CN113024527A - Compound derived from Zhejiang ophiopogon root, application and pharmaceutical composition thereof - Google Patents

Compound derived from Zhejiang ophiopogon root, application and pharmaceutical composition thereof Download PDF

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CN113024527A
CN113024527A CN202110313549.6A CN202110313549A CN113024527A CN 113024527 A CN113024527 A CN 113024527A CN 202110313549 A CN202110313549 A CN 202110313549A CN 113024527 A CN113024527 A CN 113024527A
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dichloromethane
cancer
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钱勇
宋波
辛振强
吴佳
蔡赞
谢天培
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Shanghai Standard Technology Co ltd
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    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract

The invention provides a novel compound derived from Zhejiang ophiopogon root, the structure of which is shown in the formula (I), and a preparation method of the compound. The novel compounds show antitumor activity.
Figure DDA0002990904600000011

Description

Compound derived from Zhejiang ophiopogon root, application and pharmaceutical composition thereof
Technical Field
The invention relates to a compound and medical application thereof, and also relates to a pharmaceutical composition containing the compound.
Background
Obtaining anti-tumor drugs from natural products is a popular field for the development of tumor drugs at home and abroad at present. The american National Cancer Institute (NCI) commissioned a phytologist of the american ministry of agriculture (USDA) in 1960 to provide 1000 plants annually to the national cancer chemotherapy service center (CCNSC) for anti-cancer drug screening. Over the years of efforts, the anticancer of natural products has also made great progress, and many natural small molecules have been successfully put on the market and become the star therapeutic drugs in the corresponding fields, such as taxus, camptothecin, vincristine, ginsenoside Rg3, and the like. As a natural product, China has huge natural product resources and also has a history of developing and using natural products which are far away, so that a plurality of scientists in China are always dedicated to the development of natural anti-tumor drugs. The traditional Chinese medicine has unique advantages in the aspects of resisting and preventing cancers, reducing adverse reactions and the like, and is a treasure house for researching and developing novel anti-tumor medicines.
In order to find more desirable anti-cancer compounds, scientists have not stopped the step of finding compounds of plant origin with anti-cancer activity.
Thunberg lilyturf root (Ophiopogon japonica (Thunb.) Ker-Gawl), is a perennial evergreen herb of the genus Ophiopogon of the family Liliaceae. The fibrous root is thicker, and the top or middle part of the root is often expanded to form spindle-shaped small fleshy blocks, which are Chinese medicinal materials. The traditional Chinese medicine believes that the Zhejiang dwarf lilyturf tuber is slightly bitter and cold. It enters heart, lung and stomach meridians. Has the effects of nourishing yin, promoting the production of body fluid, moistening lung and clearing away heart-fire. Can be used for treating lung dryness, dry cough, consumptive disease, cough, thirst due to body fluid consumption, vexation, insomnia, internal heat, diabetes, constipation due to intestinal dryness, and pharyngeal diphtheria. Simultaneously, the medicine is used for treating little body fluid, thirst, dry cough and hemoptysis caused by lung-stomach yin deficiency; palpitation due to heart yin deficiency and fluid impairment due to heat in the late stage of fever.
In the experiment of screening the anti-tumor compound, the inventor tries to screen the lead compound with anti-tumor activity from the natural compound derived from the thunberg dwarf lilyturf tuber, thereby providing a new choice for the research, development and preparation of novel anti-cancer drugs.
Disclosure of Invention
The inventor of the invention carries out intensive research on chemical components of the traditional Chinese medicine Zhe dwarf lilyturf tuber, and separates out a novel flavonoid compound of the dwarf lilyturf tuber, the structural formula of which is shown as the formula (I):
Figure BDA0002990904580000021
depending on the skeletal classification of the compound, the compound should belong to the homoisoflavonoid class of compounds. Homoisoflavonoids are a special class of flavonoids, which have a parent structure with one more carbon atom than isoflavones, are found in nature rarely and are present in only a few plants.
The homoisoflavone of the invention is specifically methyl homoisoflavone, also called Ophiopogonone (Ophiopogonone) compound, and has two more carbon atoms compared with the conventional isoflavone skeleton.
