CN114751891A - (2- (1H-indole-3-yl) -1H-imidazole-4-yl) phenyl ketone compound and application thereof - Google Patents
(2- (1H-indole-3-yl) -1H-imidazole-4-yl) phenyl ketone compound and application thereof Download PDFInfo
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Abstract
The invention relates to a (2- (1H-indole-3-yl) -1H-imidazole-4-yl) phenyl ketone compound, the chemical structure of which is shown in the following formula (I); in the formula (I), X, Y, Z is deuterium atom, or two are deuterium atoms, or all are deuterium atoms. The compound has obvious inhibition effect on human breast cancer cells MCF-7, human cervical cancer cells HeLa, human liver cancer cells HepG-2 and mouse melanoma cells B16-F10, and can be used for preparing antitumor drugs.
Description
Technical Field
The invention relates to (2- (1H-indole-3-yl) -1H-imidazole-4-yl) phenyl ketone compounds, which can inhibit the proliferation of tumor cells and can be used for treating tumors.
Background
Microtubules (microtubule) have a number of important functions, including cellular structure and support, movement of cells, transport of organelles, and segregation of chromosomes during cell division. Microtubules are long hollow tubular structures consisting of 13 tubulin fibrils (protofilament). Whereas tubulin fibrils are composed of tubulin (tubulin) subunits. Tubulin subunits are mainly dimers formed by the association of two structurally similar globular proteins (alpha-tubulin and beta-tubulin). The growth of cancer cells is highly dependent on the dynamic instability of tubulin (dynamic equilibrium of elongation and contraction), which, given the critical role microtubules play in cancer cell proliferation and division, has become the target of many anticancer drugs (e.g. paclitaxel, vinblastine). Tubulin inhibitors interfere with the mitotic process of cancer cells by inhibiting tubulin polymerization (microtubule elongation) or depolymerization (microtubule shortening), disrupting mitosis and arresting the cell cycle in the G2/M phase, leading to apoptosis of cancer cells.
All currently marketed tubulin inhibitors bind to the paclitaxel site or vinca alkaloid site. Although these inhibitors have a broad spectrum of anticancer activity, their clinical use faces a number of problems, including: it can not be taken orally, and has great toxic and side effects, drug resistance, etc. Whereas tubulin inhibitors targeted to the colchicine binding site substantially overcome the above-mentioned disadvantages, they have the following advantages over the tubulin inhibitors already on the market: overcoming the drug resistance of paclitaxel and vinblastine: due to different binding sites and not being a substrate for multidrug resistance/MDR (e.g., P-gp); ② the oral bioavailability is high: due to the relative simple structure, good physicochemical property/water solubility and pharmacokinetic property; thirdly, the toxic and side effects are relatively small: high water solubility, no need of cosolvent and less side reaction.
Given the critical role tubulin plays in cancer cell proliferation and division, and currently, there is no anticancer drug on the market targeting the colchicine binding site. The novel microtubulin inhibitor which can overcome the drug resistance of the paclitaxel, can be orally taken and has good pharmacokinetic property and targeted micro-colchicine binding sites is designed and developed, and has important significance and wide application prospect as an anti-cancer drug.
Disclosure of Invention
The invention aims to provide a (2- (1H-indole-3-yl) -1H-imidazole-4-yl) phenyl ketone compound which has obvious inhibition effects on human cervical cancer cells HeLa, human breast cancer cells MCF-7, human liver cancer cells HepG-2 and mouse melanoma cells B16-F10.
The scheme for solving the technical problems is as follows:
a (2- (1H-indole-3-yl) -1H-imidazole-4-yl) phenyl ketone compound has a chemical structure shown in a formula (I),
in the formula (I), X, Y, Z is deuterium atom, or two are deuterium atoms, or all are deuterium atoms.
