CN114539282A - Compound with anti-osteoporosis effect and preparation method and application thereof - Google Patents

Compound with anti-osteoporosis effect and preparation method and application thereof Download PDF

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CN114539282A
CN114539282A CN202210177651.2A CN202210177651A CN114539282A CN 114539282 A CN114539282 A CN 114539282A CN 202210177651 A CN202210177651 A CN 202210177651A CN 114539282 A CN114539282 A CN 114539282A
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陈勇
谭仁祥
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Abstract

The invention discloses a compound with an anti-osteoporosis effect, the invention prepares a compound spirolimonin with a novel skeleton through a large number of experiments, in vivo animal experiments show that the limonin prepared by the invention and the skeleton compound spirolimodione thereof have obvious treatment effect on prednisolone-induced osteoporosis of zebra fish, and the spirolimonin compound prepared by the invention has stronger osteogenic activity and can be used for preparing medicines for preventing and treating osteoporosis.

Description

Compound with anti-osteoporosis effect and preparation method and application thereof
Technical Field
The invention relates to a natural product derived from microorganisms, and in particular relates to a compound with an anti-osteoporosis effect, and a preparation method and application thereof.
Background
Osteoporosis is a systemic bone disease characterized by increased bone tissue fragility due to low bone mass, destruction of bone microstructure, reduced bone strength, and increased risk of fracture and premature mortality, and currently more than 2 billion people worldwide suffer from it. The prevention and treatment research of osteoporosis arouses the wide attention of various national medical and pharmaceutical communities, and the prevention and treatment of the disease and the complications thereof are placed in the same important position as hypertension, cerebral apoplexy, hyperlipidemia, coronary heart disease and the like internationally. The incidence rate of osteoporosis in China accounts for about 13% of the total population, and particularly the incidence rate of osteoporosis of women over 50 years old is up to 30%, and the incidence rate tends to increase year by year. It is predicted that by 2050, the number of patients with osteoporotic hip fractures alone will reach 600 million cases in China, with a corresponding medical expenditure of up to $ 254 million per year. It is expected that with the increasing aging trend of the whole society and the pursuit of people for the later healthy life, the demand of the anti-osteoporosis drug treatment in the future is huge.
At present, the anti-osteoporosis treatment drugs mainly comprise bone resorption inhibitors (bisphosphonates, estrogens and analogues thereof, calcitonin and the like), bone mineralization promoting drugs (calcium, vitamin D and the like) and bone formation promoting drugs (parathyroid hormone, fluoride and the like). The drugs have certain limitations and side effects in the long-term use and dose maintenance process of clinical treatment, and anti-osteoporosis drugs with high curative effect and low side effect still need to be further researched for clinical application.
The microorganisms and human body have long-term reciprocal symbiosis, and produce many metabolites with physiological activity, such as 6-N-hydroxyiminopurine (6-HAP) which is an anti-tumor active ingredient produced by human skin symbiotic bacteria Staphylococcus epidermidis, and mutanobacterin which is an antibacterial active ingredient secreted by oral microorganisms Streptococcus mutans. Although the research on the active secondary metabolites in the human symbiotic fungi is still in the primary stage, the human symbiotic fungi contains rich chemical and biological diversity information and is an important source for developing new anti-osteoporosis medicines.
Disclosure of Invention
The purpose of the invention is as follows: the invention aims to solve the defects of the prior art and separate a novel compound with osteoporosis resistance from a secondary metabolite of human symbiotic bacteria Penicillium velutinum.
The technical scheme is as follows: in order to achieve the above purpose, the invention adopts the technical scheme that:
a compound with anti-osteoporosis effect, which is characterized in that: the compound has the following parent nucleus structure:
Figure BDA0003520944090000021
preferably, the compound having anti-osteoporosis effect, wherein R is1-R7Is hydrogen, hydroxyl, carboxyl, straight-chain alkyl or substituted straight-chain alkyl, cycloalkyl, alkenyl or substituted alkenyl, carbonyl or substituted carbonyl, five-membered or six-membered heterocyclic ring, benzene ring or benzene ring containing substituent, cyano, nitro, alkoxy or alkylamino. X1-X2Is oxygen, sulfur or NR8Wherein R is8Is R1-R7Any of the groups described.
