CN113717046B - Bisphenol compound in herba Artemisiae Scopariae, and its preparation method and application - Google Patents

Bisphenol compound in herba Artemisiae Scopariae, and its preparation method and application Download PDF

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CN113717046B
CN113717046B CN202111148971.7A CN202111148971A CN113717046B CN 113717046 B CN113717046 B CN 113717046B CN 202111148971 A CN202111148971 A CN 202111148971A CN 113717046 B CN113717046 B CN 113717046B
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ethyl acetate
herba artemisiae
water
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曾小斌
谢秋杰
葛岚岚
姚杰
缪雨阳
江园园
李阳芳
周伯平
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Shenzhen Peoples Hospital
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Abstract

The invention discloses a novel bisphenol compound in herba artemisiae scopariae and a preparation method and application thereof. Suspending the total extract with water, sequentially extracting with petroleum ether, ethyl acetate and n-butanol, and concentrating the extractive solution under reduced pressure to obtain petroleum ether, ethyl acetate, n-butanol and water. The ethyl acetate part is separated and purified from ethyl acetate part of herba Artemisiae Scopariae by chromatographic techniques such as silica gel, octadecylsilane chemically bonded silica gel (ODS), sephadex (Sephadex LH-20), preparative high performance liquid chromatography (Pre-HPLC), etc., to obtain 4 bisphenol compounds (capillarisenols A-D) which are all new compounds. The compound capillarissenolC has good inhibition effect on human liver cancer cell lines (HepG 2 and Huh-7) and better effect than first-line anti-liver cancer drug lenvatinib, so that the compound capillarissenolC can be prepared into a novel anti-cancer drug. The invention provides a material basis for novel anticancer drugs, and is beneficial to further development of the medicinal value and clinical application of Chinese herbal medicine virgate wormwood herb.

Description

Bisphenol compound in herba Artemisiae Scopariae, and its preparation method and application
Technical Field
The invention relates to the technical field of natural medicinal chemistry, in particular to a novel bisphenol compound separated from Chinese medicinal capillary artemisia, a preparation method thereof and application of the novel bisphenol compound in preparation of anticancer medicaments.
Background
The Chinese medicinal herb herba Artemisiae Scopariae is dry aerial part of Asteraceae plant herba Artemisiae Scopariae Artemisia scoparia Waldst et kit or herba Artemisiae Scopariae Artemisia capillaris Thunb, and is mainly produced in Shandong, shanxi, hebei, etc., and is mainly distributed in Japanese Korea and Mongolia. Herba Artemisiae Scopariae is bitter and pungent in taste, slightly cold in nature, nontoxic, and has effects of clearing heat and promoting diuresis, and promoting bile flow for treating icterus urine, damp-heat and summer-heat, and damp sore and pruritus (Chinese plant emotion, 1991,76 (2): 216). Herba Artemisiae Scopariae has wide therapeutic effects and is recorded in the tissue of Shennong Ben Cao Jing (Shennong's herbal medicine meridian), shang Han Lun (Shang Kui Yao Lloyd's Ohwi (jin Kui Yao Lloyd) and Ben Cao gang mu (Ben Cao gang mu) and the like and in the edition 2020 of Chinese pharmacopoeia. The chemical composition research shows that the capillary artemisia contains various chemical compositions such as coumarin, flavonoid, organic acids, volatile oil and the like. Pharmacological action researches show that the herba artemisiae scopariae has the traditional pharmacological actions of cholagogue, liver protection and the like, and also has various pharmacological activities of relieving fever, easing pain, resisting bacteria, resisting inflammation, resisting oxidation, resisting virus, resisting tumor, reducing blood pressure, regulating blood fat, resisting osteoporosis, protecting nerves, regulating immunity, regulating metabolism, preventing Alzheimer disease and the like (Liu Yuping and the like. Chinese herbal medicines 2019,50 (9): 2235-2241; golden and the like. Natural products research and development 2021,33 (4): 676-690).
