CN111135181B - Application of jolkinolide B and analogue thereof in preparation of anti-tuberculosis drugs - Google Patents

Application of jolkinolide B and analogue thereof in preparation of anti-tuberculosis drugs Download PDF

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CN111135181B
CN111135181B CN201911239610.6A CN201911239610A CN111135181B CN 111135181 B CN111135181 B CN 111135181B CN 201911239610 A CN201911239610 A CN 201911239610A CN 111135181 B CN111135181 B CN 111135181B
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jolkinolide
tuberculosis
drugs
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CN111135181A (en
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王超
马骁驰
马郁芳
鄢秋龙
冯磊
宁静
霍晓奎
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Dalian Medical University
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P31/06—Antibacterial agents for tuberculosis

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Abstract

The invention discloses application of jolkinolide B and analogues thereof in preparation of anti-tuberculosis drugs, and relates to the technical field of new application of jolkinolide B and analogues thereof. The invention discovers that jolkinolide B and analogues thereof can obviously inhibit mycobacterium tuberculosis H37Ra and a plurality of clinical multi-drug resistant mycobacterium tuberculosis, further discloses application of jolkinolide B and analogues thereof in preparation of anti-tuberculosis drugs, provides a new anti-tuberculosis drug with good effect and small side effect, can be combined with clinical first-line anti-tuberculosis drugs (rifampicin, isoniazid, ethambutol and the like) to achieve the synergistic effect.