The chemical formula of the compound shown in the formula (I) according to the general systematic numbering of the flavonoids in natural products is as follows:
Figure BDA0002990904580000031
according to the inventor's examination, the compound with methylation at the 6-position of the skeleton and methoxyl at the 2' -position, and the 4 'and 3' ring-forming has not been reported from the natural product world, and the compound is not synthesized, and is determined to be the first discovered compound.
The content of the compound of the invention in natural medicinal materials is lower through the measurement of the dry medicinal materials and the finally obtained compound magnitude, according to the calculation of the inventor, the content in the dry medicinal materials is about 1.2ppm, and the related activity of the natural medicinal materials cannot be directly related to the activity of the compound.
Furthermore, the novel structural compound described in the formula (I) shows obvious anticancer activity in an anticancer activity test. The compounds from Thunberg lilyturf root, which have anticancer activity potential reported so far, have larger structural difference with the compounds of the formula (I) of the invention, and provide a new choice for the research, development and preparation of novel anticancer drugs.
Specifically, the invention provides the following technical scheme:
the invention provides a compound, which has a structure shown in a formula (I):
Figure BDA0002990904580000041
in the present invention, unless otherwise specified, chemical elements generally include the concept of chemically identical isotopes, such as the expression "hydrogen" and also the concept of chemically identical "deuterium" and "tritium", and carbon (C) includes12C、13C, etc., will not be described in detail. That is, the compound of the present invention includes a case where the element is replaced with an isotope.
The compound or the physiologically acceptable salt thereof can be applied to the preparation of a medicament for treating cancer because the compound or the physiologically acceptable salt thereof shows anticancer activity (see the specific embodiment), and the medicament for treating cancer is preferably a medicament for treating leukemia, liver cancer, breast cancer and colon cancer, but is not limited to the anticancer medicaments, and is preferably a medicament for treating leukemia.
In addition, the invention also provides a pharmaceutical composition which comprises the compound shown in the formula (I) and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may be used in combination with pharmaceutically acceptable adjuvants when the compound of the present invention is formulated, and examples of the adjuvants include solvents (e.g., water, ethanol, propylene glycol, oil for injection, etc.) which are conventional in the pharmaceutical field, diluents (e.g., starch, sugar powder, dextrin, lactose, pregelatinized starch, microcrystalline fiber, inorganic calcium salts (e.g., calcium sulfate, calcium hydrogen phosphate, calcium carbonate for pharmaceutical use, etc.), mannitol, etc., vegetable oils, polyethylene glycol, etc.), binders (e.g., water, ethanol, starch slurry, sodium carboxymethylcellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose, etc.), disintegrants (e.g., dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, etc.), lubricants (e.g., magnesium stearate, sodium lauryl sulfate, lauryl sulfate, Aerosil, talc, hydrogenated vegetable oil, polyethylene glycol, magnesium lauryl sulfate, etc.), absorption enhancer (such as surfactant, Azone, EDTA, salicylic acid, amino acid ethylamine derivatives, acetoacetates, β -dicarboxylate, aromatic acidic compound, fatty acid, etc.), preservative (such as benzoic acid, hydroxypropyl butyl ester, hydroxypropyl methyl ester, phenol, m-cresol, etc.), taste corrigent (such as sucrose, steviosin, etc.), etc. But is not limited thereto.
The pharmaceutical composition of the present invention can be used in various dosage forms, i.e., can be administered by conventional preparation methods, such as tablets, capsules, dripping pills, granules, powders, oral films and oral liquids, or injections, ointments, creams, suppositories, and the like, but is not limited thereto. The compound of the present invention is preferably formulated into an oral preparation for the purpose of treatment and convenience.
The compound can be extracted from the root bark of the Zhejiang ophiopogon root traditional Chinese medicinal material. The invention also provides an extraction preparation method, which is characterized by comprising the following steps:
an enrichment step, extracting dry root tuber powder of the thunberg lilyturf root with 80-95% ethanol, dissolving extraction residues in water, and extracting with dichloromethane to obtain dichloromethane fraction;