Research shows that the traditional use and pharmacological action of herba Artemisiae Scopariae are different depending on the harvesting time. Collected in spring is called "Mian Ying" and collected in autumn is called "Hua Ying" respectively. The main chemical components of the capillary artemisia vary with the seasons: herba Artemisiae Scopariae contains abundant volatile oil components and chlorogenic acid, and herba Artemisiae Scopariae mainly contains flavonoids and coumarin compounds. For example, scoparone, capillarisin and cirsilineol levels peak at the beginning of 9 months of capillary artemisia. Thus, capillary wormwood is more suitable for treating jaundice, while capillary wormwood is generally used for treating other liver and gall diseases including cirrhosis, fatty liver, drug-toxic hepatitis, pancreatitis, chronic metabolic diseases, eczema and other inflammatory diseases. The chemical components in the capillary artemisia are rich and complex, and more than 200 active compounds are separated from the capillary artemisia. Wherein the composition mainly comprises flavone and its glycosides, chromones, alkynes, phenolic acids, coumarin, terpenes and lignans. Pharmacological studies show that the herba Artemisiae Scopariae extract and its active ingredients have good biological activity in vivo and in vitro. A great deal of researches show that the herba artemisiae capillaris extract and important components thereof, such as flavonoids, coumarin and dicaffeoylquinic acid compounds, have the activities of relieving fever, resisting inflammation, resisting lipolysis, resisting oxidization, resisting bacteria, resisting cancer, protecting liver and the like. The unique and remarkable biological activity of the capillary artemisia draws attention of a plurality of researchers worldwide, and lays a good foundation for further development and utilization of the capillary artemisia (Ding et al journal of Ethnopharmacology,2021, 273:113960).
In order to further find out the novel compounds with good activity, the invention adopts various chromatographic separation means such as silica gel, sephadex LH-20, ODS column chromatography, analysis and preparative HPLC, and adopts various spectroscopic techniques such as nuclear magnetic resonance, high resolution mass spectrum, ultraviolet and the like, 4 bisphenol compounds (capillarisenols A-D) are found in the ethyl acetate part of the traditional Chinese medicine capillary artemisia, are novel compounds, and comprise the preparation method and the application in the aspect of liver cancer resistance.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention aims to provide a novel bisphenol compound in herba artemisiae capillaries, a preparation method and application thereof, and a compound capillarisenol C has anticancer activity and can be used for preparing anticancer drugs.
In order to achieve the above object, the present invention is realized by the following technical scheme: novel bisphenol compounds in herba Artemisiae Scopariae include the following compounds, specifically:
the preparation method of the novel bisphenol compound in the capillary artemisia comprises the following steps: the compounds 1-4 are prepared and separated from ethyl acetate parts of capillary artemisia.
The preparation method of the novel bisphenol compound in the capillary artemisia comprises the following steps:
(1) Pulverizing dried aerial parts of herba Artemisiae Scopariae at room temperature, cold soaking with 80% ethanol for 4 times, mixing extractive solutions, and concentrating under reduced pressure to obtain total extract;
(2) Suspending the total extract with water, sequentially extracting with petroleum ether, ethyl acetate and n-butanol, concentrating the extractive solution under reduced pressure to obtain petroleum ether part, ethyl acetate part, n-butanol part and water part;
(3) The ethyl acetate part is subjected to ODS column chromatography and is eluted with a gradient of methanol-water (1:10-10:0) until 10 main fractions (Fr.1-Fr.10) are reached;
(4) Subjecting fraction Fr.5 to Sephadex LH-20 column, and subjecting to methanol-water (95:5) isocratic elution to obtain secondary fractions SFr.5a-SFr.5i, wherein fraction SFr.5e and fraction SFr.5g are purified by preparative HPLC respectively to obtain compounds capillarisenol A and capillarisenol B;
(5) Fractions fr.9 were eluted with a gradient of dichloromethane-methanol (10:1-0:10) by silica gel column chromatography, and the same fractions were combined by TLC analysis to give 6 secondary fractions (sfr.9 a-sfr.9 f), and fractions sfr.9a were purified by preparative HPLC to give the compounds capillarisenol C and capillarisenol D.
