CN109111390B - Met-modified indoloethanol derivative, and synthesis, activity and application thereof - Google Patents
Met-modified indoloethanol derivative, and synthesis, activity and application thereof Download PDFInfo
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- CN109111390B CN109111390B CN201710484569.3A CN201710484569A CN109111390B CN 109111390 B CN109111390 B CN 109111390B CN 201710484569 A CN201710484569 A CN 201710484569A CN 109111390 B CN109111390 B CN 109111390B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention discloses 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indoles of the formula. Discloses a preparation method thereof, discloses the antitumor activity thereof, discloses the anti-tumor metastasis activity thereof and discloses the anti-inflammatory activity thereof, and thus the invention discloses the application thereof in preparing antitumor drugs, anti-tumor metastasis drugs and anti-inflammatory drugs.
Description
Technical Field
The invention relates to 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole, relates to a preparation method thereof, relates to anti-tumor activity thereof, relates to anti-tumor metastasis activity thereof and relates to anti-inflammatory activity thereof, and thus the invention relates to application thereof in preparing anti-tumor drugs, anti-tumor metastasis drugs and anti-inflammatory drugs. The invention belongs to the field of biological medicine.
Background
Malignant tumors seriously threaten human health. Among them lung cancer is one of the most aggressive human cancers. For patients with advanced lung cancer, 10% -15% of the patients typically survive for only 5 years. The situation of this difficulty has not improved significantly over the last 30 years. In many clinical cases, lung cancer has metastasized to surrounding tissues before it is diagnosed. Tumor metastasis, especially tumor lung metastasis, is the greatest risk of death in tumor patients. To date, there is no antitumor drug that can prevent tumor metastasis for clinical use. Inflammation further worsens the prognosis of patients with tumors and tumor metastases. To date, no antitumor drug that can prevent inflammation and tumor metastasis has been used clinically. The invention relates to a medicament with triple effects of resisting tumor, tumor metastasis and inflammation, which is the leading edge of research on anti-tumor medicaments. Hair-like deviceThe prior invention of Ming (patent application publication No. CN 106349148A, application No. CN 201510409682.6) has disclosed that amino acid benzyl ester substituted diindolylacetic alcohol has triple effects of anti-tumor, anti-tumor metastasis and anti-inflammatory (formula left) at 0.2 mu mol/kg. The inventors have had two unsatisfactory points with respect to this type of benzyl bisindoloethanol amino acid. The first dissatisfaction was that the MTT models showed that their antitumor activity was derived from cytotoxic effects (IC of all compounds except 1 inhibiting proliferation of 5 tumor cells)508.2-62.2. mu.M). Clinical application shows that cytotoxic drugs have large toxic and side effects. That is, such benzyl bisindoloethanol amino acid ester is at great risk of toxic side effects. The second point of dissatisfaction is that their minimum effective dose for exerting the triple effects of anti-tumor, anti-tumor metastasis and anti-inflammatory is 0.2. mu. mol/kg, which is higher. Over the past two years, the inventors have been searching for non-cytotoxic compounds with triple effects of anti-tumor, anti-tumor metastasis and anti-inflammatory, with a minimum effective dose of less than 0.2 μmol/kg. Finally, the inventor finds that the benzyl methionine ester modified indoleethanol (right formula) has triple effects of anti-tumor, anti-tumor metastasis and anti-inflammatory at the dose of 0.02 mu mol/kg. Because the toxic and side effects of the medicine can disappear along with the reduction of the dosage, the reduction of the effective dosage by 10 times shows that the structure modification has outstanding technical effect. In addition, MTT model showed its IC for tumor cell proliferation50Are all larger than 200. mu.M. That is, the indole ethanol modified by the methionine amino acid benzyl ester has no toxic side effect of cytotoxic compounds. The inventor proposes the invention according to two advantages.
Disclosure of Invention
In a first aspect of the invention, there is provided 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indoles of the formula.