and a crude separation step, namely performing normal phase silica gel column chromatography on the dichloromethane fraction obtained in the step, and performing gradient elution by adopting a petroleum ether-dichloromethane gradient solvent system, wherein the solvent ratio is changed into petroleum ether: the volume ratio of dichloromethane is changed from 10:1 to 2:1 to obtain corresponding components;
and a fine separation step, namely performing normal phase silica gel column chromatography on the components separated in the fine separation step again, performing gradient by using dichloromethane-methanol, and changing the solvent ratio into dichloromethane: changing methanol from 65:1 to 5:1 in volume ratio, and eluting to obtain corresponding components;
and a purification step, namely performing chromatography on the components separated in the fine separation step on a reverse phase silica gel column chromatography to obtain the target compound.
The invention can of course also be obtained according to fully synthetic or semi-synthetic methods, which can be obtained according to organic synthetic methods well known in the art.
Drawings
FIG. 1 is a drawing of a compound of the present invention1H NMR spectrum;
FIG. 2 is a drawing of a compound of the present invention13C NMR spectrum;
FIG. 3 is a drawing of a compound of the present invention1H-1H COSY spectrogram;
FIG. 4 is a HSQC spectrum of a compound of the present invention;
FIG. 5 is a HMBC spectrum of a compound of the present invention;
FIG. 6 is a NOESY spectrum of a compound of the present invention;
FIG. 7 is a high resolution mass spectrum of a compound of the present invention;
FIG. 8 is an HPLC chromatogram of a compound of the present invention;
FIG. 9 is a UV spectrum of a compound of the present invention.
Detailed Description
The following describes how the compounds of formula (I) of the present invention (also referred to simply as "compounds of the present invention") can be obtained. Also specifically disclosed are specific experimental methods for the anticancer activity of the compounds of formula (I).
The experimental procedures in the following examples are conventional unless otherwise specified. The raw materials and reagent materials used in the following examples are all commercially available products unless otherwise specified.
Obtaining a compound of formula (I):
the extraction and separation process of the compound of the invention is as follows:
the Zhejiang ophiopogon root is purchased from Cixi Zhejiang, and the product package is provided with a geographical sign registration certificate of agricultural products and is morphologically identified as Zhejiang ophiopogon root.
Extracting 20kg of dried root tuber powder of the medicinal materials with 95% ethanol at room temperature for 3 times, each time for 4 hr. The solvent was removed by concentration under reduced pressure, and the residue (1960 g) was dissolved in water and separated by extraction with petroleum ether (3X 5L), methylene chloride (3X 5L) and ethyl acetate (3X 5L) in that order. The dichloromethane extraction fraction (180g) was separated by silica gel column chromatography eluting with a petroleum ether-dichloromethane (10: 1-1: 1v/v) gradient to give eight fractions (fr.a-fr.h).
② the product (180g) of the extraction part of the dichloromethane in the step (I) is separated by silica gel column chromatography and is eluted by petroleum ether-dichloromethane (10: 1-1: 1v/v) in a gradient way to obtain eight parts (Fr.A-Fr.H).
③ the Fr.C fraction obtained in step (25g) was subjected to silica gel column chromatography and eluted with a gradient (60: 1; 40: 1; 20: 1; 10: 1; 5:1v/v) of dichloromethane-methanol to give six fractions (Fr.1-6).
Fr.2 fraction was prepared by preparative HPLC using YMC Pack ODS-A (50 × 250mm,7um) column, eluting with methanol-water (80:20, v/v), to give the compound represented by formulA (1) of the present invention (25.6mg, tR ═ 10.72 min).
Structural characterization of the compounds of formula (I):
product analysis of the novel compounds obtained in the examples; of the compounds of the invention1The H NMR spectrum is shown in FIG. 1, and the compound of the invention13The C NMR spectrum is shown in FIG. 2, of the compound of the present invention1H-1The HCOSY spectrum is shown in figure 3, the HSQC spectrum of the compound of the invention is shown in figure 4, the HMBC spectrum of the compound of the invention is shown in figure 5, the NOESY spectrum of the compound of the invention is shown in figure 6, the high-resolution mass spectrum of the compound of the invention is shown in figure 7, and the HPLC spectrum of the compound of the invention is shown in figure 8.
In addition, the HPLC detection conditions of FIG. 8 of the present invention are as follows:
a chromatographic column: agilent SB-C18 (4.6X 250mm,5 μm)
Eluent: acetonitrile (A) water (B)
Gradient conditions: 0 → 15 → 23 → 24 → 50 min; 8% → 20% → 28% → 65% → 70% (A)