The application of the capelisenol C in preparing anti-liver cancer drugs.
The invention has the beneficial effects that: the compound capillarisenol C prepared by the invention has good inhibition effect on human liver cancer cell lines (HepG 2 and Huh-7), so that the compound capirisenol C can be prepared into novel anticancer drugs. The invention provides a material basis for novel anticancer drugs, and is beneficial to further development of the medicinal value and clinical application of Chinese herbal medicine virgate wormwood herb.
Drawings
The invention is described in detail below with reference to the drawings and the detailed description;
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of compound 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the compound 1 of the present invention;
FIG. 3 is a DEPT spectrum of compound 1 of the present invention;
FIG. 4 is a chart of a 1H-1H COSY spectrum of Compound 1 of the present invention;
FIG. 5 is a HSQC spectrum of Compound 1 of the present invention;
FIG. 6 is a HMBC spectrum of compound 1 of the present invention;
FIG. 7 is a nuclear magnetic resonance hydrogen spectrum of compound 2 of the present invention;
FIG. 8 is a nuclear magnetic resonance carbon spectrum of compound 2 of the present invention;
FIG. 9 is a DEPT spectrum of Compound 2 of the present invention;
FIG. 10 is a chart of a 1H-1H COSY spectrum of Compound 2 of the present invention;
FIG. 11 is a HSQC spectrum of Compound 2 of the present invention;
FIG. 12 is a HMBC pattern of compound 2 of the present invention;
FIG. 13 is a nuclear magnetic resonance hydrogen spectrum of compound 3 of the present invention;
FIG. 14 is a nuclear magnetic resonance carbon spectrum of compound 3 of the present invention;
FIG. 15 is a DEPT spectrum of compound 3 of the present invention;
FIG. 16 is a chart of a 1H-1H COSY spectrum of Compound 3 of the present invention;
FIG. 17 is a HSQC spectrum of Compound 3 of the present invention;
FIG. 18 is a HMBC spectrum of Compound 3 of the present invention;
FIG. 19 is a nuclear magnetic resonance hydrogen spectrum of compound 4 of the present invention;
FIG. 20 is a nuclear magnetic resonance carbon spectrum of compound 4 of the present invention;
FIG. 21 is a DEPT spectrum of Compound 4 of the present invention;
FIG. 22 is a chart of a 1H-1H COSY spectrum of Compound 4 of the present invention;
FIG. 23 is a HSQC spectrum of Compound 4 of the present invention;
FIG. 24 is a HMBC spectrum of Compound 4 of the present invention;
FIG. 25 is an HPLC analysis and UV absorption spectrum of the compound capillarisenol A of the present invention;
FIG. 26 is an HPLC analysis and UV absorption spectrum of the compound capillarisenol B of the present invention;
FIG. 27 is an HPLC analysis and UV absorption spectrum of the compound capillarisenol C of the present invention;
FIG. 28 is an HPLC analysis and UV absorption spectrum of the compound capillarisenol D of the present invention;
fig. 29 is a schematic diagram of Key 2D NMR correlations of 1and 2 of the present invention;
fig. 30 is a schematic diagram of Key 2D NMR correlations of 3and 4 of the present invention;
FIG. 31 is a schematic representation of the compounds of the present invention inhibiting the growth of human hepatoma cell lines HepG2 and Huh-7.
Detailed Description
The invention is further described in connection with the following detailed description, in order to make the technical means, the creation characteristics, the achievement of the purpose and the effect of the invention easy to understand.