The second aspect of the present invention provides a process for the preparation of 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole, which comprises the steps of:
1) indole ethanol and ethyl bromoacetate react in tetrahydrofuran at 80 ℃ under the catalysis of sodium hydride to generate 1-ethoxycarbonylmethyl-3-ethoxycarbonylmethoxyethyl-indole (1);
2) saponifying the compound 1 in a 2N NaOH aqueous solution to obtain 1-carboxymethyl-3-carboxymethoxyethyl indole (2);
3) the compound 2 reacts with Met-OBzl in anhydrous tetrahydrofuran in the presence of dicyclohexylcarbodiimide and N-hydroxybenzotriazole to generate 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole.
The third aspect of the present invention is to evaluate the anti-tumor metastasis activity of 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole.
The fourth aspect of the present invention is to evaluate the antitumor activity of 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole.
The fifth aspect of the present invention is to evaluate the anti-inflammatory activity of 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole.
Drawings
FIG. 1. scheme for the synthesis of 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole I) ethyl bromoacetate, NaH, 80 ℃; ii) 2N NaOH in water; iii) dicyclohexylcarbodiimide, N-hydroxybenzotriazole, N-methylmorpholine, Met-OBzl.
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of 1-ethoxycarbonylmethyl-3-ethoxycarbonylmethoxyethyl-indole (1)
To a solution of 5.00g (31mmol) of indoloethanol and 50mL of anhydrous Tetrahydrofuran (THF) was slowly added 2.98g (4mmol, 60%) of NaH at room temperature, and stirred for 30 minutesThen, 17.22mL (5mmol) of ethyl bromoacetate was slowly added dropwise thereto, and the mixture was heated at 80 ℃ for 48 hours. TLC (petroleum ether/ethyl acetate, 3/1) showed the reaction was complete. The heating was stopped and the reaction mixture was cooled to room temperature. The solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1) to give 1.54g (15%) of the title compound as a yellow syrup. ESI-MS (M/e) 334[ M + H]+。
EXAMPLE 2 preparation of 1-carboxymethyl-3-carboxymethoxyethyl indole (2)
1.31g (3.9mmol) of 1-ethoxycarbonylmethyl-3-ethoxycarbonylmethoxyethyl-indole (1) are dissolved in 10mL of methanol in ice. To the resulting solution was added dropwise a 2N aqueous NaOH solution to adjust the pH of the solution to 12, and after stirring for 5 hours TLC (petroleum ether/ethyl acetate, 3/1) indicated that the reaction was complete. The reaction mixture was saturated with KHSO4Adjusting pH of the aqueous solution to 7, concentrating under reduced pressure, extracting the residue with 15mL ethyl acetate for 3 times, and collecting the water layer with saturated KHSO4The aqueous solution was adjusted to pH 4 and extracted 3 times with 15mL of ethyl acetate. The separated aqueous layer was continuously saturated with KHSO4Adjusting pH to 2 with water solution, extracting with 15mL ethyl acetate for 3 times, combining the separated ethyl acetate layers, washing with 15mL saturated aqueous NaCl solution for 3 times, and adding anhydrous Na2SO4Drying for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave 0.68g (62%) of the title compound as a yellow syrup. ESI-MS (M/e):276[ M-H]-；Mp 97-100℃；
IR(KBr,cm-1):3196, 3051,2892,1651,1469,1435,1175,1124,840,901,724；1H NMR(300MHz,DMSO-d6)δ/ppm ＝12.731(s,2H),7.549(d,J＝7.8Hz,1H),7.324(d,J＝6.9Hz,1H),7.172(s,1H),7.114(t,J ＝6.9Hz,1H),7.021(t,J＝6.9Hz,1H),4.937(s,2H),4.053(s,2H),3.725(t,J＝7.2Hz,2H), 2.947(t,J＝7.2Hz,2H)。
EXAMPLE 3 preparation of 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole (3)
