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CN106928298A - The structure composition of ring dinucleotides cGAMP derivatives, preparation method and its application in antitumor - Google Patents

The structure composition of ring dinucleotides cGAMP derivatives, preparation method and its application in antitumor Download PDF

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CN106928298A
CN106928298A CN201710147711.5A CN201710147711A CN106928298A CN 106928298 A CN106928298 A CN 106928298A CN 201710147711 A CN201710147711 A CN 201710147711A CN 106928298 A CN106928298 A CN 106928298A
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cgamp
derivatives
derivative
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ring
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CN106928298B (en
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张跃茹
向道凤
谭瀛轩
谭相石
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HANGZHOU XING'AO BIOLOGICAL TECHNOLOGY Co.,Ltd.
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Liaocheng City Run Bio Pharmaceutical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7084—Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
    • C07H19/213—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids containing cyclic phosphate
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    • C12P19/26—Preparation of nitrogen-containing carbohydrates
    • C12P19/28—N-glycosides
    • C12P19/30—Nucleotides
    • C12P19/36—Dinucleotides, e.g. nicotineamide-adenine dinucleotide phosphate
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

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Abstract

The present invention relates to biomedicine technical field, be prepared for the innovation derivative of series of loops dinucleotides cGAMP, the derivative of the serial cGAMP has notable antitumor action, its it is antitumor and in antineoplastic is prepared have important potential application.

Description

The structure composition of ring dinucleotides cGAMP derivatives, preparation method and its antitumor In application
Technical field
The present invention relates to biomedicine technical field, the innovation for being specially prepared for series of loops dinucleotides cGAMP derives Thing, the derivative of the serial cGAMP has notable antitumor action, and it is antitumor and have in preparing antineoplastic important Using.
Background technology
Malignant tumour is the common frdquently encountered disease for seriously threatening human health, it has also become a major reason of human death. At present, the essential therapeutic arsenals of tumour include drug therapy, surgical operation therapy and radiotherapy.Although with molecular targeted agents For the new type antineoplastic medicine for representing constantly is emerged, within the quite a long period, traditional cell toxicant antineoplastic according to So leading position is occupied in the drug therapy of tumour.
Traditional cell toxicant antineoplastic mainly by influenceing the nucleic acid and protein structure and function of tumour cell, directly Suppress tumor cell proliferation or inducing apoptosis of tumour cell.Although people make many effort in the drug treatment of tumour, The new chemotherapeutics of research, improves chemotherapy regimen, but therapeutic effect is still undesirable.Traditional cell toxicant antineoplastic is to tumour Cell and normal cell lack preferable selection index system, while malignant cell is killed, to the normal structure of human body There is infringement, so as to cause serious systemic adverse reactions, wherein relatively common adverse reaction is bone marrow suppression, digestive tract reaction And alopecia.So many patients cannot adhere to, or even chemotherapy is abandoned, be clinically difficult to be expected that by increasing drug dose obtain Preferable effect.These factors have had a strong impact on chemotherapeutic efficacy.
Recently there are some researches show ring dinucleotides synzyme（cGAS）It is catalyzed under the activation condition after combining DNA The synthesis of cGAMP, further mediates the activation of IRF-3, and then promote the synthesis of IFN-β by STING.It is exogenous to give weight Group cGAS promotes the generation of ring dinucleotides cGAMP under DNA conjugation conditions, plays effect antiviral, that enhancing is immune. There is patent report, the ring dinucleotides cGAMP of external synthesis has antineoplastic application.Sulphur (selenium) is for phosphoric acid ring dinucleotides CGAMP has antitumor activity more more preferable than cGAMP.
The present invention is prepared for the innovation derivative of-cGAMP of series of loops dinucleotides 2 ' 3 ', and the series derivates compare cGAMP Compatibility with more preferable stability and with target protein STING, with more preferable antitumor action, it is in antitumor and preparation There is important potential application in antineoplastic.
The content of the invention
The technical scheme is that structure composition, the preparation side of the series derivates there is provided ring dinucleotides cGAMP Method and its in application antitumor and in preparing antineoplastic.
