CN113717046A - Novel bisphenol compound in oriental wormwood as well as preparation method and application thereof - Google Patents
Novel bisphenol compound in oriental wormwood as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a novel bisphenol compound in oriental wormwood, a preparation method and application thereof, wherein the method comprises the steps of taking the overground part of the oriental wormwood as a raw material, drying, crushing, carrying out cold-leaching extraction by 80% ethanol, combining extracting solutions, and carrying out reduced pressure concentration to obtain a total extract. 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 fraction, ethyl acetate fraction, n-butanol fraction and water fraction. Separating and purifying the ethyl acetate part by chromatographic techniques such as silica gel, octadecylsilane chemically bonded silica (ODS), Sephadex LH-20, preparative high performance liquid chromatography (Pre-HPLC) and the like to obtain 4 bisphenol compounds (capillarisenols A-D) which are new compounds from the ethyl acetate part of the herba artemisiae scopariae. The compound capillarisenol C has good inhibition effect on human liver cancer cell lines (HepG2 and Huh-7), and the effect is superior to that of a first-line anti-liver cancer drug Lovatinib, so that the compound 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 medicinal value and clinical application of traditional Chinese medicine capillary artemisia.
Description
Technical Field
The invention relates to the technical field of natural medicinal chemistry, in particular to a novel bisphenol compound separated from traditional Chinese medicine capillary artemisia, a preparation method thereof and application thereof in preparing anticancer drugs.
Background
The traditional Chinese medicine herba artemisiae scopariae is a dry overground part of Artemisia scoparia Waldst. et. kit or Artemisia capillaris Artemisia capitaria Thunb. the traditional Chinese medicine herba artemisiae scopariae is distributed in all parts of China, mainly produced in Shandong, Shaanxi, Shanxi, Hebei and other provinces, and is mainly distributed in Japan Korea, Mongolia and other countries abroad. Herba Artemisiae Scopariae is bitter and pungent in flavor, slightly cold in nature, and nontoxic, and has effects of clearing heat, promoting diuresis, promoting bile flow, and eliminating jaundice, and can be used for treating jaundice, oliguria, damp warmth, summer dampness, and eczema pruritus (Chinese plant zhi, 1991,76(2): 216). Herba Artemisiae Scopariae is exactly recorded in the book of record materia Medica in Shennong Ben Cao Jing (Shennong's herbal Manual) (jin Kui Yao L ü e (Qian jin Fang) (Ben Cao gang mu) and the book of Chinese pharmacopoeia (2020 edition) because of its wide curative effect. The research on chemical components shows that the oriental wormwood contains various chemical components such as coumarins, flavonoids, organic acids, volatile oil and the like. Pharmacological action researches show that the oriental wormwood has the traditional pharmacological actions of cholagogic action, liver protection and the like, and also has various pharmacological activities of antipyresis, analgesia, antibiosis, anti-inflammation, antioxidation, antivirus, antitumor, blood pressure reduction, blood fat regulation, osteoporosis prevention, neuroprotection, immunoregulation, metabolic regulation, Alzheimer disease prevention and the like (Leirodela and the like, Chinese herbal medicines, 2019,50(9): 2235-.
Research shows that the traditional application and pharmacological action of oriental wormwood are different according to the harvesting time. Collected in spring is called Mian Yin Chen and collected in autumn is called Hua Yin Chen. The main chemical components of oriental wormwood change with the change of seasons: herba Artemisiae Scopariae contains abundant volatile oil components and chlorogenic acid, and herba Artemisiae Scopariae mainly contains flavonoids and coumarin compounds. For example, the levels of scoparone, capillarisin and cirsilinols peak at the beginning of oriental wormwood 9 months. Accordingly, oriental wormwood is more suitable for treating jaundice, and oriental wormwood is generally used for treating other liver and gall diseases including liver cirrhosis, fatty liver, drug-toxic hepatitis, pancreatitis, chronic metabolic disease, eczema and other inflammatory diseases. The chemical components in oriental wormwood are rich and complex, and more than 200 active compounds are separated from oriental wormwood at present. The extract mainly comprises flavones, glycosides, chromones, alkynes, phenolic acids, coumarins, terpenes and lignans. Pharmacological research shows that the capillary artemisia extract and the active ingredients thereof show good biological activity in vivo and in vitro. A large number of researches show that the herba Artemisiae Scopariae extract and its important components, such as flavonoids, coumarins and dicaffeoylquinic acid compounds, have antipyretic, anti-inflammatory, anti-lipolysis, antioxidant, antibacterial, anticancer and hepatoprotective activities. The unique and remarkable biological activity of oriental wormwood attracts the attention of numerous researchers worldwide, and lays a good foundation for further development and utilization (Ding et al. journal of Ethnopharmacology,2021,273: 113960).