The (2- (1H-indole-3-yl) -1H-imidazole-4-yl) phenyl ketone compound is one of the following compounds:
when X is deuterium atom and Y and Z are hydrogen atom, the chemical structure of the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound is as follows:
when Y is deuterium atom and X and Z are hydrogen atom, the chemical structure of the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound is as follows:
when X and Z are deuterium atoms and Y is a hydrogen atom, the chemical structure of the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound is as follows:
When X and Y are deuterium atoms and Z is a hydrogen atom, the chemical structure of the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound is as follows:
when X, Y, Z are deuterium atoms, the chemical structure of the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound is as follows:
the preparation method of the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound comprises the following steps:
(1) dissolving the raw material indole 3-formaldehyde (1) in ethanol, adding 1.1 mol times of potassium hydroxide according to the mol weight of the raw material 1, and stirring the mixture until the mixture is completely dissolved. The ethanol was removed in vacuo and the concentrate was dissolved in acetone, then 1.1 molar times of benzenesulfonyl chloride was added and reacted at room temperature for half an hour. Filtering to remove precipitate, concentrating the filtrate and recrystallizing with methanol to obtain intermediate 2;
the chemical reaction formula of the step (1) is as follows:
(2) taking the intermediate 2 obtained in the step (1) to dissolve in ethanol, and adding 1.1 mol times of glyoxal aqueous solution and 10.0 mol times of ammonium hydroxide aqueous solution according to the mol amount of the intermediate 2 at 0 ℃. After stirring at room temperature for 2 days, the reaction was quenched with water and extracted with dichloromethane. Collecting an organic layer, concentrating, and performing column chromatography separation and purification to obtain an intermediate 3;
The chemical reaction formula of the step (2) is as follows:
(3) dissolving the intermediate 3 obtained in the step (2) in super-dry tetrahydrofuran, adding 1.2 mol times of sodium hydride according to the mol amount of the intermediate 3, and stirring for 20 minutes. Then 1.2 times by mole of benzenesulfonyl chloride was added and stirred overnight. The reaction solution is saturatedNaHCO3Extracting the aqueous solution with ethyl acetate, drying the organic layer with magnesium sulfate, concentrating, and separating and purifying by column chromatography to obtain an intermediate 4;
the chemical reaction formula of the step (3) is as follows:
(4) and (3) dissolving the intermediate 4 obtained in the step (3) in an ultra-dry tetrahydrofuran solution, adding 1.2 mol times of a pentane solution of tert-butyl lithium at the temperature of 0 ℃ according to the molar weight of the intermediate 4, and stirring for 10 minutes. Then 1.2 molar times of a THF solution of trimethoxybenzoyl chloride (5) was added and stirred overnight. Adding saturated NaHCO into reaction liquid3Extracting the aqueous solution with ethyl acetate, drying the organic layer with magnesium sulfate, concentrating, and separating and purifying by column chromatography to obtain an intermediate 6;
the chemical reaction formula of the step (4) is as follows:
(5) dissolving the intermediate 6 obtained in the step (4) in an ethanol/water (10/1) solution, adding 10.0 times by mole of sodium hydroxide according to the molar amount of the intermediate 6, and heating and stirring under reflux under the condition of keeping out light overnight. The reaction solution was diluted with water and extracted with ethyl acetate. Drying and concentrating the organic layer by magnesium sulfate, and separating and purifying by column chromatography to obtain a compound Ia;
The chemical reaction formula of the step (5) is as follows:
the process route of the method for synthesizing the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound is as follows:
the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound has obvious inhibition effects on human breast cancer cells MCF-7, human cervical cancer cells HeLa, human liver cancer cells HepG-2 and mouse melanoma cells B16-F10, and can be used for preparing antitumor drugs.
