CN110934876B - C 27 H 27 N 7 O 2 Application of S in preparation of medicament for inhibiting organ allograft rejection - Google Patents
C 27 H 27 N 7 O 2 Application of S in preparation of medicament for inhibiting organ allograft rejection Download PDFInfo
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- CN110934876B CN110934876B CN201911115394.4A CN201911115394A CN110934876B CN 110934876 B CN110934876 B CN 110934876B CN 201911115394 A CN201911115394 A CN 201911115394A CN 110934876 B CN110934876 B CN 110934876B
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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Abstract
The invention discloses C 27 H 27 N 7 O 2 Application of S in preparing a medicament for inhibiting organ allograft rejection. The invention discovers that C 27 H 27 N 7 O 2 S, after the mice are treated by the medicament, the heart allograft rejection reaction of the mice can be obviously delayed; further detecting the change of the gene expression level, finding C 27 H 27 N 7 O 2 S can inhibit the expression of nzyme B, TNF-alpha and IL-12 cytokines. Indication C 27 H 27 N 7 O 2 S can be used for preparing medicaments for inhibiting organ allograft rejection reaction, and has a great application prospect.
Description
Technical Field
The invention relates to the technical field of biological medicine. And more particularly to C 27 H 27 N 7 O 2 Application of S in preparing a medicament for inhibiting organ allograft rejection.
Background
Organ transplantation is currently the most desirable means of treating end-stage organ dysfunction or failure, but the immune system of the organ recipient often develops rejection reactions against foreign grafts. Cellular immune responses elicited after T cell activation by allograft antigens play a leading role in the development of acute rejection. For example, in skin and heart transplant models, massive T cell activation is the primary cause of immune rejection. Therefore, in order to increase the success rate of organ transplantation, immunosuppressants are often used clinically before and after surgery, so that the activity of the immune system is reduced, and the survival rate of an organ recipient is improved.
FK506 is the most commonly used immunosuppressant in clinic, and blocks T lymphocyte activation signaling by inhibiting the function of phosphatase of calcineurin, thereby affecting the transcription and secretion of IL-2. However, clinical data indicate that patients with long-term immunosuppressants have significant adverse effects, such as strong hepatorenal toxicity and allergy. Based on the fact that a plurality of immunosuppressive agents acting on different mechanisms can be selected clinically, the current use of immunosuppressants tends to be combined with the use of a plurality of agents, so that the target curative effect can be achieved, and side effects caused by the use of a single agent can be avoided. It is therefore important to develop new agents for organ transplant rejection, particularly cardiac allograft rejection agents.
Disclosure of Invention
The present invention is to solve the above-mentioned drawbacks and disadvantages of the prior art and to provide C 27 H 27 N 7 O 2 Application of S in preparing a medicament for inhibiting organ allograft rejection.
The above object of the present invention is achieved by the following technical solutions:
C 27 H 27 N 7 O 2 s,2- (4-methyl-1, 4-diaza-1-yl) -N- [ (5-methylpyrazin-2-yl) methyl]-5-oxo- [1,3]Benzothiazole [3,2-a ]][1,8]Naphthyridine-6-carboxamide has a chemical structural formula as shown in formula (I):C 27 H 27 N 7 O 2 s is an effective and orally-taken small molecule inhibitor for rRNA synthesis, specifically inhibits RNA polymerase (Pol) I mediated transcription, has antiproliferative activity in tumor cells such as human pancreatic cancer cells MIA Paca-2, human melanoma cells A375 and colorectal cancer cells HCT-116, regulates apoptosis through a P53 pathway, can lead to release of Ribonucleoprotein (RPs) from a nucleolar emergency pressure pathway, and enables RPL5 and RPL11 to bond with MDM2 so as to inhibit the combination of the RPL5 and the RPL11 with P53, thus leading to the increase of P53 expression and further regulating apoptosis of the cells. At present, the application of the compound in the aspect of organ allograft rejection is not seen.
The invention discovers that C 27 H 27 N 7 O 2 S, after the mice are treated by the medicament, the heart allograft rejection of the mice can be obviously delayed; further lead toDetecting the change of the expression level of the gene, finding C 27 H 27 N 7 O 2 S can inhibit the expression of Granzyme B, TNF-alpha and IL-12 cytokines.