In order to further discover compounds with novel structures and good activity, the invention adopts various chromatographic separation means, such as silica gel, Sephadex LH-20, ODS column chromatography and analytical and preparative HPLC, and applies various spectrum technologies, such as nuclear magnetic resonance, high resolution mass spectrum, ultraviolet and the like, to discover 4 bisphenol compounds (capillarisenols A-D) from the ethyl acetate part of the traditional Chinese medicine capillary artemisia, wherein the compounds are all new compounds, and the invention comprises the preparation method and the application in the aspect of liver cancer resistance.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a novel bisphenol compound in oriental wormwood, and a preparation method and application thereof.
In order to achieve the purpose, the invention is realized by the following technical scheme: the novel bisphenol compounds in the oriental wormwood comprise the following compounds:
the preparation method of the novel bisphenol compound in the oriental wormwood comprises the following steps: the compounds 1-4 are isolated from the ethyl acetate fraction of Artemisia capillaris.
The preparation method of the novel bisphenol compound in the oriental wormwood comprises the following steps:
(1) pulverizing dried aerial parts of herba Artemisiae Scopariae at room temperature, cold extracting 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, and concentrating the extractive solution under reduced pressure to obtain petroleum ether fraction, ethyl acetate fraction, n-butanol fraction and water fraction;
(3) performing ODS column chromatography on the ethyl acetate part, and performing gradient elution by using methanol-water (1: 10-10: 0) to obtain 10 main fractions (Fr.1-Fr.10);
(4) subjecting the fraction Fr.5 to Sephadex LH-20 column and methanol-water (95:5) isocratic elution to obtain secondary fractions SFr.5a-SFr.5i, wherein the fraction SFr.5e and the fraction SFr.5g are respectively subjected to preparative HPLC purification to obtain compounds capillarisenol A and capillarisenol B;
(5) performing gradient elution on the fraction Fr.9 through silica gel column chromatography dichloromethane-methanol (10: 1-0: 10), combining the same fractions through TLC analysis to obtain 6 secondary fractions (SFr.9a-SFr.9f), and purifying the fraction SFr.9a through preparative HPLC to obtain the compounds capillarisenol C and capillarisenol D.
The application of the capillarisenol C in preparing anti-liver cancer drugs.
The invention has the beneficial effects that: the prepared compound capillarisenol C has good inhibition effect on human liver cancer cell lines (HepG2 and Huh-7), so that the compound capillarisenol C can be prepared into a novel anti-cancer medicament. The invention provides a material basis for novel anticancer drugs, and is beneficial to further development of medicinal value and clinical application of traditional Chinese medicine capillary artemisia.
Drawings
The invention is described in detail below with reference to the drawings and the detailed description;
FIG. 1 is a NMR spectrum of Compound 1 of the present invention;
FIG. 2 is a NMR carbon spectrum of Compound 1 of the present invention;
FIG. 3 is a DEPT spectrum of Compound 1 of the present invention;
FIG. 4 is a 1H-1H COSY spectrum of Compound 1 of the present invention;
FIG. 5 is an HSQC spectrum of Compound 1 of the present invention;
FIG. 6 is an HMBC spectrum of compound 1 of the present invention;
FIG. 7 is a NMR spectrum of Compound 2 of the present invention;
FIG. 8 is a NMR 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 1H-1H COSY spectrum of Compound 2 of the present invention;
FIG. 11 is an HSQC spectrum of Compound 2 of the present invention;
FIG. 12 is an HMBC spectrum of compound 2 of the present invention;
FIG. 13 is a NMR spectrum of Compound 3 of the present invention;
FIG. 14 is a NMR 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 1H-1H COSY spectrum of Compound 3 of the present invention;
FIG. 17 is an HSQC spectrum of Compound 3 of the present invention;
FIG. 18 is an HMBC spectrum of compound 3 of the present invention;
FIG. 19 is a NMR spectrum of Compound 4 of the present invention;
FIG. 20 is a NMR 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 1H-1H COSY spectrum of compound 4 of the present invention;
FIG. 23 is an HSQC spectrum of Compound 4 of the present invention;
FIG. 24 is an HMBC spectrum of compound 4 of the present invention;
FIG. 25 is an HPLC analysis of the compound capillarisenol A of the present invention and its UV absorption spectrum;
FIG. 26 is an HPLC analysis of the compound capillarisenol B of the present invention and its UV absorption spectrum;
FIG. 27 is an HPLC analysis of the compound capillarisenol C of the present invention and its UV absorption spectrum;
FIG. 28 is an HPLC analysis of the compound capillarisenol D of the present invention and its UV absorption spectrum;
FIG. 29 is a schematic representation of Key 2D NMR spectra of 1and 2 of the present invention;
FIG. 30 is a schematic representation of Key 2D NMR spectra of 3and 4 of the present invention;
FIG. 31 is a schematic diagram of the compounds of the present invention inhibiting the growth of human hepatoma cell lines HepG2 and Huh-7.