A detector: 296nm ultraviolet detector
Column temperature: 30 deg.C
Flow rate: 1ml/min
Ultraviolet spectra of the compounds of the invention are shown in FIG. 9
By subjecting it to high resolution MS (M/z 357.0992[ M-H)]-Theoretical value of 357.0980), and the molecular formula of the compound is determined to be C19H18O7。
Analysis of NMR spectra by reference to the following solutionsTo say that: in that1The proton signal of 1 biphenylmethyl group [ delta 1.59(3H, s) ] is shown in the H-NMR spectrum]Proton signal of 1 methoxy group [3.64(3H, s) ]]Proton Signal of 1 methine group [2.48(1H, m)]1 benzene ring methine proton Signal [5.62(1H, s)]1 methylene proton signal with 2 oxygen functional groups [5.58(2H, s)]。1H-1HCOSY spectrum shows that delta 2.22 and delta 2.83 are homocarbon protons, and delta 3.69 and delta 3.85 are homocarbon protons, and the proton signals of 1 group of methylene in the structure are [2.22(1H, m), 2.83(1H, m)]Group 1 methylene proton signals of oxygen-linked functional groups [3.69(1H, m), 3.85(1H, m)]δ 6.10 is related to δ 6.25, and there are 1 groups of benzenoid proton signals in the structure [6.10(1H, d, J ═ 7.9), 6.25(1H, d, J ═ 7.9)]. According to13C-NMR spectroscopy can infer the presence of 1 carbonyl carbon, 1 methyl carbon, 1 methoxy carbon, 1 methylene carbon, 1 methine carbon, 1 methylene carbon attached to an oxygen functionality, 1 methylene carbon attached to a 2 oxygen functionality, 1 penta-substituted phenyl and 1 tetra-substituted phenyl in the structure. Based on comprehensive analysis of HSQC and HMBC, the structure contains a chromone-like fragment and a methoxy methylenedioxybenzyl fragment, and is shown in the following specific structure, wherein the structure is formed by remotely correlating delta 68.22 with delta 2.22 and 2.83, 6.10, remotely correlating delta 0121.98 with delta 12.22, 2.83, 6.10, remotely correlating delta 135.24 with delta 5.58 and 6.10, remotely correlating delta 147.30 with delta 5.58 and 6.25, remotely correlating delta 140.71 with delta 2.22, 2.83, 3.64 and 6.25, and remotely correlating delta 103.08 with delta 1.59, 5.62 and 12.02:
Figure BDA0002990904580000091
the specific nuclear magnetic data attribution is shown in table 1:
table 1.
Figure BDA0002990904580000092
Example (b): proliferation inhibitory Effect of the Compound of the present invention on cancer cells
Cytotoxic activity assay methods:
tumor development is the result of loss of regulation of cell function, and abnormalities in growth signaling and cell cycle regulation lead to abnormalities in cell proliferation, ultimately leading to malignant clones. One of the characteristics of cancer cells is abnormal proliferation. Inhibition of cancer cell proliferation is one of the important approaches for cancer treatment and is also a basic requirement for anti-tumor drugs. The new compound is respectively acted on leukemia HL-60, liver cancer SMMC-7721 and breast cancer MCF-7 for 24 hours, and then the absorbance value is measured at the wavelength of 450nm by a CCK-8 method to detect the proliferation inhibition effect of cancer cells.
HL-60, SMMC-7721 and MCF-7 cells at a ratio of 1 × 105Each/mL of the cells was inoculated into a 96-well plate, incubated in a 5% carbon dioxide incubator to the logarithmic phase, and a blank group, a control group and an administration group (the blank group contained only medium and no cells, and each group contained 8 parallel wells) were set, and 40. mu. mol/L of the compound solution was added to each of the administration groups, and the incubation was continued for 24 hours. After 24 hours, 10uL of CCK-8 solution is added into each hole, the culture is continued for 4 hours, the absorbance value OD450nm is detected at 450nm, and the proliferation inhibition effect of the compound on each tumor cell is calculated by using the following formula:
inhibition (%) [ (control OD450 nm-administered group OD450 nm)/((control OD450 nm-blank OD450nm) ] × 100
The specific experimental results are shown in table 2:
TABLE 2
Figure BDA0002990904580000101
The experiment evaluates the tumor cell proliferation inhibition activity of the ophiopogonone compound, and the result shows that the compound has proliferation inhibition effect on human leukemia HL-60 cells and breast cancer MCF-7 at the concentration of 40 mu mol/L, is an ideal candidate lead compound, and can provide a new research direction for further structure modification and structure-activity relationship research.
The above-mentioned embodiments are merely illustrative of the preferred embodiments of the present invention, and do not limit the scope of the present invention, and various modifications and improvements made to the technical solution of the present invention by those skilled in the art without departing from the spirit of the present invention shall fall within the protection scope defined by the claims of the present invention.