When R is1-R7Are each hydrogen, X1-X2When all are oxygen, the structure is named as: spirolemione, having the structural formula:
Figure BDA0003520944090000022
preferably, the compound with anti-osteoporosis effect is characterized in that: the molecular formula of the compound is C14H10O8The structure is as follows:
Figure BDA0003520944090000023
and is named as: spirocitrulline.
The preparation method of the compound with the anti-osteoporosis effect comprises the following steps:
a. extracting Penicillium velutinum fermentation liquor with an organic solvent to obtain an organic phase, and recovering the organic phase to obtain the extract.
b. Separating the extract by chromatography to obtain the target compound.
Preferably, in the above method for preparing a compound with anti-osteoporosis effect, the organic solvent used for extraction in step a is one of n-butanol and ethyl acetate or a mixed solvent thereof; the material for chromatographic separation is silica gel, alumina, silane bonded silica gel containing cyano or amino.
Preferably, the preparation method of the compound having anti-osteoporosis effect comprises the following steps:
a. inoculating the strain Peniciliumlutellinum on a PDA (personal digital Assistant) plate, culturing in an incubator at 28 ℃ for 2-3d, connecting to a malt liquid culture medium, and continuously culturing on a shaking table for 7 d;
b. after fermentation is finished, filtering with double-layer gauze to obtain fermentation liquor, extracting for 1-3 times with ethyl acetate, combining ethyl acetate phases, and recovering a solvent to obtain an extract;
c. separating the extract with normal phase silica gel column chromatography, gradient eluting with ethyl acetate-methanol at different volume ratios, collecting fractions, and combining into 10 fractions F1-F10 according to thin layer chromatography; separating F3 part by normal phase silica gel column chromatography, gradient eluting with ethyl acetate-methanol at different volume ratios, and separating into 8 parts F11-F18 according to fraction thin layer chromatography; and (4) taking the combined precipitate of the F13 and recrystallizing the precipitate by using ethyl acetate-methanol to obtain the compound.
Has the advantages that: compared with the prior art, the invention has the following advantages:
the spirolimonin compound with a novel framework is prepared through a large number of experiments, and the experimental result of the anti-osteoporosis activity shows that the spirolimonin compound prepared by the invention has strong osteogenic activity. Can be used for preparing medicine for preventing and treating osteoporosis.
Drawings
FIG. 1 is a HR-ESI-MS graph of spirocitrulline.
FIG. 2 is a representation of spirocitrin1H NMR chart (DMSO-d)6，400MHz)。
FIG. 3 is a representation of spirocitrin13C NMR chart (DMSO-d)6，100MHz)。
FIG. 4 is the HSQC spectrum (DMSO-d) of spirocitrulline6，400MHz)。
FIG. 5 is H of spirocitrullineMBC spectrum (DMSO-d)6，400MHz)。
FIG. 6 is a graph of X-ray single crystal diffraction data for spirocitrin.
Fig. 7 is a graph of the anti-osteoporosis activity of spirolimonin and spirolemione (n-10).
Detailed Description
The present invention is further illustrated by the following examples, which are intended to be purely exemplary and are not intended to limit the scope of the invention, as various equivalent modifications of the invention will occur to those skilled in the art upon reading the present disclosure and fall within the scope of the appended claims.
EXAMPLE 1 preparation of the novel Compound spirolimonin
Inoculating the strain Penicillium velutinum on a PDA plate, culturing in an incubator at 28 ℃ for 2-3d, inoculating to 50 bottles of wort liquid culture medium (400 mL each), and culturing on a shaker at 28 ℃ for 7 d. After the fermentation is finished, filtering by using double-layer gauze to obtain fermentation liquor. The extract was extracted 2 times with 2 times the amount of ethyl acetate, and the ethyl acetate phases were combined and the solvent was recovered to obtain 9g of an extract. Separating the extract with normal phase silica gel column chromatography, eluting with ethyl acetate-methanol (1: 0-0: 1) gradient, collecting 150 parts of fraction, and combining into 10 parts according to thin layer chromatography (F1-F10). The F3 fraction (130mg) was subjected to column chromatography on normal phase silica gel, and was eluted with ethyl acetate-methanol (volume ratio 1: 0-1: 5) in a gradient manner to obtain 8 fractions (F11-F18) according to the fraction thin layer chromatography. Taking F13 part of the mixed solution, separating out, recrystallizing with ethyl acetate-methanol to obtain new compound, named as Citrobacter spiraeum extract, with purity of 99.5% by high performance liquid chromatography detection.