Referring to fig. 1-31, the present embodiment adopts the following technical scheme: the chemical general formula of the bisphenol compound and the derivative thereof is as follows:
TABLE 1 bisphenol substituents and names
Sequence number R 1 R 2 Name of the name
1 OH COOH capillarisenolA
2 OCH 3 COOH capillarisenolB
3 CH 3 CH(CH 3 ) 2 capillarisenolC
4 CH(CH 3 ) 2 CH 3 capillarisenolD
Example 1: extraction and separation of novel compounds:
pulverizing dried aerial parts (about 7.0 kg) of herba Artemisiae Scopariae, cold soaking with 80% ethanol for 4 times, mixing extractive solutions, and concentrating under reduced pressure to obtain total extract about 1.4kg. Suspending the total extract with water, sequentially extracting with petroleum ether, ethyl acetate and n-butanol, and concentrating the extractive solution under reduced pressure to obtain petroleum ether 94g, ethyl acetate 114g, n-butanol 401g and water 667g. The ethyl acetate part is subjected to ODS column chromatography and is eluted with a gradient of methanol-water (1:10-10:0) until 10 main fractions (Fr.1-Fr.10) are reached. Wherein, the fraction Fr.5 (2.0 g) is subjected to Sephadex LH-20 column and methanol-water (95:5) isocratic elution to obtain secondary fractions SFr.5 a-SFr.5 i. Fraction SFr.5e was subjected to preparative HPLC (mobile phase methanol-water 40:60, t R 62.10 min) to give the compound capillarisenol B (1.9 mg); fraction SFr.5g was subjected to preparative HPLC (mobile phase methanol-water 39:61, t R 43.64 min) to give the compound capillarisenol A (27.8 mg). Fractions fr.9 (15 g) were eluted with a silica gel column chromatography dichloromethane-methanol (10:1-0:10) gradient and the same fractions were combined by TLC analysis to give 6 secondary fractions (sfr.9a-sfr.9f). Fraction SFr.9a was further purified by preparative HPLC (mobile phase methanol-water 66:34) to give compound capillarisenol C (2.4 mg, t) R 52.69 min) and capillarisenol D (4.0 mg, t) R 62.60min)。
Example 2: structural identification of novel compounds:
compound 1 is a white amorphous powder having the chemical structural formula:
the spectral data are as follows: ESI-MS M/z283.0653[ M+Na ]] + 。 1 H NMR(DMSO-d 6 ,400MHz)δ H :7.31 (1H, s, H-6), 6.91 (2H, d, J=8.2 Hz, H-2 'and H-6'), 6.63 (2H, d, J=8.2 Hz, H-3 'and H-5'), 6.52 (1H, s, H-3), 4.10 (2H, s, H) 2 -7'). The nuclear magnetic resonance hydrogen spectrum is shown in FIG. 1. 13 C NMR(DMSO-d 6 ,100MHz)δ C ：168.3(C-7)，155.3(C-4')，148.9(C-4)，142.8(C-5), 135.8 (C-2), 132.0 (C-1 '), 129.6 (C-2' and C-6 '), 120.0 (C-1), 118.2 (C-3), 118.1 (C-6), 115.0 (C-3' and C-5 '), 37.1 (C-7'). The nuclear magnetic resonance carbon spectrum is shown in fig. 2.
Synthesis of Compound 1 1 H NMR、 13 C NMR、DEPT-135、 1 H– 1 H COSY, HSQC and HMBC spectra information, as shown in FIGS. 3-6,29, compound 1 was identified as a novel bisphenol and designated as capillarisenol A.
Compound 2 is yellow amorphous powder with a chemical structural formula:
the spectral data are as follows: ESI-MS M/z274.2749[ M ]] + 。 1 H NMR(DMSO-d 6 ,400MHz)δ H :7.30 (1H, s, H-6), 6.93 (2H, d, J=8.2 Hz, H-2 'and H-6'), 6.77 (1H, s, H-3), 6.61 (2H, d, J=8.2 Hz, H-3 'and H-5'), 4.16 (2H, s, H) 2 -7')，3.75(3H,s,H 3 -8). The nuclear magnetic resonance hydrogen spectrum is shown in FIG. 7. 13 C NMR(DMSO-d 6 ,100MHz)δ C :168.1 (C-7), 155.2 (C-4 '), 150.4 (C-4), 144.0 (C-5), 135.3 (C-2), 132.0 (C-1 '), 129.4 (C-2 ' and C-6 '), 121.6 (C-1), 117.6 (C-6), 114.6 (C-3), 114.9 (C-3 ' and C-5 '), 55.5 (C-8), 37.3 (C-7 '). The nuclear magnetic resonance carbon spectrum is shown in FIG. 8.