The structure composition of ring dinucleotides cGAMP-XYZ derivatives, refers mainly to carry out modification transformation system by 2 ' 3 '-cGAMP Standby cGAMP derivatives.It is divided into following several classes：
（1）The derivative of 2 ' 3 '-cGAMP-X, cGAMP in the substituted base modification of Adenine moiety（2-R1 / 8-R2, R1/R2 =amino, halogen, methoxyl group etc.）
（2）The derivative of 2 ' 3 '-cGAMP-Y, cGAMP in the substituted base modification in guanine part（8-R3, R3=amino, halogen Element, methoxyl group etc.）
（3）The derivative of 2 ' 3 '-cGAMP-XY, cGAMP in all substituted base modification in adenine and guanine part（2-R1 / 8-R2, R1/R2=amino, halogen, methoxyl group etc.；8-R3, R3=amino, halogen, methoxyl group etc.）
（4）2 ' 3 '-cGAMP-XZ, cGAMP are modified in the substituted base of Adenine moiety, while being cyclized the phosphorus of phosphate ester key section Acid group has the derivative that sulphur replaces or selenium replaces.
（5）2 ' 3 '-cGAMP-YZ, cGAMP are modified in the substituted base in guanine part, while being cyclized phosphate ester key section Phosphate radical has the derivative that sulphur replaces or selenium replaces.
（6）2 ' 3 '-cGAMP-XYZ, cGAMP are modified in the substituted base in adenine and guanine part, while being cyclized phosphorus The phosphate radical of sour fat key section has the derivative that sulphur replaces or selenium replaces.
The preparation method of 2 ' 3 '-cGAMP-XYZ derivatives：
（1）The substitution radical derivative of adenosine triphosphate atp and GTP GTP, by the ring for combining duplex DNA post activations Dinucleotides synzyme（cGAS）Catalysis, prepares 2 ' 3 '-cGAM-XY derivatives（Including：2 ' 3 '-cGAMP-X, 2 ' 3 '- CGAMP-Y, 2 ' 3 '-cGAMP-XY）；
（2）Alpha-phosphate sulphur replaces（Selenium replaces）Adenosine triphosphate atp and GTP GTP）Substitution radical derivative, lead to Cross the ring dinucleotides synzyme with reference to duplex DNA post activations（cGAS）Catalysis, prepares the substitution of alpha-phosphate sulphur（Selenium）Substitution -2 ' 3 '-cGAMP derivatives（Including：2 ' 3 '-cGAMP-XZ, 2 ' 3 '-cGAMP-YZ, 2 ' 3 '-cGAMP-XYZ）；
During purposes of 2 ' 3 ' described-cGAMP derivatives in antitumor refers to the technical fields such as medicine, food or reagent, use It is including medicine, reagent, food or class etc. health food in the product of prevention, protection, treatment tumour and its directly related disease One or more in type.
In the present invention, the tumour includes but is not limited to colon cancer, lung cancer, oophoroma, melanoma, stomach cancer etc..
Antineoplastic in the present invention prepared by 2 ' 3 '-cGAMP derivatives routinely pharmacy can be prepared into various doses Type, including tablet, capsule, granule, supensoid agent, emulsion, solution, syrup or injection etc..
2 ' 3 '-cGAMP derivatives antineoplastics can take oral or injection in the present invention（Including intravenous injection, vein One or more in instillation, intramuscular injection or hypodermic injection etc.）It is related that one or more method of administration in carries out tumour Prevention, protection or the treatment of disease.
2 ' the 3 '-cGAMP derivatives antineoplastics that the present invention is provided have good application in the drug therapy of tumour Prospect.
Specific embodiment
Below by embodiment, present disclosure is illustrated.In the present invention, embodiments discussed below is in order to more preferable Ground illustrates the present invention, is not for limiting the scope of the present invention.