Structural analysis of spirocitrulline shows that the spirocitrulline is a light yellow crystal (ethyl acetate-methanol 10:1),1h NMR and13the C NMR data are shown in Table 1, FIG. 2 and FIG. 3; high resolution electrospray mass spectrometry (HR-ESI-MS): m/z329.0264 (C)14H10O8Na+Cacl.329.0268), mass spectral data are shown in fig. 1. The molecular weight is 306 and C14H10O8。13C-NMR(DMSO-d6100MHz) data showed 4 carbonyl or enol carbon signals (δ c 198.5,191.9,180.7, and 168.0), 7 enol carbon signals (δ c 157.1,156.8,139.3,122.0,107.8,104.4,102.8), and 3 sp3 carbon signals (86.8,70.1and 16.8). Considering that there are a total of 10 unsaturations in the molecular structure, it is speculated that there should be 3 rings in the structure.1H-NMR(DMSO-d6400MHz) data showed 1 methyl group attached to the olefinic bond (2.30ppm), 1 methylene group (4.51 and 4.63ppm, further confirmed by HSQC spectrum (fig. 4), 2 olefinic proton signals (5.68 and 6.41ppm), and three undetected protons, presumably hydroxyl groups. These signals were compared with citromycetin, and it was estimated that lemonacin contains a chromanone ring substituted with one carboxyl group and two ortho-hydroxyl groups. By analyzing the signals of HSQC and HMBC spectrogram (FIG. 5), the structure of the spirocitrulline is finally determined, and the structure is further confirmed by X-ray single crystal diffraction (FIG. 6).
TABLE 1 NMR data for spirocitrulline (DMSO-d)6，400MHz)
Figure BDA0003520944090000041
EXAMPLE 2 preparation of Spirolimonin basic skeleton Spirocitranedione
Figure BDA0003520944090000051
a.3-bromo-chromanone (2.3g,10mmol) is dissolved in EtOH (25mL) and 15% NaSCH is added at 0 deg.C3(5.1g,11mmol), the reaction mixture was stirred at room temperature for 12 hours, then ethyl acetate 100mL was added, the reaction mixture was washed with saturated NaCl solution 3 times, and the organic phase was evaporated to dryness to obtain an intermediate. The intermediate and trimethyloxytetrafluoroborate (0.6g,4mmol) were dissolved in nitromethane (10mL) at 0 ℃ under Ar protection, reacted at room temperature with stirring for 3h, and the solvent was evaporated. The precipitate was washed with appropriate amount of ether and recrystallized from acetone to give the intermediate dimethyl (4-chromanone-3-yl) -sulfonium tetrafluoroborate salt (0.5g,1.71mmol, 17% yield):1H NMR(400MHz,aceton-d6):δ3.32(s,3H),3.35(s,3H),5.12(dd,J＝11.4,8.5Hz,1H),5.22-5.29(m,2H),7.16(dd,J＝8.4,1.0Hz,1H),7.23(m,1H),7.73(dd,J＝8.7,7.2,1.7Hz,1H),7.90(dd,J＝7.9,1.8Hz,1H)；19F NMR(375.5MHz,aceton-d6):δ-150.53(s)；13C NMR(100MHz,aceton-d6):δ183.9,161.4,138.1,127.4,122.8,120.1,118.2,66.2,55.1,24.4,22.7；HR-ESI-MS:m/z 209.0618(C11H13O2S+,Cacl.209.0636).
b. taking dimethyl (4-chromanone-3-yl) -sulfonium tetrafluoroborate (60mg,0.4mmol) and 60% NaH (12mg,0.3mmol), dissolving in anhydrous THF (3mL), stirring at room temperature for 2h, concentrating and drying to obtain an intermediate, dissolving the intermediate in benzene (2mL), adding bis-dienone (20m L,0.25mmol), sealing at 100 ℃ for 1h, concentrating and evaporating to dryness, and performing HPLC semi-preparative separation to obtain spirocitranedione (9.2mg,0.04mmol, yield 10%):1H NMR(400MHz,CDCl3):δ7.91(dd,J＝7.9,1.8Hz,1H),7.57(ddd,J＝8.8,7.2,1.8Hz,1H),7.09(d,J＝7.9Hz,1H),7.06(d,J＝8.8Hz,1H),5.52(s,1H),4.64(d,J＝12.3Hz,1H),4.60(d,J＝12.3Hz,1H),2.35(s,3H)；13C NMR(100MHz,CDCl3):δ197.7,190.8,183.5,161.4,137.2,127.9,122.3,119.7,118.2,104.3,86.5,69.9,16.8；HR-ESI-MS:m/z 253.0477(C13H10O4Na+,Cacl.253.0471)。
example 3 evaluation of anti-osteoporosis Activity
Randomly selecting 3dpf wild AB strain type zebra fish in a 24-pore plate, and treating all tested zebra fish with 25mM prednisolone to establish an osteoporosis model. At the same time of molding, the test groups are given with 0.1,0.5 and 2.5M of spirocitrulline and spirocitradione, and the positive group is given with 60M of disodium ibandronate as a positive drug. After culturing at 28 ℃ for 5 days, carrying out killing, fixing, decoloring, alizarin red staining, photographing and data acquisition, carrying out statistics on the average optical density value of the zebra fish skull, and expressing the statistical processing result by mean +/-SD.
The results in fig. 7 show that spirocitrulline shows stronger osteogenic activity at concentrations of 0.1and 2.5M, P <0.05 compared to the model group; the spirolemione has stronger osteogenesis activity under the concentration of 2.5M, and compared with a model group, P is less than 0.05.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (7)