The invention therefore first claims protection of said C 27 H 27 N 7 O 2 The application of S in preparing a medicament for inhibiting organ allograft rejection or in inhibiting organ allograft rejection.
Preferably, the C 27 H 27 N 7 O 2 The S dosage is 2.0-3.0 mg.kg -1 (preferably 2.0 mg.kg) -1 )。
The present invention also provides an agent for inhibiting rejection of organ allografts, which comprises C 27 H 27 N 7 O 2 S。
Preferably, the medicament is a tablet, capsule, powder, oral liquid, soft capsule, pill, tincture, syrup, suppository or injection.
Compared with the prior art, the invention has the following beneficial effects:
the invention discovers that C 27 H 27 N 7 O 2 S, after the mice are treated by the medicament, the heart allograft rejection reaction of the mice can be obviously delayed; further detecting the change of the gene expression level, finding C 27 H 27 N 7 O 2 S can inhibit the expression of Granzyme B, TNF-alpha and IL-12 cytokines, indicating C 27 H 27 N 7 O 2 S can be used for preparing a medicament for inhibiting organ allograft rejection; the invention provides C 27 H 27 N 7 O 2 The novel application of S in preparing the medicament for inhibiting organ allograft rejection provides a novel efficient and safe medicament for inhibiting organ allograft rejection.
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FIG. 1 is a graph of C at the animal test level 27 H 27 N 7 O 2 S effect on heart allograft rejection.
In FIG. 1A, heart transplant rejection score (graft rejection score), in orderThe dosage of FK506 is 2.0mg.kg for the control group (Saline) -1 、C 27 H 27 N 7 O 2 S dosage is 2.0 mg.kg -1 。
In FIG. 1B, the change in body weight after treatment of each group in heart transplantation was shown to be 2.0 mg/kg in the control group (Saline) and FK506 -1 、C 27 H 27 N 7 O 2 S dosage is 2.0 mg.kg -1 。
FIG. 1C shows a pathological section of the heart, wherein the control group (Saline) and FK506 are sequentially arranged from left to right, and the dosage of FK506 is 2.0mg.kg -1 、C 27 H 27 N 7 O 2 S dosage is 2.0 mg.kg -1 。
FIG. 1D shows the CD4/CD8 ratio of the heart of the graft, which is followed by a control group (Saline) and FK506 in an amount of 2.0 mg.kg from left to right -1 、C 27 H 27 N 7 O 2 S dosage is 2.0 mg.kg -1 。
FIGS. 1E, F and G show the detection of Granzyme B, TNF- α, IL-12 expression following heart transplantation in mice by real-time quantitative PCR. The control group (Saline) and FK506 are 2.0mg.kg in order from left to right -1 、C 27 H 27 N 7 O 2 S dosage is 2.0 mg.kg -1 。
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
Example 1C 27 H 27 N 7 O 2 S delays the occurrence of heart allograft rejection at the animal experiment level
1. Mouse heart transplantation experiment
(1) Mouse heart transplant model establishment
Laboratory was purchased with C57BL/6 and C57BL/6 of 8 to 10 weeks old from the center of the university of Zhongshan and was kept in a feeding room at the center of the university of Zhongshan. BALB/C mice C57BL/6 mice were anesthetized with 10% sodium pentobarbital and BALB/C mice were heart-accessed at the carotid artery and vein sites where C57BL/6 was accessed. Mice were divided into 4 groups of 5 mice each.
(2) Preparation and administration of pharmaceutical agents
The implantation is counted as day 0, the administration is started on the day of implantation, the administration mode adopts intraperitoneal injection, 1 time of injection per day, continuous injection is carried out until heart is transplanted to stop beating, and C 27 H 27 N 7 O 2 The S injection is diluted with physiological saline according to the administration dosage. The injection groups were divided into: the blank control group is injected with physiological saline; FK506 dosage is 2.0mg.kg -1 、C 27 H 27 N 7 O 2 S dosage is 2.0 mg.kg -1 。
(3) Graft survival
When heart transplant rejection occurs, the heart of its transplant will beat down or stop beating, and the survival of its transplant heart is observed and recorded by visual inspection and touching.
