenting cell CD1d protein / KRN7000 / TCP protein on the surface of NKT cells, To achieve the secretion of Th1 or Th2 cytokines to achieve immune-driven anti-tumor activity. [0003] Many 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 researchers. Conte...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/04A61K31/7032A61P35/00
CPCA61P35/00C07H15/04
Inventor 程薇颖程青格
Owner ZHENGZHOU YUHEYUAN BIOTECHNOLOGY CO LTD
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