Embodiment 1：Ring dinucleotides cGAMP derivatives are constituted and preparation method
（1）The derivative of various ATP and GTP is bought from Sigma Co., USA.The derivative of ATP and GTP is as follows：
The derivative of (a) ATP-X, ATP substitution base modification（2-R1/8-R2, R1/R2=amino, halogen, methoxyl group etc.）
The derivative of (b) GTP-Y, GTP substitution base modification（8-R3, R3=amino, halogen, methoxyl group etc.）
(2)-the α of adenosine 5 ' is thio（Seleno）Phosphoric acid and the-α of guanosine 5 ' are thio（Seleno）Phosphoric acid is prepared by literature method. （HUANGZhen etc., Science China, Chemistry, 2012,55 (1), 80-89., Boyle N. A., et al, Nucleosides, Nucleotides and Nucleic Acids, 2005, 24, 1651-1664.）All chemistry Reagent is purchased from Sigma companies.
(3) 2 ' 3 '-cGAMP derivatives, sulphur（Selenium）The preparation of ' 3 '-cGAMP derivatives for phosphoric acid -2
With reference to the preparation method of 2 ' 3 '-cGAMP（Pingwei Li, et al., Immunity, 2013,39 (6), 1019- 1031.）, ATP-X derivatives and GTP-Y derivatives are substituted into ATP and GTP, in the case where the activation condition after DNA is combined is combined, by Cyclisation dinucleotides synzyme（cGAS）2 ' 3 '-cGAMP-XY derivatives of catalysis（Including：2 ' 3 '-cGAMP-X, 2 ' 3 '-cGAMP- Y, 2 ' 3 '-cGAMP-XY）Synthesis, purity is more than 98%.
（4）Sulphur（Selenium）The preparation of ' 3 '-cGAMP-XYZ derivatives for phosphoric acid -2, with reference to the preparation method of 2 ' 3 '-cGAMP, Adenosine derivative -5 '-α is thio（Seleno）Phosphoric acid and guanosine derivative -5 '-α is thio（Seleno）Phosphoric acid is prepared by literature method. （HUANG Zhen etc., Science China, Chemistry, 2012,55 (1), 80-89., Boyle N. A., et al, Nucleosides, Nucleotides and Nucleic Acids, 2005, 24, 1651-1664.）5’-α It is thio（Seleno）ATP and 5 '-α are thio for AMP derivative（Seleno）Guanosine 5-monophosphate derivative GTP, after DNA combinations are combined Activation condition under, by cyclisation dinucleotides synzyme（cGAS）Catalysis sulphur（Selenium）' the 3 '-cGAMP-XYZ derivatives for phosphoric acid -2 （Including：2 ' 3 '-cGAMP-XZ, 2 ' 3 '-cGAMP-YZ, 2 ' 3 '-cGAMP-XYZ）Synthesis, purity is more than 98%.
Embodiment 2：Ring dinucleotides cGAMP derivatives are tested for antitumor animal
The inhibitory action that is grown to animal subcutaneous transplantation knurl using the-cGAMP derivatives of mice with tumor model inspection 2 ' 3 ' and to animal Toxic action.
2 ' the 3 '-cGAMP derivatives for anti-tumor experiment select following five class：
（1） cGAMP-X1 （The bit amino substitutive derivative of adenine 2 in 2 ' 3 '-cGAMP）
（2） cGAMP-Y1 （The bit amino substitutive derivative of guanine 8 in 2 ' 3 '-cGAMP）
（3） cGAMP-X1Y1 （Adenine 2 and the bit amino substitutive derivative of guanine 8 in 2 ' 3 '-cGAMP）
（4） cGAMP-X1Z1 （Phosphoric acid sulphur-substitutive derivative in cGAMP-X1）
（5） cGAMP-X1Y1Z1 （Phosphoric acid sulphur-substitutive derivative in cGAMP-X1Y1）
The common mouse of BALB/c, the common mouse of C57/BL6, male, body weight 16-18g, 6-8 week old, SPF grades, be purchased from Shanghai this Rec experimental animal Co., Ltd [Quality of Experimental Animals quality certification number：SCXK （Shanghai）2007-0005 ] .