Description

Application of jolkinolide B and analogue thereof in preparation of anti-tuberculosis drugs
Technical Field
The invention relates to a new application of jolkinolide B and analogues thereof, in particular to an application of jolkinolide B and analogues thereof in preparation of anti-tuberculosis drugs.
Background
The WHO global tuberculosis report in 2018 indicates that tuberculosis is one of ten causes of death. In 2017, 1000 ten thousand new infected tuberculosis are estimated, about 160 ten thousand people die of tuberculosis, and 88.9 ten thousand new infected tuberculosis are estimated in China, which is second only to India. Approximately 17 million people (23% of the global population) are estimated to have latent tuberculosis infection, with the risk of developing active tuberculosis. Drug-resistant tuberculosis is still a public health crisis, and 55.8 million people are estimated to be rifampicin-resistant tuberculosis (RR-TB) in 2017 all over the world, 82% of the people are multi-drug-resistant tuberculosis (MDR-TB), and MDR/RR-TB cases in China account for about 13% of the world, and rank two. At present, the treatment success rate of MDR/RR-TB is still very low, and is 55 percent in the whole world. Therefore, the research and development of novel antituberculosis drugs are the priority of WHO, and can also improve the current situation of tuberculosis prevalence in China.
Jolkinolide B and its analogs (17-hydroxyjolkinolide B ) are present in medicinal plants such as euphorbia fischeriana and euphorbia lunata, and are abietane-type diterpenes, and have two ternary oxygen ring segments and five-membered α, β -unsaturated lactone groups in the structure as follows:
Figure DEST_PATH_IMAGE001
at present, reports about the antitumor activity of jolkinolide B and analogues thereof exist, but no reports about the anti-tuberculosis effect of jolkinolide B and analogues thereof exist so far.
Disclosure of Invention
The invention aims to solve the technical problems in the prior art and provides application of jolkinolide B and analogues thereof in preparation of anti-tuberculosis drugs.
The technical solution of the invention is as follows: application of jolkinolide B and its analogues in preparing antitubercular medicine is provided.
The jolkinolide B analogue is 17-hydroxyjolkinolide B.
The application of the jolkinolide B and the analogue thereof in preparing anti-tuberculosis medicaments is the application in preparing anti-tuberculosis medicaments.
The application of the jolkinolide B and the analogue thereof in preparing anti-tuberculosis drugs is the application in preparing anti-lymphoid tuberculosis drugs.
The application of the jolkinolide B and the analogue thereof in preparing anti-tuberculosis medicines is the application in preparing anti-bone tuberculosis medicines.
The application of the jolkinolide B and the analogue thereof in preparing anti-tuberculosis medicines is the application in preparing anti-tuberculosis medicines.
The application of the jolkinolide B and the analogue thereof in preparing the anti-tuberculosis medicine is the application in preparing the anti-tuberculosis mycobacterium medicine.
The application of the jolkinolide B and the analogue thereof in preparing anti-tuberculosis drugs is the application in preparing multi-drug resistant mycobacterium tuberculosis drugs.
The application of the jolkinolide B and the analogue thereof in preparing anti-tuberculosis drugs is the application in preparing drugs for resisting wide drug-resistant mycobacterium tuberculosis.
The invention discovers that jolkinolide B and analogues thereof can obviously inhibit mycobacterium tuberculosis H37Ra and a plurality of clinical multi-drug resistant mycobacterium tuberculosis, invents the application of jolkinolide B and analogues thereof in the preparation of anti-tuberculosis drugs, provides a new anti-tuberculosis drug with good effect and small side effect, can be combined with clinical first-line anti-tuberculosis drugs (rifampicin, isoniazid, ethambutol and the like) to achieve the synergistic effect.
Drawings
FIG. 1 is an electron micrograph of the inhibitory effect of jolkinolide B and 17-hydroxyjolkinolide B on Mycobacterium tuberculosis H37 Ra.
FIG. 2 is a nucleic acid staining test chart showing the effect of jolkinolide B and 17-hydroxyjolkinolide B on Mycobacterium tuberculosis H37 Ra.
FIG. 3 is a graph showing the inhibitory effect of jolkinolide B on M.tuberculosis intracellulare H37Ra macrophage Raw264.7.
FIG. 4 is a graph of the inhibitory effect of 17-hydroxyjolkinolide B on the macrophage Raw264.7 M.intracellulare H37 Ra.
FIG. 5 is a graph showing the evaluation of the synergy of jolkinolide B with antituberculosis drugs.
FIG. 6 is a graph showing the evaluation of the synergistic effect of 17-hydroxyjolkinolide B with antitubercular agents.
Figure 7 is a jolkinolide B nmr hydrogen spectrum.
Figure 8 is a jolkinolide B nmr carbon spectrum.
FIG. 9 shows the NMR spectrum of 17-hydroxylabdanolide B.
FIG. 10 is a NMR carbon spectrum of 17-hydroxylabdanolide B.
Detailed Description
1. Experimental chemical structure spectrum data of jolkinolide B and 17-hydroxyjolkinolide B
The nuclear magnetic resonance hydrogen spectrogram and nuclear magnetic resonance carbon spectrogram of the homemade jolkinolide B (white powder) are respectively shown in FIGS. 7 and 8. UV (CH)3OH) λmax239.3 nm, suggesting that the compound contains a p-pi conjugated structure. In that1H-NMR（600 MHz，CDCl3) In the spectrum of the light source,δ2.09 (3H, s), 0.94 (3H, s), 0.85 (3H, s) and 0.82 (3H, s) are methyl proton signals at 17, 18, 19 and 20 positions;δ4.04 (1H, s) is the hydrogen proton signal on the oxygen-linked carbon at position 11;δ3.68 (1H, s) is the hydrogen proton signal on the oxygen-linked carbon at position 14;δ2.29 (1H, s) is the signal for the hydrogen proton at position 9 (Table 1). In that13C-NMR（150 MHz，CDCl3) In the spectrum, 20 carbon signals are given in total, whereinδ169.6 is the signal for the carbon of the carbonyl,δ148.6, 130.3 are two double bond carbon signals,δ66.1, 61.0, 85.2, 55.3 are four vicinal oxygen carbon signals (Table 1). From the analysis of the above spectral data, the chemical structure of jolkinolide B was determined as follows, which is identical to that of the existing jolkinolide B.
Figure 821667DEST_PATH_IMAGE002
The nuclear magnetic resonance hydrogen spectrogram and the nuclear magnetic resonance carbon spectrogram of the homemade 17-hydroxyjolkinolide B (white powder) are respectively shown in figures 9 and 10. MS (Mass Spectrometry) m/z390.20 shows the molecular formula C20H26O5. Process for preparing compounds1H NMR (CD3OD, 500 MHz) showed 3 methyl signals [ δ H0.88 (3H, s), 0.84 (3H, s), 0.94 (3H, s)]1 hydroxymethyl signal [ delta ]H4.53(2H,s)](Table 1).13C NMR(CD3OD,125 MHz) data are shown in table 1. From the analysis of the spectral data, the chemical structure of 17-hydroxyjolkinolide B was determined as follows, in contrast to the existing 17-hydroxyjolkinolide BThe ester B is the same.
Figure DEST_PATH_IMAGE003
TABLE 1 NMR spectroscopic data for jolkinolide B and 17-hydroxyjolkinolide B
Figure 643867DEST_PATH_IMAGE004
2. Experiment on inhibition effect of jolkinolide B and 17-hydroxyjolkinolide B on mycobacterium tuberculosis and drug-resistant mycobacterium tuberculosis
The inhibition effect of jolkinolide B and 17-hydroxyjolkinolide B on mycobacterium tuberculosis H37Ra is evaluated, and the results show that the two compounds can obviously inhibit the proliferation of H37Ra, the MIC ratio is 12.5 and 1.5 mu g/mL, and the two compounds show extremely high-efficiency antibacterial activity.
Secondly, jolkinolide B and 17-hydroxyjolkinolide B also showed considerable inhibitory effects against multiple multidrug resistant mycobacterium tuberculosis (HRE resistant) (table 2), especially the 17-hydroxyjolkinolide B monomeric compound showed strong inhibitory effects against most multidrug resistant mycobacterium tuberculosis.
TABLE 2
Figure DEST_PATH_IMAGE005
Experiment for observing destructive effect of jolkinolide B and 17-hydroxyjolkinolide B on cell wall of mycobacterium tuberculosis by using electron scanning microscope
The effect of jolkinolide B and 17-hydroxyjolkinolide B on M.tuberculosis H37Ra was observed by scanning electron microscope and transmission electron microscope, and the results are shown in FIG. 1. In fig. 1, scanning electron microscope: A. blank group; B. jolkinolide B; C. 17-hydroxyjolkinolide B.
Transmission electron microscope: D. blank group; E. jolkinolide B; F. 17-hydroxyjolkinolide B.
Observing the form of pathogenic bacteria of the administration group to be shrunk to a certain extent under a scanning electron microscope; the transmission electron microscope is used for observing the pathogenic bacteria caused by irregular shapes, shrinking cells, fuzzy cell wall edges and suspected damage. The results indicate that jolkinolide B and 17-hydroxyjolkinolide B are able to interfere with the cell wall formation of pathogenic bacteria. In addition, the present invention performed a pathogenic bacteria nucleic acid staining experiment, and the results are shown in fig. 2. The results show that after the jolkinolide B (6.5 mu g/L) and the 17-hydroxyjolkinolide B (2 mu g/L) act on the mycobacterium tuberculosis H37Ra, a remarkable red nucleic acid fuel is observed in the cells of pathogenic bacteria, the death or the integrity of cell walls of the pathogenic bacteria is damaged, and the interference of the jolkinolide B and the 17-hydroxyjolkinolide B on the cell wall of the pathogenic bacteria is further confirmed.
4. Experiment on inhibition effect of jolkinolide B and 17-hydroxyjolkinolide B on mycobacterium tuberculosis H37Ra in host cell
Based on a human macrophage Raw264.7 phagocytosis mycobacterium tuberculosis H37Ra model, the inhibition effect of jolkinolide B (36 #) and 17-hydroxy jolkinolide B (37 #) on intracellular pathogens is evaluated, and the results of the nucleic acid staining experiments of mycobacterium tuberculosis H37Ra are respectively shown in fig. 3 and fig. 4. The survival condition of the intracellular pathogenic bacteria is evaluated by the quantitative determination of the staining of the M.intracellulare H37Ra, and the inhibition effect of the medicament on the intracellular pathogenic bacteria is further reflected. The results show that the jolkinolide B and the 17-hydroxyjolkinolide B can enter macrophages, so that pathogenic bacteria can be effectively killed, and the feasibility of active substances in resisting tuberculosis in a body is shown.
5. Experiments on synergistic effect of combination of jolkinolide B and 17-hydroxyjolkinolide B with clinical first-line antituberculosis drugs
The feasibility of synergistic effect of combination of jolkinolide B and 17-hydroxyjolkinolide B with common antituberculosis drugs is evaluated. Selecting Isoniazid (INH), Rifampicin (RFP) and Ethambutol (EMB), respectively combining with jolkinolide B (36 #) and 17-hydroxyjolkinolide B (37 #) to act on Mycobacterium tuberculosis H37Ra, evaluating the antibacterial activity (MIC), and evaluating the action mode of the combined drug by grading antibacterial concentration index (FIC). The results are shown in fig. 5 and 6, which show that 17-hydroxyjolkinolide B (37 #) has an additive combination mode of action with rifampicin and ethambutol, and jolkinolide B (36 #) has an additive combination mode of action with isoniazid and ethambutol.