Detailed Description
In order to make the technical means, the creation characteristics, the achievement purposes and the effects of the invention easy to understand, the invention is further described with the specific embodiments.
Referring to fig. 1 to 31, the following technical solutions are adopted in the present embodiment: the chemical general formula of the bisphenol compound and the derivative thereof is as follows:
TABLE 1 bisphenol Compound substituents and names
| Serial number | R1 | R2 | Name (R) | |
| 1 | | COOH | capillarisenolA | |
| 2 | OCH3 | COOH | capillarisenolB | |
| 3 | CH3 | CH(CH3)2 | |
|
| 4 | CH(CH3)2 | CH3 | capillarisenolD |
Example 1: extraction and separation of new compounds:
pulverizing dried aerial parts (about 7.0kg), extracting with 80% ethanol for 4 times, mixing extractive solutions, and concentrating under reduced pressure to obtain total extract about 1.4 kg. 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 94g of petroleum ether fraction, 114g of ethyl acetate fraction, 401g of n-butanol fraction and 667g of water fraction. Performing ODS column chromatography on the ethyl acetate part, and performing gradient elution by using methanol-water (1: 10-10: 0) to obtain 10 main fractions (Fr.1-Fr.10). Wherein, the fraction Fr.5(2.0g) passes through a Sephadex LH-20 column and methanol-water (95:5) isocratic elution to obtain a secondary fraction SFr.5a-SFr.5i. The fraction SFr.5e is subjected to preparative HPLC (the mobile phase is methanol-water 40:60, t)R62.10min) to yield the compound, capillarisenol B (1.9 mg); separating SFr.5g, and performing preparative HPLC (mobile phase is methanol-water 39:61, t)R43.64min) to yield the compound, capillarisenol A (27.8 mg). Fraction Fr.9(15g) was subjected to silica gel column chromatography with dichloromethane-methanol (10: 1-0: 10) gradient elution, and the same fractions were combined by TLC analysis to obtain 6 secondary fractions (SFr.9a-SFr.9f). The fraction SFr.9a was further purified by preparative HPLC (methanol-water as mobile phase 66:34) to give the compound capillarisenol C (2.4mg, tR52.69min) and capillarisenol D (4.0mg, t)R 62.60min)。
Example 2: structural identification of the novel compounds:
the spectral data are as follows: ESI-MS M/z283.0653[ M + Na ]]+。1H NMR(DMSO-d6,400MHz)δH: 7.31(1H, s, H-6), 6.91(2H, d, J ═ 8.2Hz, H-2', and H-6'), 6.63(2H, d, J ═ 8.2Hz, H-3)'and H-5'), 6.52(1H, s, H-3), 4.10(2H, s, H)2-7'). The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 1.13C NMR(DMSO-d6,100MHz)δC: 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 NMR spectrum is shown in FIG. 2.