Rearing conditions
All mouse are freely looked for food and drink water, in room temperature（23±2）Raised at DEG C in army medical university of Chinese People's Liberation Army reality Test animal center.Feed and water are processed through autoclaving, and all experimentss feeding process is SPF grades.
Dosage is set
Intravenous injection into mice, sets 1 dosage group：10 mg/kg
Experimental control
Negative control：Normal saline solution
Positive control：CGAMP, the mg/kg of dosage 10
Medication
Method of administration：Tail vein injection is administered
Administered volume：100 microlitres/only
Administration number of times：Once a day, continuous 21 days
Every group of number of animals：10
Tumor cell line
Mouse colorectal cancer cell lines CT26, mice lung cancer Lewis knurl strain LL/2, human oophoroma cell line SK-OV-3, people are black Pigment tumor cell strain A375, human stomach cancer cell line MNK-45 are purchased from Chinese Academy of Sciences's cell bank.
Experiment key step
1. the foundation of tumor model mouse and intervention
Cell culture, passage collects cell in the cell log phase, and it is (1.0 × 10 to make concentration7) every milliliter of cell suspension, 0.2 ml cell suspensions are injected in mouse right fore oxter, and (cell number is 2.0 × 106Individual/only), tumour is long extremely within 10 days or so The mm of diameter about 5, tumorigenesis success, is divided into 5 groups at random.Respectively A：Negative control group（Intravenous injection physiological saline group）； B： CGAMP groups (intravenous injection cGAMP) 10mg/kg; C、D、E、F、G：2 ' 3 '-cGAMP derivatives groups (intravenous injection 2 ' 3 '- CGAMP derivatives) 10 mg/kg.It is administered once daily, successive administration 21 days.After 21 days, put to death mouse and claim tumor weight, press down Ratio of outflow=[the average knurl weight of 1- experimental groups (B, C, D, E, F, G group)/average knurl weight of A groups)] × 100%.
Subcutaneous transplantation knurl model is prepared respectively：Mouse colorectal cancer cell lines CT26, mice lung cancer Lewis knurl strain LL/2, Human oophoroma cell line SK-OV-3, human melanoma cell strain A375, human stomach cancer cell line MNK-45, observes cGAMP derivatives Antitumous effect.
2. statistical analysis
Data are represented with x ± s, processed using SPSS10.0 softwares, using one-way analysis of variance（one-way ANOVA） The conspicuousness of each group knurl weight difference, significance a=0.05 are compared in inspection.
As a result
Subcutaneous transplantation knurl model is successfully prepared after mouse hypodermic inoculation tumour cell, 2 ' 3 '-cGAMP-XYZ derivatives can be obvious Suppress tumour growth, the knurl weight after being administered 21 days is substantially less than negative control group（P<0.05, P<0.01）, 2 ' 3 '-cGAMP- XYZ is better than cGAMP independent medications, shows that 2 ' 3 '-cGAMP-XYZ have more excellent antitumor action.Concrete outcome table 1- tables 5：
Effect of the table 1, cGAMP-XYZ to BalB/C mouse colorectal cancer cell CT26 subcutaneous transplantation knurls
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.268 ± 0.246（g） -
CGAMP groups 0.769 ± 0.185（g）** 66.0
CGAMP-X1 groups 0.558 ± 0.154（g）** 75.0
CGAMP-Y1 groups 0.590 ± 0.146（g）** 73.9
CGAMP-X1Y1 groups 0.436 ± 0.215（g）* 80.7
CGAMP-X1Z1 groups 0.442 ± 0.210（g）* 80.5