Synthesis of Compound 2 1 H NMR、 13 C NMR、DEPT-135、 1 H– 1 H COSY, HSQC and HMBC spectra information (shown in FIGS. 9-12, 29), compound 2 was identified as a novel bisphenol compound and designated as capillarisenol B.
Table 2 NMR data of 1and 2in DMSO-d 6 (δin ppm,J in Hz)
Compound 3 is a yellow oil of the formula:
the spectral data are as follows: ESI-MS M/z255.1310[ M-H ]] – 。 1 H NMR(DMSO-d 6 ,400MHz)δ H :6.86 (2H, d, J=8.4 Hz, H-2 'and H-6'), 6.77 (1H, s, H-3), 6.67 (1H, s, H-6), 6.64 (2H, d, J=8.4 Hz, H-3 'and H-5'), 3.73 (2H, s, H 2 -7')，2.98(1H,m,H-7)，2.04(3H,s,H 3 -10)，1.00(6H,d,J＝6.8Hz,H 3 -8 and H 3 -9). The nuclear magnetic resonance hydrogen spectrum is shown in FIG. 13. 13 C NMR(DMSO-d 6 ,100MHz)δ C :155.2 (C-4 '), 153.9 (C-1), 144.7 (C-5), 132.4 (C-3), 132.0 (C-1 '), 129.1 (C-2 ' and C-6 '), 127.9 (C-4), 121.6 (C-1), 120.7 (C-2), 115.0 (C-3 ' and C-5 '), 111.6 (C-6), 36.5 (C-7 '), 28.2 (C-7), 23.8 (C-8 and C-9), 15.6 (C-10). The nuclear magnetic resonance carbon spectrum is shown in FIG. 14.
Synthesis of Compound 3 1 H NMR、 13 C NMR、DEPT-135、 1 H– 1 H COSY, HSQC and HMBC spectra information (FIGS. 15-18, 30), compound 3 was identified as a novel bisphenol compound and designated as capillarisenol C.
Compound 4 was a pale yellow oil of the formula:
the spectral data are as follows: ESI-MS M/z255.1309[ M-H ]] – 。 1 H NMR(DMSO-d 6 ,400MHz)δ H :6.87 (2H, d, j=8.4 hz, H-2 'and H-6'), 6.84 (1H, s, H-3), 6.63 (2H, d, j=8.4 hz, H-3 'and H-5'), 6.53 (1H, s, H-6), 3.68 (2H, s, H 2 -7')，3.11(1H,m,H-7)，2.02(3H,s,H 3 -10)，1.11(6H,d,J＝6.9Hz,H 3 -8 and H 3 -9). Nuclear magnetic resonanceThe hydrogen spectrum is shown in FIG. 19. 13 C NMR(DMSO-d 6 ,100MHz)δ C :155.2 (C-4 '), 152.4 (C-1), 133.5 (C-5), 127.3 (C-3), 131.3 (C-1 '), 129.1 (C-2 ' and C-6 '), 129.7 (C-4), 121.6 (C-1), 131.2 (C-2), 115.0 (C-3 ' and C-5 '), 116.7 (C-6), 37.4 (C-7 '), 26.1 (C-7), 22.6 (C-8 and C-9), 18.9 (C-10). The nuclear magnetic resonance carbon spectrum is shown in FIG. 20.
Synthesis of Compound 4 1 H NMR、 13 C NMR、DEPT-135、 1 H– 1 H COSY, HSQC and HMBC spectra information (FIGS. 21-24, 30), compound 4 was identified as a novel bisphenol compound and designated as capillarisenol D.