Synthesis of Compound 11H NMR、13C NMR、DEPT-135、1H–1H COSY, HSQC and HMBC spectrogram information is shown in figures 3-6 and 29, and the compound 1 is identified as a novel bisphenol compound and named as capillarisenol A.
the spectral data are as follows: ESI-MS M/z274.2749[ M ]]+。1H NMR(DMSO-d6,400MHz)δH: 7.30(1H, s, H-6), 6.93(2H, d, J ═ 8.2Hz, H-2', and H-6'), 6.77(1H, s, H-3), 6.61(2H, d, J ═ 8.2Hz, H-3', and H-5'), 4.16(2H, s, H-6, H-5')2-7')，3.75(3H,s,H3-8). The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 7.13C NMR(DMSO-d6,100MHz)δC: 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 NMR spectrum is shown in FIG. 8.
Synthesis of Compound 21H NMR、13C NMR、DEPT-135、1H–1H COSY, HSQC and HMBC spectrogram information (shown in figures 9-12 and 29), and the compound 2 is identified as a novel bisphenol compound and is named as capillarisenol B.
TABLE 2 NMR data of 1and 2in DMSO-d6(δin ppm,J in Hz)
the spectral data are as follows: ESI-MS M/z255.1310[ M-H ]]–。1H NMR(DMSO-d6,400MHz)δH: 6.86(2H, d, J ═ 8.4Hz, H-2', and H-6'), 6.77(1H, s, H-3), 6.67(1H, s, H-6), 6.64(2H, d, J ═ 8.4Hz, H-3', and H-5'), 3.73(2H, s, H-3 '), and H-5')2-7')，2.98(1H,m,H-7)，2.04(3H,s,H3-10)，1.00(6H,d,J＝6.8Hz,H3-8 and H3-9). The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 13.13C NMR(DMSO-d6,100MHz)δC: 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 NMR spectrum is shown in FIG. 14.
Synthesis of Compound 31H NMR、13C NMR、DEPT-135、1H–1H COSY, HSQC and HMBC spectrogram information (FIGS. 15-18,30), and compound 3 is identified as a novel bisphenol compound and named as capillarisenol C.
the spectral data are as follows: ESI-MS M/z255.1309[ M-H ]]–。1H NMR(DMSO-d6,400MHz)δH: 6.87(2H, d, J ═ 8.4Hz, H-2 'and H-6'), 6.84(1H, s, H-3), 6.63(2H, d, J ═ 8.4Hz, 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,H3-10)，1.11(6H,d,J＝6.9Hz,H3-8 and H3-9). The hydrogen nuclear magnetic resonance spectrum is shown in FIG. 19.13C NMR(DMSO-d6,100MHz)δC: 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 NMR spectrum is shown in FIG. 20.
Of compounds 41H NMR、13C NMR、DEPT-135、1H–1H COSY, HSQC and HMBC spectrogram information (FIGS. 21-24,30), and compound 4 is identified as a novel bisphenol compound and named as capillarisenol D.
TABLE 3 NMR data of 3and 4in DMSO-d6(δin ppm,J in Hz)
Example 3: the growth inhibitory effect of the compound (capillarisenols A-D) on human hepatoma cell lines was evaluated by the MTT method:
the method comprises the following steps: HepG2 liver cancer cell line (purchased from cell bank of Chinese academy of sciences) was subcultured until the cells grew to logarithmic phase, and the cell density was adjusted to 2500 cells/well and inoculated into 96-well culture plates. The original culture medium is aspirated after 24h of cell culture adherence. The experiment is provided with a blank control group and a drug treatment group. The blank group is replaced with DMEM medium containing 10% fetal bovine serum; the drug treatment group was cultured in a medium containing bisphenols (capillarisenols A-D) at concentrations of 20. mu.M and 50. mu.M for 48h, then DMEM medium containing 10% CCK-8 solution was added, and the mixture was placed in CO2Culturing in incubator for 4h, measuring light absorption value (wavelength of 450nm) with microplate reader, and measuring light absorption valueCell survival was calculated by setting 5 replicates per treatment and cell survival (%). DELTA.ODDrug treatment/ΔODBlank control×100％。
As a result: the compound capillarisenol C has a remarkable inhibitory effect on the growth of human liver cancer cell strains HepG2 and Huh-7 (figure 31). IC of the compound for inhibiting growth of human hepatoma cell strains HepG2 and Huh-750The values are respectively: 9.9. + -. 2.38. mu.M and 4.455. + -. 1.41. mu.M. However, the current first-line clinical liver cancer treatment drug Lovatinib (Len) inhibits the growth of human liver cancer cell line HepG2 with the IC50 value of 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. Therefore, the compound capillarisenol C has the anti-liver cancer activity and can be used for preparing anti-liver cancer drugs.