CGAMP-X1Y1Z1 groups 0.429 ± 0.263（g）* 81.0
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups
Effect of the table 2, cGAMP-XYZ to C57 mice lung cancer Lewis knurls strain LL-2 subcutaneous transplantation knurls
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.638 ± 0.356（g） -
CGAMP groups 0.880 ± 0.252（g）* 66.7
CGAMP-X1 groups 0.669 ± 0.154（g）** 74.6
CGAMP-Y1 groups 0.680 ± 0.165（g）** 74.2
CGAMP-X1Y1 groups 0.582 ± 0.186（g）** 78.0
CGAMP-X1Z1 groups 0.646 ± 0.254（g）* 75.5
CGAMP-X1Y1Z1 groups 0.496 ± 0.268（g）* 81.2
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups
Effect of the table 3, cGAMP-XYZ to human melanoma cell strain A375 mouse subcutaneous transplantation knurls
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.690 ± 0.356（g） -
CGAMP groups 0.882 ± 0.248（g）* 67.3
CGAMP-X1 groups 0.678 ± 0.149（g）** 75.0
CGAMP-Y1 groups 0.698 ± 0.253（g）** 74.0
CGAMP-X1Y1 groups 0.586 ± 0.292（g）* 78.3
CGAMP-X1Z1 groups 0.624 ± 0.352（g）* 76.8
CGAMP-X1Y1Z1 groups 0.499 ± 0.253（g）** 81.4
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups
Effect of the table 4, cGAMP-XYZ to human stomach cancer cell line MNK-45 mouse subcutaneous transplantation knurls
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.686 ± 0.328（g） -
CGAMP groups 0.868 ± 0.284（g）** 74.5
CGAMP-X1 groups 0.656 ± 0.219（g）** 75.6
CGAMP-Y1 groups 0.598 ± 0.235（g）** 77.7
CGAMP-X1Y1 groups 0.529 ± 0.228（g）** 80.3
CGAMP-X1Z1 groups 0.524 ± 0.238（g）** 80.5
CGAMP-X1Y1Z1 groups 0.499 ± 0.228（g）** 81.4
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups
Effect of the table 5, cGAMP-XYZ to human oophoroma cell line's SK-OV-3 mouse subcutaneous transplantation knurls
（N=10, mean ± SD）
The average knurl weight of group（g）Average tumour inhibiting rate（%）
Negative control group 2.726 ± 0.318（g） -
CGAMP groups 0.869 ± 0.245（g）** 68.0
CGAMP-X1 groups 0.628 ± 0.263（g）** 76.9
CGAMP-Y1 groups 0.586 ± 0.216（g）** 78.5
CGAMP-X1Y1 groups 0.529 ± 0.234（g）** 80.5
CGAMP-X1Z1 groups 0.519 ± 0.215（g）** 80.9
CGAMP-X1Y1Z1 groups 0.499 ± 0.237（g）** 81.7
Note：*P<0.05 vs negative control groups；**P<0.01 vs negative control groups
The studies on acute toxicity of the cGAMP derivatives of embodiment 3
Experiment material
ICR mouse 20（It is purchased from Shanghai Slac Experimental Animal Co., Ltd.'s [Quality of Experimental Animals quality certification number： SCXK （Shanghai）2007-0005 ] ）, male and female half and half, 18~22g of body weight, animal with pellet feed, freely ingest and drink Water.
CGAMP derivatives are prepared by embodiment 1, with normal saline into the solution that concentration is 200 mg/mL.
Experimental technique
ICR mouse observe mouse 14 days after being administered by the cGAMP derivative slow releasing pharmaceuticals of body weight single tail vein injection 2g/kg Interior toxic reaction and death condition.Result finds, after the administration of mouse single tail vein injection, mouse activity is normal.After administration In 14 days, there is not death in mouse, and the 15th day, whole sacrifices were dissected, and each internal organs of visual inspection are showed no obvious lesion.
Experimental result
Above-mentioned acute toxicity testing result shows that intravenous injection administration maximal tolerance dose MTD is not less than 2 g/Kg, illustrates cGAMP The acute toxicity of derivative medicine is low.