Claims (7)

1. A compound with a structure shown as a formula (I),
Figure FDA0002990904570000011
2. use of a compound according to claim 1 and physiologically acceptable salts thereof for the manufacture of a medicament for the treatment of cancer.
3. The use according to claim 2, wherein the medicament for the treatment of cancer is a medicament for the treatment of blood cancer or breast cancer.
4. The use according to claim 2, wherein the medicament for the treatment of cancer is a medicament for the treatment of leukemia.
5. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
6. The composition of claim 5, which is an oral preparation selected from the group consisting of tablets, capsules, dripping pills, granules, powders, oral films and oral liquids; or a non-oral preparation selected from injection, ointment, cream and suppository.
7. A process for the preparation of a compound according to claim 1, comprising the steps of:
an enrichment step, extracting dry root tuber powder of the thunberg dwarf lilyturf tuber with 80-95% ethanol, dissolving concentrated residues of an extracting solution in water, and extracting with dichloromethane to obtain dichloromethane fractions;
and a crude separation step, namely performing normal phase silica gel column chromatography on the dichloromethane fraction obtained in the step, and performing gradient elution by adopting a petroleum ether-dichloromethane gradient solvent system, wherein the solvent ratio is changed into petroleum ether: the volume ratio of dichloromethane is changed from 10:1 to 2:1 to obtain corresponding components;
and a fine separation step, namely performing normal phase silica gel column chromatography on the components separated in the fine separation step again, performing gradient by using dichloromethane-methanol, and changing the solvent ratio into dichloromethane: changing methanol from 65:1 to 5:1 in volume ratio, and eluting to obtain corresponding components;
and a purification step, namely performing chromatography on the components separated in the fine separation step on a reverse phase silica gel column chromatography to obtain the target compound.
CN202110313549.6A 2021-03-24 2021-03-24 Compound derived from Zhejiang ophiopogon root, application and pharmaceutical composition thereof Pending CN113024527A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102180850A (en) * 2011-03-26 2011-09-14 浙江大学 Dwarf lilyturf tuber medium-high isoflavone compounds, and preparation method and application thereof
CN102949388A (en) * 2011-08-29 2013-03-06 苏州同立医药技术有限公司 Isoflavones composition and medicine made of same
KR20200124630A (en) * 2019-04-24 2020-11-03 가천대학교 산학협력단 chromane derivatives, and pharmaceutical composition for preventing or treating neovascular eye disease or cancer containing the same as an active ingredient

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102180850A (en) * 2011-03-26 2011-09-14 浙江大学 Dwarf lilyturf tuber medium-high isoflavone compounds, and preparation method and application thereof
CN102949388A (en) * 2011-08-29 2013-03-06 苏州同立医药技术有限公司 Isoflavones composition and medicine made of same
KR20200124630A (en) * 2019-04-24 2020-11-03 가천대학교 산학협력단 chromane derivatives, and pharmaceutical composition for preventing or treating neovascular eye disease or cancer containing the same as an active ingredient

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHANG-LING DUAN等: "麦冬须根脂溶性成分研究(英文)", 《JOURNAL OF CHINESE PHARMACEUTICAL SCIENCES》 *
YONGYI WANG,ET AL.: "Three New Homoisoflavanones from the Ophiopogon japonicus Ker-Gawler (Liliaceae)", 《HELVETICA CHIMICA ACTA》 *
姜醒 等: "麦冬中具有生物活性的高异黄酮类化学成分研究", 《中国现代中药》 *
江洪波 等: "天然高异黄酮的研究进展", 《药学学报》 *

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Application publication date: 20210625