Table 3 NMR data of 3and 4in DMSO-d 6 (δin ppm,J in Hz)
Example 3: the inhibition of growth of the human hepatoma cell line by the compound (capillarisenols A-D) was evaluated by MTT method:
the method comprises the following steps: hepG2 liver cancer cell lines (purchased from cell banks of China academy of sciences) were subcultured until cells were grown to the logarithmic phase, and the cells were seeded at 2500 cells/well in 96-well culture plates. After cell culture for 24 hours, the original culture medium is sucked. The experiments were co-arranged with a blank control group and a drug treatment group. The blank group was replaced with DMEM medium containing 10% fetal bovine serum; the drug treatment group was cultured in a medium containing bisphenol compound (capillarisenols A-D) at a concentration of 20. Mu.M and 50. Mu.M for 48 hours, and then added with DMEM medium containing 10% CCK-8 solution, and then placed on CO 2 Culturing in incubator for 4 hr, measuring absorbance (wavelength 450 nm) with enzyme-labeled instrument, and calculating cell survival according to absorbance, wherein 5 compound wells are arranged for each treatment, and cell survival rate (%) =Δod Drug treatment /ΔOD Blank control ×100％。
Results: chemical treatmentThe compound capillarisenol C has remarkable inhibition effect on the growth of human liver cancer cell strains HepG2 and Huh-7 (figure 31). The compound inhibits IC of human liver cancer cell lines HepG2 and Huh-7 growth 50 The values are respectively: 9.9.+ -. 2.38. Mu.M and 4.455.+ -. 1.41. Mu.M. However, the IC50 value of the first-line clinical liver cancer treatment drug of the prior art, namely, len, for inhibiting the growth of the human liver cancer cell line HepG2 is 148.6+/-21.0 mu M.
The above examples show that the compound capillarisenol C of the invention has good inhibition effect on the growth of human liver cancer cell strains HepG2 and Huh-7. The compound capillarisenol C has anti-liver cancer activity, and can be used for preparing anti-liver cancer medicines.
The foregoing has shown and described the basic principles and main features of the present invention and the advantages of the present invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, and that the above embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made without departing from the spirit and scope of the invention, which is defined in the appended claims. The scope of the invention is defined by the appended claims and equivalents thereof.

Claims (1)

1. A preparation method of bisphenol compounds in herba artemisiae scopariae is characterized by comprising the following steps:
(1) Pulverizing dried aerial parts of herba Artemisiae Scopariae at room temperature, cold soaking with 80% ethanol for 4 times, mixing extractive solutions, and concentrating under reduced pressure to obtain total extract;
(2) Suspending the total extract with water, sequentially extracting with petroleum ether, ethyl acetate and n-butanol, concentrating the extractive solution under reduced pressure to obtain petroleum ether part, ethyl acetate part, n-butanol part and water part;
(3) Subjecting the ethyl acetate part to ODS column chromatography, and performing gradient elution with methanol-water=1:10-10:0 to obtain 10 main stream fractions Fr.1-Fr.10;
(4) Subjecting the fraction Fr.5 to Sephadex LH-20 column, and subjecting methanol-water=95:5 to isocratic elution to obtain secondary fractions SFr.5a-SFr.5i, wherein the fractions SFr.5e and SFr.5g are purified by preparative HPLC respectively to obtain compounds 1and 2;
(5) Subjecting fraction Fr.9 to silica gel column chromatography, performing gradient elution with dichloromethane-methanol=10:1-0:10, combining the same fractions by TLC analysis to obtain 6 secondary fractions SFr.9a-SFr.9f, and purifying fraction SFr.9a by preparative HPLC to obtain compounds 3and 4;
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Title
A sensitive electrochemical sensor for bisphenol F detection and its application in evaluating cytotoxicity;Yi Xing等;《Microchemical Journal》;第168卷;106414 *
Genotoxic activity of bisphenol A and its analogues bisphenol S, bisphenol F and bisphenol AF and their mixtures in human hepatocellular carcinoma (HepG2) cells;Klara Hercog等;《Science of the Total Environment》;第687卷;267-276 *
Metabolomic modulations of HepG2 cells exposed to bisphenol analogues;Siqing Yue等;《Environment International》;第129卷;59-67 *
MUTAGENICITY AND DNA DAMAGE OF BISPHENOL A AND ITS STRUCTURAL ANALOGUES IN HEPG2 CELLS;Anja FIC等;《Arh Hig Rada Toksikol》;第64卷;189-200 *
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