CN113599380A - Application of berberine compounds in preparing antitumor drugs - Google Patents
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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Abstract
The invention provides an application of berberine compounds in preparing antitumor drugs, and the berberine compounds are berberine hydrochloride compounds, tetrahydroberberine compounds or dihydroberberine compounds. Therefore, the berberine compounds are derivatives taking isoquinoline as a parent nucleus, have the activity of inhibiting LSD1, and open up a new way for searching antitumor drugs based on LSD1 targets.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry, and particularly relates to an application of berberine compounds in preparation of antitumor drugs.
Background
Berberine, a natural alkaloid with isoquinoline as the parent nucleus, has a wide range of pharmacological actions such as urease activity inhibition, anti-inflammation, antioxidant, anti-Alzheimer's effect, cytochrome P450 enzyme activity inhibition, etc.
Histone lysine-specific demethylase 1(LSD1) is the first histone lysine demethylase to be discovered and is closely related to cell proliferation and differentiation, embryo pluripotency and carcinogenesis and development. LSD1 has been found to be overexpressed in many tumor cells, resulting in the development of various cancers, such as leukemia, lung cancer, etc. The LSD1 inhibitor can inhibit the activity of LSD1 in tumor cells, thereby influencing the growth, metastasis and invasion of the tumor cells, so that the LSD1 inhibitor with high selectivity, high efficiency and low toxicity is designed and synthesized as a new way for treating cancer.
Over the last decade, significant progress has been made in the development of LSD1 inhibitors. Currently, various irreversible inhibitors of the phenylpropylamine (TCP) class are being tested in clinical trials for the treatment of Small Cell Lung Cancer (SCLC) and Acute Myeloid Leukemia (AML), including TCP, GSK2879552, IMG-7289, ORY-1001, INCB059872, and ORY-2001. Of the reversible inhibitors, only CC-90011 and SP-2577 are currently in clinical research phase, and thus the discovery of novel reversible LSD1 inhibitors with different chemical structures and significant biological activity has become a promising strategy for cancer treatment.
However, reports of the berberine compounds for antitumor research targeting LSD1 are few, so the research has important significance.
Disclosure of Invention
In view of the above, in order to fully exploit and utilize the existing natural product resources, the present invention provides a new use of berberine compounds, so as to solve the above problems.
The invention aims to provide the application of berberine compounds in preparing antitumor drugs, and opens up a new way for searching antitumor drugs based on LSD1 targets.
Specifically, the application of berberine compounds in preparing antitumor drugs is disclosed, wherein the antitumor drugs are LSD1 inhibitors, and the berberine compounds are berberine hydrochloride compounds, tetrahydroberberine compounds or dihydroberberine compounds.
Based on the above, the general structure of the berberine hydrochloride compoundCan be represented by
Preferably, the berberine hydrochloride compound has a structural formula as follows:
based on the above, the structural general formula of the tetrahydroberberine compound can be shown as
Preferably, the structural formula of the tetrahydroberberine compound is as follows:
based on the above, the structural formula of the dihydroberberine compound is as follows:
the berberine compounds are derivatives taking isoquinoline as a parent nucleus, have the activity of inhibiting LSD1, can be used for preparing LSD1 inhibitors and open up a new way for searching antitumor drugs based on LSD1 targets according to the verification.
Detailed Description
The technical solution of the present invention is further described in detail by the following embodiments. Unless otherwise specified, the technical means used in the following examples are conventional means well known to those skilled in the art.
