CN114404404A - Application of tetracyclic diterpenoid compounds in preparation of medicines for treating and/or preventing mesangial proliferative glomerulonephritis and medicines - Google Patents

Application of tetracyclic diterpenoid compounds in preparation of medicines for treating and/or preventing mesangial proliferative glomerulonephritis and medicines Download PDF

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CN114404404A
CN114404404A CN202111681702.7A CN202111681702A CN114404404A CN 114404404 A CN114404404 A CN 114404404A CN 202111681702 A CN202111681702 A CN 202111681702A CN 114404404 A CN114404404 A CN 114404404A
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王润秀
谢富华
郭艳
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Gannan Medical University
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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Abstract

The invention relates to the technical field of medical treatment, in particular to application of a tetracyclic diterpenoid compound in preparing a medicament for treating and/or preventing mesangial proliferative glomerulonephritis, wherein the tetracyclic diterpenoid compound has a structure shown in a formula (I); r1、R2、R3Each independently selected from one or two of hydrogen, hydroxyl, halogen, C1-C8 alkyl or C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 acyloxy, C1-C8 acyl, amino, C1-C8 alkylamino, C1-C8 amide, C2-C8 alkyl imide, nitro, mercapto, alkylthio, acylthio, phosphoryloxy, sulfonyloxy, sulfinoyloxy, amidino, guanidino, carboxyl, phosphonic acid group, sulfonic acid group, sulfinic acid group and cyano. The compoundCan specifically inhibit the abnormal proliferation of mesangial cells and induce the apoptosis of mesangial cells, and is particularly suitable for treating and/or preventing mesangial proliferative glomerulonephritis.
Figure DDA0003447283980000011