Detailed Description
Example 1 (preparation Ia)
The structural formula of (2- (1H-indol-3-yl) -1H-imidazol-4-yl) (3, 4-dimethoxy-5- (trideuteromethoxy) phenyl) methanone (Ia) prepared in this example is:
the preparation method of the compound shown in the formula (Ia) comprises the following steps:
(1) the method comprises the following steps: preparation of Compound 2
The structural formula is prepared by the following method
The compound of (1):
indole-3-carbaldehyde (1) (14.5g,100mmol) was dissolved in 500ml of ethanol, and potassium hydroxide (6.16g,110mmol) was added thereto, followed by stirring at room temperature until completely dissolved. Ethanol was removed in vacuo and the concentrate was dissolved in 250ml acetone, then benzenesulfonyl chloride (19.5g, 110mmol) was added. After stirring the reaction solution at room temperature for half an hour, the precipitate was removed by filtration, and the filtrate was concentrated and recrystallized from methanol to give a white solid. Yield: 33 percent. 1H NMR(400MHz,CDCl3)δ10.18(s,1H),8.24-8.38(m,2H),7.98-8.08(m,3H),7.68(t,J＝7.33Hz,1H),7.60(t,J＝7.5Hz,2H),7.38-7.53(m,2H).MS(ESI)C15H11NO3S calculated 285.1, found 286.0[ M + H ]]+。
(2) Step two: preparation of Compound 3
The structural formula is prepared by the following method
The compound of (1):
1- (benzenesulfonyl) -1H-indole-3-carbaldehyde (2) (28.5g,100mmol) was dissolved in 400mL of ethanol, and 40% aqueous glyoxal solution (22mL,110mmol) and 29% aqueous ammonium hydroxide solution (136mL,1000mmol) were added at 0 ℃. After stirring at room temperature for 2 days, the reaction mixture was quenched with water and extracted with dichloromethane. The collected organic layer was distilled under reduced pressure, and the concentrate was subjected to column chromatography using n-hexane/ethyl acetate (4:1-2:1) to give a yellow powder. Yield: 12 percent.1H NMR(400MHz,DMSO-d6)δ8.34(d,J＝2.9Hz,2H),8.12(d,J＝7.8Hz,2H),7.99-8.05(m,1H),7.63-7.69(m,1H),7.56(d,J＝7.82Hz,2H),7.23-7.36(m,4H).MS(ESI)C17H13N3O2Calculated value of S is 323.1, found 324.0[ M + H ]]+。
(2) Step three: preparation of Compound 4
The structural formula is prepared by the following method
The compound of (1):
3- (1H-imidazol-2-yl) -1- (phenylsulfonyl) -1H-indole (3) (6.46g,20mmol) was dissolved in 300ml of ultra-dry tetrahydrofuran, and sodium hydride (60% dispersion in mineral oil) (0.96g, 24mmol) was added thereto at 0 ℃ and stirred for 20 minutes. Benzenesulfonyl chloride (4.25g, 24mmol) was then added and stirred overnight. 200ml of saturated NaHCO is added into the reaction solution3After dilution of the aqueous solution, it was extracted with 600ml of ethyl acetate. The organic layer was dried over magnesium sulfateDrying and concentrating, and subjecting to n-hexane/ethyl acetate (5: 1) column chromatography to obtain white solid. Yield: 40 percent. 1H NMR(CDCl3,400MHz)δ8.01-8.09(m,4H),7.73(d,J＝1.5Hz,1H),7.37-7.63(m,8H),7.25(d,J＝1.5Hz,1H),7.12-7.18(m,3H).MS(ESI)C23H17N3O4S2Calcd for 463.1, found 486.0[ M + Na ]]+。
(2) Step four: preparation of Compound 6a
The structural formula is prepared by the following method
The compound of (1):
1- (benzenesulfonyl) -3- (1- (benzenesulfonyl) -1H-imidazol-2-yl) -1H-indole (4) (2.32g,5.0mmol) was dissolved in 100mL of ultra-dry tetrahydrofuran, and a 1.7M solution of tert-butyllithium in pentane was added at-78 deg.C and stirred for 10 minutes. A solution of 3, 4-dimethoxy-5- (trideuteromethoxy) benzoyl chloride (5a) in tetrahydrofuran was then added (1.38g,6.0mmol) and stirred overnight. 100ml of saturated NaHCO is added into the reaction solution3The reaction was quenched with aqueous solution and extracted with 300ml of ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated, and subjected to column chromatography using n-hexane/ethyl acetate (3: 1) to give a white solid. Yield: 30 percent.1H NMR(CDCl3400MHz) δ 8.12(d, J ═ 10Hz,1H),8.06(d, J ═ 10Hz,2H),7.90(s,1H),7.78(d, J ═ 5Hz,2H),7.67(t, J ═ 10Hz,1H),7.54-7.59(m,5H),7.42(s,2H),7.35-7.38(m,3H),7.24(t, J ═ 10Hz,1H),4.07(s,3H),4.05(s,3H), ms (esi)) calculated as C33H27N3O8658.0, found 681.1[ M + Na]+。
(2) Step five: preparation of Compound Ia
The structural formula is prepared by the following method
The compound of (1):
(0.66g, 1mmol) of (1- (benzenesulfonyl) -2- (1- (benzenesulfonyl) -1H-indol-3-yl) -1H-imidazol-4-yl) (3,4, 5-trimethoxyphenyl) methanone (6a) was dissolved in 40ml of ethanol and 4ml of water, and sodium hydroxide (0.4g, 10mmol) was added thereto, and the mixture was stirred under reflux overnight under dark conditions. The reaction solution was diluted with 50ml of water and extracted with 200ml of ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated, and subjected to column chromatography using n-hexane/ethyl acetate (1: 1) to give a yellow solid. Yield: 60 percent.