Example one
This example provides compound 1, having the structural formula:
the preparation route of the compound 1 is as follows:
the preparation method of the compound 1 comprises the following steps:
(1) preparation of Compounds 1-3:
0.50g (about 3.01mmol) of 2, 3-dimethoxybenzaldehyde (compound 1-1) and 0.50g (about 3.01mmol) of 2- [3,4- (methylenedioxy) phenyl ] ethylamine (compound 1-2) were added to 10ml of methanol, reacted at room temperature for 2 hours, and 0.17g (about 4.51mmol) of sodium borohydride was slowly added and reacted at room temperature, and the reaction system was monitored by TLC. After the reaction is completed, extracting by using ethyl acetate and saturated potassium carbonate aqueous solution, combining organic phases, drying by using anhydrous magnesium sulfate, evaporating to dryness, and performing column chromatography to obtain a compound 1-3, wherein the compound 1-3 is a light yellow liquid, and the yield is about 81%.
(2) Preparation of compound 1:
0.5g (about 1.59mmol) of the above-mentioned compounds 1 to 3 was charged into a reaction flask, 5ml of a formic acid solution was added, 1.01g (about 6.34mmol) of anhydrous copper sulfate, 0.37mg (about 3.17mmol) of a 50% aqueous glyoxal solution were added and heated under reflux at 80 ℃ and the reaction system was monitored by TLC. And after the reaction is finished, immediately performing suction filtration, adding ethyl acetate into the filtrate to separate out a large amount of yellow solids, and performing suction filtration to obtain the compounds 1-4 which are yellow solids.
Adding the yellow solid into 10ml methanol, adding 0.5ml concentrated hydrochloric acid for acidification, stirring at normal temperature for 12h, evaporating to dryness, stir-frying, and performing column chromatography to obtain a compound 1. The compound was a yellow solid with a yield of 53% for compound 1.1HNMR(400MHz,DMSO-d6)δ9.90(s,1H),8.96(s,1H),8.20(d,J＝8.9Hz,1H),8.01(d,J＝8.9Hz,1H),7.79(s,1H),7.09(s,1H),6.17(s,2H),4.94(t,J＝6.2Hz,2H),4.10(s,3H),4.07(s,3H),3.21(t,J＝6.2Hz,2H)。
Example two
This example provides Compound 2, Compound 2 having the formula
The preparation route of the compound 2 is as follows:
the preparation method of the compound 2 comprises the following steps:
(1) preparation of Compounds 2-3:
0.50g (about 3.20mmol) of 2-naphthaldehyde (compound 2-1) and 0.58g (about 3.20mmol) of 3, 4-dimethoxyphenethylamine (compound 2-2) were added to 10ml of methanol, reacted at ordinary temperature for 2 hours, slowly added with 0.18g (about 4.80mmol) of sodium borohydride, and reacted at room temperature, and the reaction system was monitored by TLC. After the reaction is completed, extracting by using ethyl acetate and saturated potassium carbonate aqueous solution, combining organic phases, drying by using anhydrous magnesium sulfate, evaporating to dryness, and performing column chromatography to obtain a compound 2-3, wherein the compound 2-3 is a light yellow liquid, and the yield is about 89%.
(2) Preparation of compound 2:
0.5g (about 1.56mmol) of the above-mentioned compounds 2 to 3 was charged into a reaction flask, 5ml of a formic acid solution was added, 0.99g (about 6.22mmol) of anhydrous copper sulfate, 0.36mg (about 3.11mmol) of a 50% aqueous glyoxal solution were added and heated under reflux at 80 ℃ and the reaction system was monitored by TLC. And after the reaction is finished, immediately performing suction filtration, adding ethyl acetate into the filtrate to separate out a large amount of yellow solids, and performing suction filtration to obtain a compound 2-4 which is a yellow solid.