Description

Application of tetracyclic diterpenoid compounds in preparation of medicines for treating and/or preventing mesangial proliferative glomerulonephritis and medicines
Technical Field
The invention relates to the technical field of medical treatment, in particular to application of a tetracyclic diterpenoid compound in preparing a medicine for treating and/or preventing mesangial proliferative glomerulonephritis and a medicine.
Background
Mesangial proliferative glomerulonephritis (MesPGN) is a glomerular disease which is characterized by the diffuse proliferation of mesangial cells and the expansion of mesangial matrixes in different degrees and takes nephrotic syndrome as a main clinical expression. MesPGN accounts for about 60% of cases of primary glomerulonephritis in China, and is the main cause of chronic kidney disease and uremia. However, the etiology and pathogenesis of MesPGN are not completely clear at present, and clinical specific drugs are lacked, so that only glucocorticoids (such as prednisone and the like) and cytotoxic drugs (such as cyclophosphamide and mycophenolate mofetil and the like) with large toxic and side effects can be adopted for symptomatic treatment.
Disclosure of Invention
The invention aims to solve the problems of large toxic and side effects and low specificity of the existing medicines for treating mesangial proliferative glomerulonephritis, and provides application of a tetracyclic diterpenoid compound in preparing medicines for treating and/or preventing mesangial proliferative glomerulonephritis and medicines.
In order to achieve the above objects, one aspect of the present invention provides a tetracyclic diterpenoid compound for use in the preparation of a medicament for treating and/or preventing mesangial proliferative glomerulonephritis; the tetracyclic diterpenoid compound has a structure shown in a formula (I):
Figure BDA0003447283960000021
wherein R is1、R2、R3Each independently selected from hydrogen, hydroxyl, halogen, C1-C8 alkyl or C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 acyloxy, C1-C8 acyl, amino, C1-C8 alkylamino, C1-C8 acylamino, C2-C8 alkyl imido, nitro, sulfhydryl, hydrocarbon sulfhydryl sulfenylOne of an acylthio group, a phosphoryloxy group, a sulfonyloxy group, a sulfinyloxy group, an amidino group, a guanidino group, a carboxyl group, a phosphonic acid group, a sulfonic acid group, a sulfinic acid group and a cyano group.
According to a second aspect of the present invention, there is provided a medicament, said medicament being a tetracyclic diterpenoid or a pharmaceutically acceptable salt thereof.
The tetracyclic diterpenoid compound or the pharmaceutically acceptable salt thereof provided by the invention is particularly suitable for preparing a medicament for treating and/or preventing mesangial proliferative glomerulonephritis, can specifically inhibit abnormal proliferation of mesangial cells and induce mesangial cell apoptosis, and is particularly suitable for treating and/or preventing mesangial proliferative glomerulonephritis.
Drawings
FIG. 1 is a diagram showing the fluorescence of immunofluorescence confocal images of example 2 and comparative example 1 of the present invention;
FIG. 2 is a graph showing the results of apoptosis in flow cytometry in example 2 of the present invention and comparative examples 2-3.
Detailed Description
The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.
According to a first aspect of the invention, the invention provides a use of the tetracyclic diterpenoid compound in the preparation of a medicament for treating and/or preventing mesangial proliferative glomerulonephritis; the tetracyclic diterpenoid compound has a structure shown in a formula (I):
Figure BDA0003447283960000031
wherein R is1、R2、R3Each independently selected from one of hydrogen, hydroxyl, halogen, C1-C8 alkyl or C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 acyloxy, C1-C8 acyl, amino, C1-C8 alkylamino, C1-C8 amide, C2-C8 alkyl imide, nitro, mercapto, alkylthio, acylthio, phosphoryloxy, sulfonyloxy, sulfinoyloxy, amidino, guanidino, carboxyl, phosphonic acid, sulfonic acid, sulfinic acid and cyano. The tetracyclic diterpenoid compound or the pharmaceutically acceptable salt thereof can specifically inhibit the abnormal proliferation of mesangial cells and induce the apoptosis of the mesangial cells, and is particularly suitable for treating and/or preventing mesangial proliferative glomerulonephritis.
According to a preferred embodiment of the invention, R1、R2、R3Each independently selected from one of C1-C3 alkyl, C1-C3 alkoxy, C1-C3 acyloxy, C1-C3 acyl, C1-C3 alkylamino, C1-C3 acylamino or C2-C3 alkyl acylamino.
According to a preferred embodiment of the invention, R1、R2、R3Each independently selected from R1、R2、 R3Each independently selected from C1-C3 alkyl or C1-C3 alkoxy.
According to a preferred embodiment of the invention, R1、R2、R3Each independently selected from one of methyl, ethyl, methoxy or ethoxy.
According to a preferred embodiment of the invention, R1、R2、R3Each independently selected from one of hydrogen, hydroxyl, halogen or carboxyl.
According to a preferred embodiment of the invention, the halogen is selected from fluorine or chlorine.
According to a preferred embodiment of the invention, R1、R2、R3All are hydroxyl, and the tetracyclic diterpenoid compound is oridonin. Oridonin or a pharmaceutically acceptable salt thereof,can specifically induce mesangial cell apoptosis, efficiently inhibit abnormal proliferation of mesangial cells, effectively relieve and treat mesangial proliferative glomerulonephritis, and greatly reduce harm of glucocorticoid and cytotoxic drugs to patients, and oridonin can be extracted from natural herbaceous plants with sufficient source, has small toxic and side effects on human bodies and low cost, is suitable for large-scale promotion, and can greatly reduce harm of glucocorticoid and cytotoxic drugs to mesangial proliferative glomerulonephritis patients.
In a second aspect, the invention provides a medicament comprising the tetracyclic diterpenoid compound or a pharmaceutically acceptable salt thereof.
According to a preferred embodiment of the invention, the medicament further comprises one or more of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant and vehicle.
According to a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the tetracyclic diterpenoid is selected from one or more of hydrochloride, hydrobromide, mesylate, sulfate, fumarate, tartrate, maleate, malate and citrate; preferably one or more of hydrochloride, sulphate, fumarate, tartrate, maleate, malate and citrate.
In the present invention, carriers, excipients, diluents, adjuvants and vehicles are not particularly limited, and pharmaceutically commonly used substances may be used, and will not be described in detail.
The present invention will be described in detail below by way of examples.
Examples 1 to 3
Preparing a 100mM solution by using a DMSO solvent, and then diluting the solution to be 1mM by using a serum-free medium II; rat mesangial cells cultured with 25% fetal bovine serum were allowed to act for 24 hours at the concentrations shown in Table 1.
Comparative example 1
Comparative example 1 rat mesangial cells were treated with an equal amount of phosphate buffer as in example 1.
TABLE 1
Example 1 Example 2 Example 3 Comparative example 1
Oridonin concentration (μ M) 10 15 20 0
Test example 1
And (5) observing cell morphology.
The cells of examples 1-3 began to change in cell morphology 6h after oridonin administration: the cell volume is gradually reduced, the cell is solidified and contracted into a round shape, and the wall-sticking capability is reduced to the growth of the cell after the cell is separated from the wall. The cells of comparative example 1 grew well.
Test example 2
MTT test: the absorbance values of the cells in examples 1-3 and comparative example 1 were measured using the method specified in the EPOCH microplate reader, and the wavelength of the measurement was 570 nm. The experimental data are shown in table 2.
TABLE 2
Example 1 Example 2 Example 3 Comparative example 1
Absorbance value of 570nm 0.42 0.12 0.06 0.48
Table 2 the results show that: compared with comparative example 1, the proliferation rate of the cells is obviously reduced after the oridonin is given to act on rat mesenteric cells in examples 1 to 3.
Comparative example 2
The difference from example 2 is that the same amount of phosphate buffer was used instead of the oridonin-DMSO solution treated rat mesenteric cells.
Comparative example 3
The difference from example 2 is that 15% fetal bovine serum was used to culture and the oridonin-DMSO solution-treated rat mesenteric cells were replaced with an equal amount of phosphate buffer.
Test example 3
Example 2 and comparative examples 2-3 were tested according to the flow cytometry protocol and the effect of the drug on cell cycle and apoptosis was observed. The results are shown in Table 3.
TABLE 3
Example 2 Comparative example 2 Comparative example 3
Stage G0/G1 64.93%±6.69% 44.3%±7.8% 40.23%±7.83%
Stage G2/M 9.57%±5.83% 27.33%±10.52% 21.02%±8.58%
The results in Table 3 show that the cells of example 2 were mostly blocked in the G1 phase (40% for comparative example 3G1 cells, 65% for example 2G1 cells, P < 0.05).
Test example 4
The green and red fluorescence of the cells were photographed for example 2 and comparative example 2, respectively, according to the method prescribed by immunofluorescence confocal microscopy. The results of the experiment are shown in FIG. 1.
FIG. 1 shows that only a small amount of cells in comparative example 2 show green fluorescence, while the fluorescence of example 2 is enhanced, and intracellular red fluorescence with obvious late apoptosis can be seen, which indicates that a large amount of apoptotic bodies can be detected by the cells under the action of oridonin.
Test example 5
The cells in example 4 and comparative examples 2 to 3 were examined for the proportion of apoptosis according to the flow cytometry requirements. The results of the experiment are shown in FIG. 2.
As can be seen from the flow cytometry apoptosis results of example 2 of the present invention and comparative examples 2-3 in FIG. 2, the apoptosis rates of comparative examples 2, 3 and 4 were 6.63% + -6.90%, 5.03% + -2.64%, and 62.43% + -4.01, respectively, indicating that the cells of example 4 were apoptotic after 24 hours of treatment with oridonin, while the cells of comparative examples 2 and 3 were almost non-apoptotic.
The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.