Claims (8)

1. the molecular structure of ring dinucleotides cGAMP derivatives constitutes
2 ' the 3 '-cGAMP-XYZ derivatives for carrying out modification transformation preparation by the-cGAMP of ring dinucleotides 2 ' 3 ' are divided into following several classes：
The derivative of 2 ' 3 '-cGAMP-X, cGAMP in the substituted base modification of Adenine moiety（2-R1 / 8-R2, R1/R2 = Amino, halogen, methoxyl group etc.）
The derivative of 2 ' 3 '-cGAMP-Y, cGAMP in the substituted base modification in guanine part（8-R3, R3=amino, halogen, Methoxyl group etc.）
The derivative of 2 ' 3 '-cGAMP-XY, cGAMP in all substituted base modification in adenine and guanine part（2-R1 / 8- R2, R1/R2=amino, halogen, methoxyl group etc.；8-R3, R3=amino, halogen, methoxyl group etc.）
2 ' 3 '-cGAMP-XZ, cGAMP are modified in the substituted base of Adenine moiety, while being cyclized the phosphate radical of phosphate ester key section There is the derivative that sulphur replaces or selenium replaces
2 ' 3 '-cGAMP-YZ, cGAMP are modified in the substituted base in guanine part, while being cyclized the phosphate radical of phosphate ester key section There is the derivative that sulphur replaces or selenium replaces
2 ' 3 '-cGAMP-XYZ, cGAMP are modified in the substituted base in adenine and guanine part, while being cyclized phosphate ester key portion The phosphate radical for dividing has the derivative that sulphur replaces or selenium replaces.
The preparation method of 2.2 ' 3 '-cGAMP derivatives：
The substitution radical derivative of adenosine triphosphate atp and GTP GTP, by the ring two for combining duplex DNA post activations Nucleotide synthetase（cGAS）Catalysis, prepares 2 ' 3 '-cGAM-XY derivatives（Including：2 ' 3 '-cGAMP-X, 2 ' 3 '-cGAMP- Y, 2 ' 3 '-cGAMP-XY）；
Alpha-phosphate sulphur replaces（Selenium replaces）Adenosine triphosphate atp and GTP GTP）Substitution radical derivative, by knot Close the ring dinucleotides synzyme of duplex DNA post activations（cGAS）Catalysis, prepares the substitution of alpha-phosphate sulphur（Selenium）Substitution -2 ' 3 ' - CGAMP derivatives（Including：2 ' 3 '-cGAMP-XZ, 2 ' 3 '-cGAMP-YZ, 2 ' 3 '-cGAMP-XYZ）.
3. the antineoplastic for using 2 ' 3 '-cGAMP derivatives to prepare, it is characterised in that：It comprising different size 2 ' 3 '- 2 ' the 3 '-cGAMP derivative formulations that the unit formulation and pharmaceutically acceptable carrier of cGAMP derivatives are prepared into, including piece One or more in agent, capsule, granule, supensoid agent, emulsion, solution, syrup or injection etc., take it is oral or Injection（One or more in including intravenous injection, drip-feed, intramuscular injection or hypodermic injection etc.）One kind or many in Planting method of administration carries out prevention, protection or the treatment of tumour and its directly related disease.
4.-cGAMP the derivatives of ring dinucleotides 2 ' 3 ' according to described in claim 1, prepare the ring of various liposomes - cGAMP the derivatives of dinucleotides 2 ' 3 '.
5. the medicine of other the species diseases for being prepared using-cGAMP the derivatives of ring dinucleotides 2 ' 3 ', including nervus retrogression disease Disease, inflammation, cardiovascular and cerebrovascular diseases, diabetes, rheumatoid arthritis, multiple sclerosis etc., but it is not limited to the medicine of these disease classes.
Purposes of 6.2 ' the 3 '-cGAMP derivatives in antitumor, for preventing, protecting, treating tumour and its directly related disease The product of disease, including medicine, reagent, food or one or more etc. health food in type.
Application of 7.2 ' the 3 '-cGAMP derivatives in antitumor chemical drug drug combination.
Application of 8.2 ' the 3 '-cGAMP derivatives in anti-tumor monoclonal antibody drug combination.
CN201710147711.5A 2017-03-13 2017-03-13 Structural composition of cyclic dinucleotide cGAMP derivative, preparation method and application of cyclic dinucleotide cGAMP derivative in tumor resistance Active CN106928298B (en)

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