Adding the yellow solid into 10ml methanol, adding 0.5ml concentrated hydrochloric acid for acidification, stirring at normal temperature for 12h, evaporating to dryness, stir-frying, and performing column chromatography to obtain a compound 2. The compound was a yellow solid with a yield of 65% for compound 2.1HNMR(400MHz,DMSO-d6)δ9.92(s,1H),9.55(s,1H),9.41(d,J＝7.8Hz,1H),8.27–8.19(m,2H),8.13(d,J＝9.0Hz,1H),8.06–7.95(m,3H),7.17(s,1H),4.92(t,J＝6.5Hz,2H),4.04(s,3H),3.91(s,3H),3.30(t,J＝6.5Hz,2H)。
EXAMPLE III
This example provides Compound 3, having the formula
The preparation route of the compound 3 is as follows:
the preparation method of the compound 3 comprises the following steps:
(1) preparation of Compound 3-1:
1.00g of 3-hydroxy-4-methoxybenzaldehyde (about 6.57mmoL) and 1.36g (about 9.86mmoL) of potassium carbonate were added to a reaction flask, respectively, then about 10ml of N, N-dimethylformamide was added, 1.69g (about 9.86mmoL) of benzyl bromide was added to the above system, and the reaction was monitored by thin layer chromatography TLC under reflux with heating at 80 ℃. After the reaction is finished, extracting with ethyl acetate and water, combining organic phases, evaporating to dryness, stir-frying a sample, and performing column chromatography to obtain a pure compound 3-1.
(2) Preparation of Compounds 3-3:
0.50g (about 2.06mmol) of the compound 3-1 and 0.38g (about 0.26mmol) of 3, 4-dimethoxyphenethylamine (the compound 1-2) were added to 10ml of methanol, reacted at ordinary temperature for 2 hours, slowly added with 0.12g (about 3.10mmol) of sodium borohydride, and reacted at room temperature, and the reaction system was monitored by TLC. After the reaction is completed, extracting by using ethyl acetate and saturated potassium carbonate aqueous solution, combining organic phases, drying by using anhydrous magnesium sulfate, evaporating to dryness, and performing column chromatography to obtain a compound 3-3, wherein the compound 3-3 is a light yellow liquid, and the yield is about 89%.
(3) Preparation of compound 3:
0.5g (about 1.32mmol) of the above-mentioned compound 3-3 was charged into a reaction flask, 5ml of a formic acid solution was added, 0.85g (about 5.30mmol) of anhydrous copper sulfate, 0.31mg (about 2.65mmol) of a 50% aqueous glyoxal solution were added and heated under reflux at 80 ℃ and the reaction system was monitored by TLC. And after the reaction is finished, immediately performing suction filtration, adding ethyl acetate into the filtrate to separate out a large amount of yellow solids, and performing suction filtration to obtain a compound 3-4 which is a yellow solid.
Adding the yellow solid into 10ml methanol, adding 0.5ml concentrated hydrochloric acid for acidification, stirring at room temperature for 12 hr, evaporating to dryness, parching, and performing column chromatography to obtain chemical productCompound 3. The compound 3 was a yellow solid, and the yield of the compound 3 was 24%.1HNMR(400MHz,DMSO-d6)δ9.55(s,1H),8.81(s,1H),7.66(s,1H),7.61(s,1H),7.53(s,1H),7.09(s,1H),4.75(t,J＝6.2Hz,2H),4.08(s,3H),3.93(s,3H),3.87(s,3H),3.21(t,J＝6.2Hz,2H)。
Example four
This example provides Compound 4, having the formula
The preparation route of the compound 4 is as follows:
the preparation method of the compound 4 comprises the following steps:
(1) preparation of Compounds 4-3:
0.46g (about 2.76mmol) of 2, 3-dimethoxybenzaldehyde (compound 1-1) and 0.5g (about 2.76mmol) of 3, 4-dimethoxyphenethylamine (compound 1-2) were added to 10ml of methanol, reacted at ordinary temperature for 2 hours, and 0.16g (about 4.14mmol) of sodium borohydride was slowly added and reacted at room temperature, and the reaction system was monitored by TLC. After the reaction is completed, extracting by using ethyl acetate and saturated potassium carbonate aqueous solution, combining organic phases, drying by using anhydrous magnesium sulfate, evaporating to dryness, and performing column chromatography to obtain a compound 4-3, wherein the compound 4-3 is a light yellow liquid, and the yield is about 92%.