Claims (10)

1. An application of a tetracyclic diterpenoid compound in preparing a medicament for treating and/or preventing mesangial proliferative glomerulonephritis, wherein the tetracyclic diterpenoid compound has a structure shown in a formula (I):
Figure FDA0003447283950000011
wherein R is1、R2、R3Each independently selected from one of hydrogen, hydroxyl, halogen, C1-C8 alkyl or C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 acyloxy, C1-C8 acyl, amino, C1-C8 alkylamino, C1-C8 amide, C2-C8 alkyl imide, nitro, mercapto, alkylthio, acylthio, phosphoryloxy, sulfonyloxy, sulfinoyloxy, amidino, guanidino, carboxyl, phosphonic acid, sulfonic acid, sulfinic acid and cyano.
2. Use according to claim 1, wherein R1、R2、R3Each independently selected from C1-C3 alkyl, C1-C3 alkoxy, C1-C3 acyloxy, C1-C3 acyl, C1One of alkylamino of C3, amido of C1-C3 or alkyl imido of C2-C3.
3. Use according to claim 1 or 2, wherein R1、R2、R3Each independently selected from R1、R2、R3Each independently selected from C1-C3 alkyl or C1-C3 alkoxy.
4. Use according to claim 1 or 2, wherein R1、R2、R3Each independently selected from methyl, ethyl, methoxy or ethoxy.
5. Use according to claim 1 or 2, wherein R1、R2、R3Each independently selected from hydrogen, hydroxy, halogen or carboxy.
6. Use according to claim 5, wherein the halogen is selected from fluorine or chlorine.
7. Use according to claim 5, wherein R1、R2、R3Are all hydroxyl groups.
8. A medicament comprising the tetracyclic diterpenoid compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7.
9. The medicament of claim 8, further comprising one or more of a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, and vehicle.
10. The medicament according to claim 8 or 9, wherein the pharmaceutically acceptable salts of the tetracyclic diterpenoids are selected from one or more of hydrochloride, hydrobromide, mesylate, sulfate, fumarate, tartrate, maleate, malate and citrate; preferably one or more of hydrochloride, sulphate, fumarate, tartrate, maleate, malate and citrate.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150297598A1 (en) * 2012-11-27 2015-10-22 Beth Israel Deaconess Medical Center, Inc. Methods for treating renal disease
JP2018131429A (en) * 2017-02-14 2018-08-23 拓己 佐藤 Use of organic acid as method to enhance effect of nrf2 activator

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150297598A1 (en) * 2012-11-27 2015-10-22 Beth Israel Deaconess Medical Center, Inc. Methods for treating renal disease
JP2018131429A (en) * 2017-02-14 2018-08-23 拓己 佐藤 Use of organic acid as method to enhance effect of nrf2 activator

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JUSHUANG LI 等: "Oridonin protects against the inflammatory response in diabetic nephropathy by inhibiting the TLR4/p38-MAPK and TLR4/NF-κB signaling pathways", INTERNATIONAL IMMUNOPHARMACOLOGY *
吴岚;包丽萍;李菊霜;吴小燕;: "冬凌草甲素通过调节氧化应激和脂代谢减轻糖尿病大鼠肾损伤", 临床肾脏病杂志 *
抗晶晶;刘晓宁;: "冬凌草甲素抗炎作用参与多种疾病治疗的新进展", 中国野生植物资源 *
李菊霜: "冬凌草甲素对2型糖尿病大鼠肾脏Toll样受体4介导免疫炎症信号通路的干预研究", 中华糖尿病杂志 *

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