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Monophosphate A conjugated-Tn anti-tumor vaccine and application thereof

A monophosphoric acid ester, anti-tumor technology, applied in the field of medicine, can solve the problems of inability to induce T cell response, poor immunogen, and inability to produce high-affinity IgG antibodies, and achieve good anti-tumor application prospects and clear structure effects

Active Publication Date: 2019-08-02
GUANGZHOU UNIVERSITY OF CHINESE MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004]TACAs are T-cell-independent antigens with poor immunogenicity, can not induce T-cell response, can only activate B-cells, and can only produce a low-affinity IgM antibody. Cannot produce high-affinity IgG antibodies

Method used

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  • Monophosphate A conjugated-Tn anti-tumor vaccine and application thereof
  • Monophosphate A conjugated-Tn anti-tumor vaccine and application thereof
  • Monophosphate A conjugated-Tn anti-tumor vaccine and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0052] Embodiment 1: the preparation of compound 1

[0053] [3-R-(dodecylcarboxylate)dodecylamino]ethyl 4-oxo-phosphoryl-6-oxo-6-{[(ethyl 2-deoxy-acetyl-α-D- Galactosyl)-1-hydrogen-1,2,3-triazolyl-4]methylene}-2-deoxy-2-[(R)-3-(tetracarboxylate) Synthesis of myristamido]-3-oxo-[(R)-3-(myristate)tetradecamido]-β-D-glucoside (compound 1)

[0054] Step 1: Preparation of 2-deoxy-2-(2-carboxybenzoyl)-D-glucose (compound 25)

[0055]

[0056] D-glucosamine hydrochloride (80.00g, 0.37mol) was added to a mixed solution of water (350.0mL) and methanol (150.0mL), the mixture was lowered to 0°C, and sodium hydroxide (15.60g , 0.39mol), after stirring in an ice bath for 1 hour, phthalic anhydride (63.20g, 0.43mol) was added, and the mixture was slowly returned to room temperature, and continued to stir overnight. (TLC) to detect the reaction process, after the detection of the complete disappearance of the raw materials, stop stirring and cool in an ice bath for 1 hour, the mixture ...

Embodiment 2

[0108] Embodiment 2: the preparation of compound 2

[0109] [3-R-(dodecylcarboxylate)tetradecylamino]ethyl 4-oxo-phosphoryl-6-oxo-6-{[(ethyl 2-deoxy-acetyl-α-D- Galactosyl)-1-hydrogen-1,2,3-triazolyl-4]methylene}-2-deoxy-2-[(R)-3-(tetracarboxylate) Synthesis of myristamido]-3-oxo-[(R)-3-(myristate)tetradecamido]-β-D-glucoside (compound 2)

[0110] Step 1: [3-R-(Dodecanoate)tetradecylamino]ethyl 4-oxo-(di-oxo-benzylphosphoryl)-6-oxo-propargyl-2-deoxy -2-[(R)-3-(tetradecyl carboxylate) tetradecyl amido]-3-oxo-[(R)-3-(tetradecyl carboxylate) tetradecyl amido]-β - Preparation of D-glucoside (compound 18)

[0111]

[0112] According to the synthesis method of step 16 in Example 1, compound 16 (0.10g, 0.07mmol) was mixed with Lipid A-2 (0.05g, 0.10mmol), N,N-diisopropylethylamine (15.3uL, 0.09mmol ) after the completion of the reaction, the crude product was obtained, and after separation and purification by column chromatography (ethyl acetate:petroleum ether=1:12, 1:8, 1:4,...

Embodiment 3

[0119] Embodiment 3: the preparation of compound 3

[0120] [3-R-(tetracarboxylate)tetradecylamino]ethyl 4-oxo-phosphoryl-6-oxo-6-{[(ethyl 2-deoxy-acetyl-α-D- Galactosyl)-1-hydrogen-1,2,3-triazolyl-4]methylene}-2-deoxy-2-[(R)-3-(tetracarboxylate) Synthesis of myristamido]-3-oxo-[(R)-3-(tetracarboxylate)tetradecamido]-β-D-glucoside (Compound 3)

[0121] Step 1: [3-R-(tetracarboxylate)tetradecylamino]ethyl 4-oxo-(di-oxo-benzylphosphoryl)-6-oxo-propargyl-2-deoxy -2-[(R)-3-(tetradecyl carboxylate) tetradecyl amido]-3-oxo-[(R)-3-(tetradecyl carboxylate) tetradecyl amido]-β - Preparation of D-glucoside (compound 19)

[0122]

[0123] According to the synthesis method of step 16 in Example 1, compound 16 (0.10mg, 0.07mmol), Lipid A-1 (0.05mg, 0.09mmol) and N,N-diisopropylethylamine (15.0uL, 0.09mmol) after the reaction was completed, the crude product was obtained, which was separated and purified by column chromatography (ethyl acetate:petroleum ether=1:12, 1:8, 1:4, 1:3, 1:2...

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Abstract

The invention provides a monophosphate A conjugated-Tn anti-tumor vaccine. The monophosphate A conjugated-Tn anti-tumor vaccine is a compound shown in a formula (I), namely Y-L-X(I). The monophosphateA conjugated-Tn anti-tumor vaccine is characterized in that a compound of the second generation of TLR4 ligand I of wholly new structure in the formula (I) is used for replacing MPLA (modified polylactic acid) and coupling with a compound (Tn) with clinical development potential in a formula (II), so as to obtain the two-component vaccine with a clear structure and a stronger anti-tumor function;the anti-tumor application prospect is better.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a monophosphoric acid ester A conjugated Tn anti-tumor vaccine and its application. Background technique [0002] Cancer prevention and treatment has become an important public health problem in our country. With the intensification of environmental pollution and changes in people's lifestyles, the incidence and mortality of cancer have increased rapidly, which seriously threatens the lives of people in our country and also increases social pressure. and personal financial burden. Although in recent years, targeted anti-tumor drugs such as small molecule targeted drugs, monoclonal antibody drugs and antibody drug conjugates (ADCs), and tumors such as programmed cell death molecules and their agonists (PD-1, PD-L1) Immunotherapy has made great progress, but all have certain limitations. At present, they still cannot overcome the shortcomings of tumor drugs, such as l...

Claims

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Application Information

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IPC IPC(8): A61K39/385A61K47/54A61K39/00A61P35/00A61P35/02
CPCA61K39/385A61K47/544A61K47/545A61K39/0011A61P35/00A61P35/02A61K2039/60A61K2039/627
Inventor 刘中秋廖国超高玲强曾莉茗马磊磊李文伟杨德盈胡丽琴吴鹏
Owner GUANGZHOU UNIVERSITY OF CHINESE MEDICINE
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