1. A compound with anti-osteoporosis effect, which is characterized in that: the compound has the following parent nucleus structure:
Figure FDA0003520944080000011
2. compound with anti-osteoporosis efficacy according to claim 1, characterized in that: r1-R7Is hydrogen, hydroxyl, carboxyl, straight-chain alkyl or substituted straight-chain alkyl, cycloalkyl, alkenyl or substituted alkenyl, carbonyl or substituted carbonyl, five-membered or six-membered heterocyclic ring, benzene ring or benzene ring containing substituent, cyano, nitro, alkoxy or alkylamino. X1-X2Is oxygen, sulfur or NR8Wherein R is8Is R1-R7Any of the groups described.
3. Compound with anti-osteoporosis effect according to claim 2, characterized in that: the molecular formula of the compound is C14H10O8Named as spirolimonin, has the following structure:
Figure FDA0003520944080000012
4. a method for preparing a compound having anti-osteoporosis effect according to any one of claims 1 to 3, comprising the steps of:
a. extracting Penicillium velutinum fermentation liquor with an organic solvent to obtain an organic phase, and recovering the organic phase to obtain the extract.
b. Separating the extract by chromatography to obtain the target compound.
5. The method for preparing a compound having anti-osteoporosis effect according to claim 4, wherein the organic solvent for extraction in step a is one of n-butanol, ethyl acetate or their mixed solvent; the material for chromatographic separation is silica gel, alumina, silane bonded silica gel containing cyano or amino.
6. The method for preparing a compound having anti-osteoporosis effect according to claim 3, comprising the steps of:
a. inoculating Penicillium velutinum to a PDA (personal digital Assistant) plate, culturing in an incubator at 28 ℃ for 2-3d, inoculating to a wort liquid culture medium, and continuously culturing on a shaking table for 7 d;
b. after fermentation is finished, filtering with double-layer gauze to obtain fermentation liquor, extracting for 1-3 times with ethyl acetate, combining ethyl acetate phases, and recovering a solvent to obtain an extract;
c. separating the extract with normal phase silica gel column chromatography, gradient eluting with ethyl acetate-methanol at different volume ratios, collecting fractions, and combining into 10 fractions F1-F10 according to thin layer chromatography; separating F3 part by normal phase silica gel column chromatography, gradient eluting with ethyl acetate-methanol at different volume ratios, and separating into 8 parts F11-F18 according to fraction thin layer chromatography; and (4) taking the combined precipitate of the F13 and recrystallizing the precipitate by using ethyl acetate-methanol to obtain the compound.
7. Use of the compound with anti-osteoporosis effect according to any one of claims 1 to 3 for preparing a medicament for preventing and treating osteoporosis.
CN202210177651.2A 2022-02-25 2022-02-25 Compound with osteoporosis resisting effect and preparation method and application thereof Active CN114539282B (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110051659A (en) * 2019-06-14 2019-07-26 贵州理工学院 Mulberrin is preparing the application in osteosporosis resistant medicament
CN110075104A (en) * 2019-06-14 2019-08-02 贵州大学 Kuwanon H is preparing the application in osteosporosis resistant medicament
CN110368379A (en) * 2019-06-14 2019-10-25 贵州大学 Kuwanon G is preparing the application in osteosporosis resistant medicament

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110051659A (en) * 2019-06-14 2019-07-26 贵州理工学院 Mulberrin is preparing the application in osteosporosis resistant medicament
CN110075104A (en) * 2019-06-14 2019-08-02 贵州大学 Kuwanon H is preparing the application in osteosporosis resistant medicament
CN110368379A (en) * 2019-06-14 2019-10-25 贵州大学 Kuwanon G is preparing the application in osteosporosis resistant medicament

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HAYASHI, YUJIRO等: "Domino Michael/Michael Reaction for the Formation of Chiral Spirocycles Using a Diphenylprolinol Silyl Ether", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 *
TROST, BARRY M等: "Carboxylative trimethylenemethane cycloadditions catalyzed by palladium", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 *

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