(2) Preparation of Compounds 4-4 and 4-5:
0.5g (about 1.51mmol) of the above-mentioned compound 4-3 was charged into a reaction flask, 5ml of a formic acid solution was added, 0.97g (about 6.03mmol) of anhydrous copper sulfate and 0.35ml (about 3.02mmol) of a 50% aqueous glyoxal solution were added and heated under reflux at 80 ℃ and the reaction system was monitored by TLC. And after the reaction is finished, immediately performing suction filtration, adding ethyl acetate into the filtrate to separate out a large amount of yellow solid, and performing suction filtration to obtain a compound 4-4 which is a yellow solid. Adding the yellow solid into 10ml methanol, adding 0.5ml concentrated hydrochloric acid for acidification, stirring at normal temperature for 12h, parching, and performing column chromatography to obtain compound 4-5.
(3) Preparation of compound 4:
0.5g of compound 4-4 (about 1.29mmol), 7.5ml (about 49.7mmol) of 3, 4-dimethoxybenzylamine (15-a) was added to the reaction flask, and refluxed at 100 ℃ for 4 hours, and the reaction system was monitored by TLC. After the reaction is completed, washing off excessive 3, 4-dimethoxybenzylamine by using ethyl acetate to obtain a red solid, stir-frying the red solid, and performing column chromatography to obtain a compound 4. The compound 4 is a dark red solid, and the yield is about 65 percent by detection,1HNMR(400MHz,Methanol-d4)δ9.60(s,1H),8.64(s,1H),7.87(d,J＝8.8Hz,1H),7.69(d,J＝8.8Hz,1H),7.64(s,1H),7.11(d,J＝8.3Hz,1H),7.05(s,1H),6.53(d,J＝2.4Hz,1H),6.42(dd,J＝8.3,2.4Hz,1H),4.81(t,J＝6.3Hz,2H),4.65(s,2H),4.00(s,3H),3.98(s,3H),3.95(s,3H),3.79(s,3H),3.76(s,3H),3.29(t,J＝6.3Hz,2H)。
EXAMPLE five
This example provides Compound 5, compound 5 having the formula
The preparation route of the compound 5 is as follows:
the preparation method of the compound 5 comprises the following steps:
(1) compounds 4-3, 4-4 and 4-5 were prepared as in example four.
(2) Preparation of compound 5:
heating 0.5g of compound 4-4 under vacuum (30-40 mmHg) at 190 deg.C for 30min to obtain red black solid, parching, and performing column chromatography to obtain compound 5. Compound 5 is a dark red solid and has a yield of about 76% as determined,1HNMR(400MHz,DMSO-d6)δ9.18(s,1H),8.15(s,1H),7.53(s,1H),7.30(d,J＝7.9Hz,1H),6.98(s,1H),6.51(d,J＝7.9Hz,1H),4.54(t,J＝6.0Hz,3H),3.89(s,3H),3.83(s,3H),3.76(s,3H),3.07(t,J＝6.0Hz,3H)。
EXAMPLE six
This example provides Compound 6, having the formula
The preparation route of the compound 6 is as follows:
the preparation method of the compound 6 comprises the following steps:
(1) compounds 1-3, 1-4 and 1 were prepared as in example one.
(2) Preparation of compound 6:
heating 0.5g of the compound 1 at 190 ℃ for 30min under vacuum (30-40 mmHg) to obtain a red-black solid, stir-frying the red-black solid, and performing column chromatography to obtain a compound 6. Compound 6 is a dark red solid and has a yield of about 85% as determined,1HNMR(400MHz,DMSO-d6)δ9.07(s,1H),7.98(s,1H),7.61(s,1H),7.21(d,J＝7.9Hz,1H),6.96(s,1H),6.35(d,J＝7.8Hz,1H),6.10(s,2H),4.48(t,J＝6.1Hz,2H),3.73(s,3H),3.04(t,J＝6.1Hz,2H)。
EXAMPLE seven
This example provides Compound 7, having the formula
The preparation route of the compound 7 is as follows:
the preparation method of the compound 7 comprises the following steps:
(1) compounds 4-3, 4-4 and 4-5 were prepared as in example four.