Claims (6)

1. The application of jolkinolide B analogues in preparation of anti-tuberculosis drugs is characterized in that the jolkinolide B analogues are 17-hydroxyjolkinolide B, and the anti-tuberculosis drugs are anti-multi-drug-resistant mycobacterium tuberculosis drugs.
2. Use of the jolkinolide B analogues according to claim 1 in the manufacture of anti-tubercular drugs, characterised by the use in the manufacture of anti-tuberculosis drugs.
3. Use of the jolkinolide B analogues according to claim 1 in the manufacture of anti-tubercular drugs, characterised by the use in the manufacture of anti-tubercular drugs.
4. Use of the jolkinolide B analogue of claim 1 in the manufacture of an anti-tubercular drug, characterised by the use in the manufacture of an anti-bone tuberculosis drug.
5. Use of the jolkinolide B analogues according to claim 1 in the manufacture of anti-tubercular drugs, characterised by the use in the manufacture of anti-tubercular drugs.
6. The application of jolkinolide B analogues in preparation of anti-tuberculosis drugs is characterized in that the jolkinolide B analogues are 17-hydroxyjolkinolide B, and the anti-tuberculosis drugs are drugs for resisting wide drug-resistant mycobacterium tuberculosis.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279081A (en) * 2016-08-23 2017-01-04 大连医科大学 Diterpene compounds and preparation method in Euphorbia fischeriana S teud．

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106279081A (en) * 2016-08-23 2017-01-04 大连医科大学 Diterpene compounds and preparation method in Euphorbia fischeriana S teud．

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ent-Abietane and Tigliane Diterpenoids from the Roots of Euphorbia fischeriana and Their Inhibitory Effects against Mycobacterium smegmatis;Chun-Jie Wang等;《J. Nat. Prod.》;20170406;第80卷;第1248-1254页 *
岩大戟内酯B诱导乳腺癌MCF-7细胞凋亡的实验研究;许惠玉等;《中国医学创新》;20120531;第9卷(第13期);第1-3页 *

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