The foregoing shows and describes the general principles and broad features of the present invention and advantages thereof. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are described in the specification and illustrated only to illustrate the principle of the present invention, but that various changes and modifications may be made therein without departing from the spirit and scope of the present invention, which fall within the scope of the invention as claimed. The scope of the invention is defined by the appended claims and equivalents thereof.
Claims (4)
1. The novel bisphenol compound in the oriental wormwood is characterized by comprising the following compounds:
2. a process for preparing the novel bisphenol compounds from oriental wormwood, characterized in that the compounds 1-4 are separated from the ethyl acetate fraction of oriental wormwood.
3. The method for preparing novel bisphenols from artemisia capillaris as claimed in claim 2, comprising the steps of:
(1) pulverizing dried aerial parts of herba Artemisiae Scopariae at room temperature, cold extracting 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, and concentrating the extractive solution under reduced pressure to obtain petroleum ether fraction, ethyl acetate fraction, n-butanol fraction and water fraction;
(3) performing ODS column chromatography on the ethyl acetate part, and performing gradient elution by using methanol-water (1: 10-10: 0) to obtain 10 main fractions (Fr.1-Fr.10);
(4) subjecting the fraction Fr.5 to Sephadex LH-20 column and methanol-water (95:5) isocratic elution to obtain secondary fractions SFr.5a-SFr.5i, wherein the fraction SFr.5e and the fraction SFr.5g are respectively subjected to preparative HPLC purification to obtain compounds capillarisenol A and capillarisenol B;
(5) performing gradient elution on the fraction Fr.9 through silica gel column chromatography dichloromethane-methanol (10: 1-0: 10), combining the same fractions through TLC analysis to obtain 6 secondary fractions (SFr.9a-SFr.9f), and purifying the fraction SFr.9a through preparative HPLC to obtain the compounds capillarisenol C and capillarisenol D.
4. Use of capillarisenol c prepared according to claims 1-3 in the preparation of a medicament against liver cancer, but not limited to liver cancer, including all other cancers.
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| CN202111148971.7A Active CN113717046B (en) | 2021-09-29 | 2021-09-29 | Bisphenol compound in herba Artemisiae Scopariae, and its preparation method and application |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115819241A (en) * | 2022-12-05 | 2023-03-21 | 深圳市人民医院 | Novel phenethyl alcohol ester compound separated from oriental wormwood and preparation method and application thereof |
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2021
- 2021-09-29 CN CN202111148971.7A patent/CN113717046B/en active Active
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| ANJA FIC等: "MUTAGENICITY AND DNA DAMAGE OF BISPHENOL A AND ITS STRUCTURAL ANALOGUES IN HEPG2 CELLS", 《ARH HIG RADA TOKSIKOL》, vol. 64, pages 189 - 200 * |
| KLARA HERCOG等: "Genotoxic activity of bisphenol A and its analogues bisphenol S, bisphenol F and bisphenol AF and their mixtures in human hepatocellular carcinoma (HepG2) cells", 《SCIENCE OF THE TOTAL ENVIRONMENT》, vol. 687, pages 267 - 276, XP085758771, DOI: 10.1016/j.scitotenv.2019.05.486 * |
| SIQING YUE等: "Metabolomic modulations of HepG2 cells exposed to bisphenol analogues", 《ENVIRONMENT INTERNATIONAL》, vol. 129, pages 59 - 67 * |
| YI XING等: "A sensitive electrochemical sensor for bisphenol F detection and its application in evaluating cytotoxicity", 《MICROCHEMICAL JOURNAL》, vol. 168, pages 106414 * |
| 金士威等: "双酚A 与四溴双酚A 对肝癌细胞Hep G2 的细胞毒性效应", 《CONFERENCE ON ENVIRONMENTAL POLLUTION AND PUBLIC HEALTH》, pages 259 - 262 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115819241A (en) * | 2022-12-05 | 2023-03-21 | 深圳市人民医院 | Novel phenethyl alcohol ester compound separated from oriental wormwood and preparation method and application thereof |
| CN115819241B (en) * | 2022-12-05 | 2023-09-01 | 深圳市人民医院 | Novel phenethyl alcohol ester compound separated from herba artemisiae capillaris and preparation method and application thereof |
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