(2) Compound 5 was prepared as in example five.
(3) Preparation of compound 7:
0.2g of Compound 5 (about 0.54mmoL) and 0.08g (about 0.82mmoL) of triethylamine were added to the reaction flask, respectively, then about 10ml of dichloromethane was added, 1.69g (about 0.54mmoL) of benzyl bromide was added to the above system, and stirred at normal temperature, and the reaction was monitored by thin layer chromatography TLC. After the reaction is finished, filtering, stir-frying the obtained filter cake, and performing column chromatography to obtain a pure compound 5. The yield is 90 percent,1HNMR(400MHz,DMSO-d6)δ9.74(s,1H),9.05(s,1H),8.23(d,J＝9.2Hz,1H),8.05(d,J＝9.2Hz,1H),7.72(s,1H),7.61–7.58(m,2H),7.44–7.35(m,3H),7.10(s,1H),5.37(s,2H),4.94(t,J＝6.3Hz,2H),4.10(s,3H),3.94(s,3H),3.87(s,3H),3.22(t,J＝6.3Hz,2H)。
example eight
This example provides Compound 8, having the formula
The preparation route of the compound 8 is as follows:
the preparation method of the compound 8 comprises the following steps:
(1) compounds 4-3, 4-4 and 4-5 were prepared as in example four.
(2) Preparation of compound 8:
0.2g (ca. 0.54mmol) of the compound 4-4 is added to 10ml of methanol solution, heated to 45 ℃ and NaBH is added40.081g (about 2.14mmol) and the reaction system is monitored by TLC. After the reaction is completed, extracting by using ethyl acetate and saturated potassium carbonate aqueous solution, combining organic phases, drying by anhydrous magnesium sulfate, evaporating to dryness, and performing column chromatography to obtain a compound 8. The compound was a white solid in about 81% yield. 1HNMR (400MHz, DMSO-d6) δ 8.58(s,1H),6.87(s,1H),6.79(d, J ═ 8.3Hz,1H),6.68(s,1H),6.60(d, J ═ 8.3Hz,1H),4.02(d, J ═ 15.7Hz,1H),3.76(s,3H),3.74(s,3H),3.72(s,3H), 3.42-3.35 (m,2H),3.29(d, J ═ 15.7Hz,2H), 3.12-3.05 (m,1H), 2.99-2.86 (m,1H), 2.64-2.52 (m,2H), 2.49-2.39 (m,1H).
Example nine
This example provides compound 9, having the formula
The preparation route of the compound 9 is as follows:
the preparation method of the compound 9 comprises the following steps:
(1) preparation of Compounds 1-3, 1-4, 1 As in example one
(2) Preparation of compound 9:
0.2g (ca. 0.54mmol) of Compound 1 are added to 10ml of methanol solution, heated to 45 ℃ and NaBH is added40.081g (about 2.15mmol) and the reaction system is monitored by TLC. After the reaction is completed, extracting by using ethyl acetate and saturated potassium carbonate aqueous solution, combining organic phases, drying by anhydrous magnesium sulfate, evaporating to dryness, and performing column chromatography to obtain a compound 9. The compound was a white solid with a yield of about 86%.1HNMR(400MHz,DMSO-d6)δ8.58(s,1H),6.91(s,1H),6.78(d,J＝8.2Hz,1H),6.66(s,1H),6.57(d,J＝8.2Hz,1H),5.94(d,J＝2.6Hz,2H),4.01(d,J＝15.6Hz,1H),3.76(s,3H),3.43–3.35(m,2H),3.27(d,J＝15.6Hz,2H),3.12–3.03(m,1H),2.95–2.85(m,1H),2.63–2.51(m,2H),2.48–2.40(m,1H)。
Example ten
This example provides compound 10, having the formula
The route for the preparation of this compound 10 is as follows:
the preparation method of the compound 10 comprises the following steps:
(1) preparation of Compound 10-1
0.50g of 3, 4-dihydroxybenzaldehyde (about 3.62mmoL), 0.75g of dibromomethane (about 4.34mmoL), 1.37g (about 4.93mmoL) of potassium carbonate were added to the reaction flask, respectively, and then about 10ml of N, N-dimethylformamide was added, and the reaction was monitored by thin layer chromatography TLC under reflux with heating at 90 ℃. After the reaction is finished, ethyl acetate and water are used for extraction, organic phases are combined, evaporation is carried out, samples are fried, and the pure compound 10-1 is obtained through column chromatography.