The obtained yellow solid powder is identified by nuclear magnetic resonance hydrogen spectrum and nuclear magnetic resonance carbon spectrum, and the identification result is as follows:1H NMR(CD3OD,400MHz)δ8.30(d,J＝6.5Hz,1H),8.00(s,1H),7.92(s,1H),7.50-7.53(m,3H),7.25-7.29(m,2H),4.02(s,3H),3.95(s,3H).MS(ESI)C21H16D3N3O4calculated 380.16, found 403.2[ M + Na ]]+。
Example 2 (preparation Ib)
The structural formula of (2- (1H-indol-3-yl) -1H-imidazol-4-yl) (3, 5-dimethoxy-4- (trideuteromethoxy) phenyl) methanone (Ib) prepared in this example is:
the compound represented by the formula (Ib) is prepared by using 1- (benzenesulfonyl) -3- (1- (benzenesulfonyl) -1H-imidazol-2-yl) -1H-indole (4), 3, 5-dimethoxy-4- (trideuteromethoxy) benzoyl chloride (5b) as a raw material in the same manner as in example 1, wherein the chemical reaction formula is as follows:
the product obtained by the method is identified by nuclear magnetic resonance spectrum, and the result is as follows:1H NMR(CD3OD,500MHz)δ8.32(d,J＝6.5Hz,1H),8.00(s,1H),7.92(s,1H),7.48-7.53(m,3H),7.25-7.32(m,2H),4.00(s,6H).MS(ESI)C21H16D3N3O4calculated value is 380.16, found 403.1[ M + Na]+。
Example 3 (preparation Ic)
The structural formula of (2- (1H-indol-3-yl) -1H-imidazol-4-yl) (4-methoxy-3, 5-bis (trideuteromethoxy) phenyl) methanone (Ic) prepared in this example is:
the compound represented by the formula (Ic) is prepared by using 1- (benzenesulfonyl) -3- (1- (benzenesulfonyl) -1H-imidazol-2-yl) -1H-indole (4), 4-methoxy-3, 5-bis (trideuteromethoxy) benzoyl chloride (5c) as a starting material in the same manner as in example 1, wherein the chemical reaction formula is as follows:
The product obtained by the method is identified by nuclear magnetic resonance spectrum, and the result is as follows:1H NMR(CD3OD,500MHz)δ8.33(d,J＝6.5Hz,1H),7.80(s,1H),7.92(s,1H),7.49-7.53(m,3H),7.25-7.30(m,2H),3.95(s,3H).MS(ESI)C21H13D6N3O4calculated 383.18, found 406.2[ M + Na]+。
Example 4 (preparation Id)
The formula of (2- (1H-indol-3-yl) -1H-imidazol-4-yl) (3-methoxy-4, 5-bis (trideuteromethoxy) phenyl) methanone (Id) prepared in this example is:
the compound represented by the formula (Id) is prepared by using 1- (benzenesulfonyl) -3- (1- (benzenesulfonyl) -1H-imidazol-2-yl) -1H-indole (4), 3-methoxy-4, 5-bis (trideuteromethoxy) benzoyl chloride (5d) as a starting material in the same manner as in example 1, wherein the chemical reaction formula is as follows:
the product obtained by the method is identified by nuclear magnetic resonance spectrum, and the result is as follows:1H NMR(CD3OD,500MHz)δ8.30(d,J＝6.5Hz,1H),7.98(s,1H),7.91(s,1H),7.47-7.51(m,3H),7.23-7.27(m,2H),4.03(s,3H).MS(ESI)C21H13D6N3O4calculated value is 383.18, found 406.3[ M + Na]+。
Example 5 (preparation Ie)
The structural formula of (2- (1H-indol-3-yl) -1H-imidazol-4-yl) (3,4, 5-tris (trideuteromethoxy) phenyl) methanone (Ie) prepared in this example is:
the compound represented by the formula (Ie) is prepared by using 1- (benzenesulfonyl) -3- (1- (benzenesulfonyl) -1H-imidazol-2-yl) -1H-indole (4), 3,4, 5-tris (trideuteromethoxy) benzoyl chloride (5e) as a raw material in the same manner as in example 1, wherein the chemical reaction formula is as follows:
the product obtained by the method is identified by nuclear magnetic resonance spectrum, and the result is as follows: 1H NMR(CD3OD,500MHz)δ8.33(d,J＝6.5Hz,1H),8.02(s,1H),7.93(s,1H),7.51-7.54(m,3H),7.26-7.32(m,2H).MS(ESI)C21H10D9N3O4Calculated 386.19, found 409.4[ M + Na]+。
Example 6 (anti-tumor Activity study)
The in vitro antitumor activity of the compounds of the present invention was demonstrated using the following method tests. These effects indicate that the compounds of the present invention are useful for the treatment of cancer, in particular solid tumors such as human breast cancer, human cervical cancer, human liver cancer and mouse melanoma. The specific test method is as follows:
(1) cells in logarithmic growth phase were grown at 5X 104one/mL, 100. mu.L/well density was plated in 96-well plates. At 37 ℃ 5% CO2And culturing in a saturated humidity incubator until the cells adhere to the wall.