(4) Histopathological examination
The transplanted heart was removed, fixed with 4% formaldehyde, paraffin-embedded, sectioned, HE stained and observed for pathological section. In agreement with the skin graft rejection scoring method, the graft heart necrosis was scored pathologically.
(5) Determination of Granzyme B, TNF-alpha and IL-12 expression in spleen
Mice were sacrificed on day seven, spleens were removed, total RNA was extracted via Trizol, and reverse transcription experiments were performed using PrimeScript RT-PCR Kit (TaKaRa) to obtain cDNA. The transcriptional levels of Granzyme B, TNF- α and IL-12, i.e., the changes in the mRNA levels of Granzyme B, TNF- α and IL-12, were detected by fluorescence quantification. Wherein, the fluorescent quantitative PCR detection uses beta-actin as a reference gene;
the PCR primer sequence for detecting the internal reference beta-actin gene by fluorescent quantitative PCR is as follows:
forward primer F:5'-GGCTGTATTCCCCTCCATCG-3';
reverse primer R:5'-CCAGTTGGTAACAATGCCATGT-3';
the primers for detecting the transcription level of Granzyme B by fluorescent quantitative PCR are as follows:
forward primer F:5'-TCGACCCTACATGGCCTTAC-3';
reverse primer R:5-TGGGGAATGCATTTTACCAT-3';
the primers for detecting the transcription level of TNF-alpha by fluorescent quantitative PCR are as follows:
forward primer F:5'-TCTCATCAGTTCTATGGCCC-3';
reverse primer R:5'-GGGAGTAGACAAGGTACAAC-3';
the primers for detecting the transcription level of IL-12 by fluorescent quantitative PCR are as follows:
forward primer F:5'-CAGCATGTGTCAATCAGCTAC-3';
reverse primer R:5'-TGTGGTCTTCAGCAGGTTTC-3'.
From the experimental results, the product of C 27 H 27 N 7 O 2 The treatment with S agent clearly delayed immune rejection of heart transplants (fig. 1A). While in terms of body weight, at C 27 H 27 N 7 O 2 The body weight of mice after S treatment was not much different (fig. 1B). From the results of HE staining (fig. 1C), it was found that the tissue of the transplanted heart of the Saline control group had a large number of inflammatory cells, mainly lymphocytes and part of neutrophils, and the muscular layer had a large number of inflammatory cells, which had been extensively infiltrated. FK506 group had a partial lymphocyte-based inflammatory cell infiltration. C (C) 27 H 27 N 7 O 2 The S group is only infiltrated by low-grade inflammatory cells, and the tissue structure is compact. Isolation of T cells from the graft heart was analyzed by flow cytometry and the results showed C 27 H 27 N 7 O 2 S can effectively inhibit CD4 + CD8 + T cells infiltrate in the graft heart. RNA isolated from spleen was analyzed via real-time quantitative PCR, and the results showed that C 27 H 27 N 7 O 2 S can inhibit the expression of Granzyme B, TNF-alpha and IL-12 cytokines. To sum up, C 27 H 27 N 7 O 2 S can delay the occurrence of heart allograft rejection; indication C 27 H 27 N 7 O 2 S can be used for preparing a medicament for deferring heart allograft rejection. Meanwhile, the C was found by other types of organ transplantation mouse model experiments 27 H 27 N 7 O 2 S has good rejection inhibition effect on organ or tissue transplantation such as kidney, heart, small intestine, bone marrow, etc., and shows that C 27 H 27 N 7 O 2 S has a great application prospect in inhibiting organ allograft rejection.
Claims (1)
1.C 27 H 27 N 7 O 2 Application of S in preparing medicament for inhibiting organ allograft rejection reaction, which is characterized in that C 27 H 27 N 7 O 2 S is 2- (4-methyl-1, 4-diaza-1-yl) -N- [ (5-methylpyrazin-2-yl) methyl]-5-oxo- [1,3]Benzothiazole [3,2-a ]][1,8]Naphthyridine-6-carboxamide has a chemical structural formula as shown in formula (I):
the C is 27 H 27 N 7 O 2 S was used in an amount of 2.0 mg/kg -1 ；
The organ is a heart;
the C is 27 H 27 N 7 O 2 S is capable of inhibiting the expression of Granzyme B, TNF-alpha and IL-12 cytokines.
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