(2) Preparation of Compounds 10-3 and 10-4
0.5g (about 1.59mmol) of the above-mentioned compound 10-3 was charged into a reaction flask, 5ml of formic acid solution was added, 1.01g (about 6.34mmol) of anhydrous copper sulfate, 0.37mg (3.17mmol) of 50% aqueous glyoxal solution were added and heated under reflux at 80 ℃ and the reaction system was monitored by TLC. And after the reaction is finished, immediately performing suction filtration, adding ethyl acetate into the filtrate to separate out a large amount of yellow solid, and performing suction filtration to obtain a compound 10-4, wherein the compound 10-4 is a yellow solid. Adding the yellow solid into 10ml methanol, adding 0.5ml concentrated hydrochloric acid for acidification, stirring at normal temperature for 12h, evaporating to dryness, parching, and performing column chromatography to obtain compound 10-5.
(3) Preparation of Compound 10
0.2g (ca. 0.54mmol) of Compound 10-4 is added to 10ml of methanol solution, heated to 45 ℃ and NaBH is added40.081g (about 2.15mmol) and the reaction system is monitored by TLC. After the reaction is completed, extracting by using ethyl acetate and saturated potassium carbonate aqueous solution, combining organic phases, drying by using anhydrous magnesium sulfate, evaporating to dryness, and performing column chromatography to obtain a compound 10 which is a white solid with the yield of 79%.1HNMR(400MHz,Chloroform-d)δ6.73(s,1H),6.71–6.67(m,1H),6.67–6.64(m,1H),6.62(s,1H),5.97(d,J＝1.5Hz,1H),5.93(d,J＝1.5Hz,1H),4.11(d,J＝15.3Hz,1H),3.89(s,3H),3.87(s,3H),3.64–3.49(m,2H),3.28(dd,J＝16.0,3.7Hz,1H),3.21–3.08(m,2H),2.82(dd,J＝15.9,11.3Hz,1H),2.72–2.60(m,2H)。
EXAMPLE eleven
This example provides compound 11, compound 11 having the formula
The route for the preparation of this compound 11 is as follows:
the preparation method of the compound 11 comprises the following steps:
(1) compounds 10-1, 10-3 and 10-4 were prepared according to the same procedure as in example 10.
(2) Preparation of compound 11:
0.2g (ca. 0.54mmol) of compound 10-4 and 0.22g K2CO3(about 1.61mmol) was added to a solution of 5ml of methanol and 0.03mg of NaBH was added4(0.16mmol) of a 5% NaOH aqueous solution was added dropwise to the above system, and the reaction system was monitored by TLC. After the reaction is completed, ethyl acetate and an aqueous solution are used for extraction, organic phases are combined, anhydrous magnesium sulfate is used for drying, evaporation is carried out, and a compound 11 is obtained through column chromatography, wherein the compound is a yellow solid, and the yield is 65%. 1HNMR (400MHz, DMSO-d6) δ 7.19(s,1H),6.98(d, J ═ 8.4Hz,1H),6.88(s, J ═ 8.4Hz,1H),6.65(s,1H),5.76(s,1H),4.11(s,2H),3.89(s,3H),3.87(s,3H), 3.64-3.49 (m,2H), 3.21-3.08 (m, 2H).