(2) The original medium was aspirated, and different concentrations of compounds were added to each group, at 0.001. mu.M, 0.003. mu.M, 0.01. mu.M, 0.03. mu.M, 0.1. mu.M, and 1. mu.M, respectively. The control group was 0.1% DMSO and the cells were further incubated in a cell incubator for 48 hours.
(3) mu.L of MTT solution was added to each well and incubated for 4h in an incubator.
(4) The medium was discarded, 150. mu.L of DMSO was added to each well, and formazan crystals were sufficiently dissolved by shaking for 10 min.
(5) The absorbance at 570nm was measured using an enzyme linked immunosorbent assay.
(6) The cell growth inhibition rate was calculated according to the following formula:
the inhibition rate is [ (As-Ab)/(Ac-Ab) ]. times.100%
As: absorbance of assay well (cell, MTT, Compound)
Ac: absorbance of control wells (cell, MTT, no Compound)
Ab: absorbance of blank wells (cell and Compound free, MTT containing)
The results of the measured activities are shown in table 1:
TABLE 1 comparison of antitumor Activity (Mean. + -. SD)
The positive control 1 in the above table is compound 17ya disclosed in the patent publication No. CN 102883607B, and the structure of compound 17ya is as follows:
the in vitro experiment results show that the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound has stronger inhibition effects on human breast cancer cells MCF-7, human cervical cancer cells HeLa, human liver cancer cells HepG-2 and mouse melanoma cells B16-F10, wherein the inhibition effects of the compounds (Ia, Ib, Ic, Id and Ie) on the cancer cells are obviously better than those of a positive control 1(17ya) and a positive control 2 (colchicine).
Claims (4)
1. A (2- (1H-indole-3-yl) -1H-imidazole-4-yl) phenyl ketone compound has a chemical structure shown in the following formula (I),
in the formula (I), one of X, Y, Z is deuterium atom, or two of X, Y, Z is deuterium atom, or all of them are deuterium atoms.
2. The (2- (1H-indol-3-yl) -1H-imidazol-4-yl) phenyl methanone compound according to claim 1, wherein the (2- (1H-indol-3-yl) -1H-imidazol-4-yl) phenyl methanone compound is one of the following compounds:
When X is deuterium atom and Y and Z are hydrogen atom, the chemical structure of the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound is as follows:
when Y is deuterium atom and X and Z are hydrogen atom, the chemical structure of the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound is as follows:
when X and Z are deuterium atoms and Y is a hydrogen atom, the chemical structure of the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound is as follows:
when X and Y are deuterium atoms and Z is a hydrogen atom, the chemical structure of the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound is as follows:
when X, Y, Z are deuterium atoms, the chemical structure of the (2- (1H-indol-3-yl) -1H-imidazole-4-yl) phenyl ketone compound is as follows:
3. the use of (2- (1H-indol-3-yl) -1H-imidazol-4-yl) phenyl methanones according to claim 1 or 2 for the preparation of anti-tumor medicaments.
4. The use according to claim 3, wherein the antitumor drug comprises (2- (1H-indol-3-yl) -1H-imidazol-4-yl) phenyl methanone compound according to claim 1 and pharmaceutically acceptable excipients.
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| CN114805307A (en) * | 2022-04-29 | 2022-07-29 | 南京雷正医药科技有限公司 | Indole compound for preparing coronavirus therapeutic drug |
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