LSD1 inhibitory Activity assay
The experimental method comprises the following steps: the samples were compounds 1-11 and ORY-1001 (purchased from MedChemExpress) synthesized in the above examples. Sample stock solution: weighing 1-2 mg of samples respectively, dissolving the samples into mother liquor with the concentration of 10mM by using DMSO (dimethyl sulfoxide), and diluting the mother liquor to the concentration to be measured by using DMSO during the experiment. The samples were respectively incubated with human-derived complex protein LSD1/CoREST purified from an E.coli expression system, and then incubated for 30min by adding a substrate H3K4me2 synthesized by Gill Biochemical (Shanghai) Co., Ltd. After the incubation was completed, fluorescent dye Amplex Red and horseradish peroxidase HRP were added to react for 5min, and then a fluorescence signal was measured using an EnVision microplate reader (PerkinElmer, Waltham, MA, USA) (E)X＝535nm，Em595nm) and the inhibition ratio was calculated, the results are shown in table 1. Specifically, the inhibition ratio calculation formula is as follows:
wherein, the "fluorescence intensity of sample group", "fluorescence intensity of standard group" and "fluorescence intensity of blank group" in the above formula are fluorescence intensity values measured by referring to the above experimental method, and the difference is that: under the same conditions, the object of measurement of "fluorescence intensity of sample group" is a sample liquid containing the above-mentioned compound to be measured, and the object of measurement of "fluorescence intensity of standard group" is a standard liquid containing no sample as compared with the above-mentioned sample liquid. The "blank fluorescence intensity" was measured on a blank sample that did not contain LSD1/CoREST complex protein and H3K4me2 polypeptide. IC of the above sample Compound was treated with Graphpad prism8.050Data, results are shown in table 1.
TABLE 1 results of inhibitory Activity of Compounds of the invention on LSD/CoREST provided in the examples of the invention
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention and not to limit it; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art will understand that: modifications to the specific embodiments of the invention or equivalent substitutions for parts of the technical features may be made; without departing from the spirit of the present invention, it is intended to cover all aspects of the invention as defined by the appended claims.
Claims (4)
1. An application of berberine compounds in preparing antitumor drugs is characterized in that the antitumor drugs are LSD1 inhibitors, and the berberine compounds are berberine hydrochloride compounds, tetrahydroberberine compounds or dihydroberberine compounds.
2. The use according to claim 1, wherein the berberine hydrochloride compound has the formula:
3. the use according to claim 1, wherein the tetrahydroberberine compound has the formula:
4. the use according to claim 1, wherein the dihydroberberine compound has the formula:
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022214303A1 (en) | 2021-04-08 | 2022-10-13 | Oryzon Genomics, S.A. | Combinations of lsd1 inhibitors for treating myeloid cancers |
| CN114149421A (en) * | 2021-11-12 | 2022-03-08 | 中国医学科学院医药生物技术研究所 | Palmatine derivative, preparation method and antithrombotic application thereof |
| CN114057723A (en) * | 2021-11-25 | 2022-02-18 | 四川大学 | Synthetic method of 13-methyl berberine alkaloid |
| WO2023174381A1 (en) * | 2022-03-16 | 2023-09-21 | 南京施江医药科技有限公司 | Nitrogen-containing heterocyclic compound and use thereof |
| WO2023174377A1 (en) * | 2022-03-16 | 2023-09-21 | 南京施江医药科技有限公司 | Tetracyclic compound and use thereof |
| CN114736202A (en) * | 2022-04-20 | 2022-07-12 | 四川大学 | Preparation and application of berberine derivative with IDO1/TDO inhibitory activity |
| WO2023217758A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating malignant peripheral nerve sheath tumor (mpnst) using lsd1 inhibitors |
| WO2023217784A1 (en) | 2022-05-09 | 2023-11-16 | Oryzon Genomics, S.A. | Methods of treating nf1-mutant tumors using lsd1 inhibitors |
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