A solution of 0.55g (2.0mmol) of 1-carboxymethyl-3-carboxymethoxyethyl indole (2), 0.54g (4.0mmol) of N-hydroxybenzotriazole and 10mL of anhydrous THF was stirred30 minutes, a reaction solution A was obtained. 0.82g (4.0mmol) of dicyclohexylcarbodiimide was dissolved in 5mL of anhydrous THF to obtain a reaction solution B. The reaction solution B was slowly added dropwise to the reaction solution A under ice-cooling, and stirred for 30 minutes. A solution of 2.20g (8.0mmol) HCl.Met-OBzl in 15mL dry THF was then added. The reaction mixture was adjusted to pH 9 with N-methylmorpholine and stirred at room temperature for 10 hours. TLC (CH)2Cl2/CH3OH, 30/1, plus 3 drops of acetic acid) showed the reaction was complete. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 30mL of ethyl acetate. The resulting solution was sequentially diluted with 20mL of saturated NaHCO3Washing with aqueous solution 3 times, washing with 20mL saturated NaCl aqueous solution 3 times, and washing with 20mL 5% KHSO4Washing with aqueous solution 3 times, washing with 20mL saturated NaCl aqueous solution 3 times, and washing with 20mL saturated NaHCO aqueous solution33 washes with aqueous solution and 3 washes with 20mL of saturated aqueous NaCl solution. Adding anhydrous Na into the ethyl acetate layer2SO4Drying for 12 hr, filtering, concentrating the filtrate under reduced pressure, and subjecting the residue to silica gel column Chromatography (CH)2Cl2/CH3OH, 30/1, plus 3 drops of acetic acid) to yield 0.35g (25%) of the title compound as a colorless powder. ESI-MS (M/e):720[ M + H]+；Mp 72-73℃；
IR(KBr,cm-1):3412,3327,3034,2916,1760,1748,1673,1517,1468, 1213,1165,1106,962,736,696；1H NMR(300MHz,DMSO-d6)δ/ppm＝8.736(d,J＝7.8Hz,1 H),8.066(d,J＝7.8Hz,1H),7.559(d,J＝7.5Hz,1H),7.355(m,10H),7.273(d,J＝8.1Hz,1 H),7.140(s,1H),7.076(t,J＝6.9Hz,1H),7.005(t,J＝6.9Hz,1H),5.130(m,4H),4.825(m, 2H),4.483(m,2H),3.963(s,2H),3.688(m,2H),2.971(t,J＝7.2Hz,2H),2.926(m,6H), 2.400(m,4H),1.990(m,10H)。
EXAMPLE 4 determination of the anti-metastatic Activity of Compound 3
The assay model was inoculated with Lewis mouse lung carcinoma cells (LLC, purchased from ATCC) in DMEM medium (containing 10% inactivated fetal bovine serum, 1X 10)5U/L penicillin and 100mg/L streptomycin), and the cells are enriched by passage every two days according to an adherent cell culture method. Digesting the cells when the cells are in good growth state and in logarithmic growth phase, and adjusting the cell density to 1 × 10 with physiological saline7one/mL. Staining with placental blue to count viable cells>95 percent. Inbred C57BL/6 male mice (SPF grade, body weight 20. + -.2 g) were taken and left-handed mice fixed. The right anterior limb axillary skin of the mouse was disinfected with 75% ethanol. The LLC tumor cell suspension is injected subcutaneously into the axilla of a mouse with a 1mL sterile syringe held in the right hand, and 0.2mL is injected into each mouse. After the mice are inoculated for 10 days, tumors with the diameter of about 4-5mm grow out, namely the tumor source. The Lewis lung cancer tumor-bearing mice are inoculated for 10 days and anesthetized by ether, and then the cervical vertebrae are removed for killing. Soaking in 75% ethanol for 10min, sterilizing, and removing tumor on clean bench. Well-grown tumor tissue was selected, minced in a sterile plate, and placed in a tissue homogenizer made of glass. Adding physiological saline with the temperature of 4 ℃ according to the ratio of the tumor mass to the volume of the physiological saline of 1 to 3(g to mL), and lightly grinding to prepare the cell suspension. The cell suspension is screened by 200-mesh cells to prepare single cell suspension. Adjusting the cell density of the single cell suspension to 1.5X 10 with physiological saline7one/mL. Staining with placental blue to count viable cells>95 percent. Left-handed inbred C57BL/6 male mice were fixed and their right anterior limb axillary skin was disinfected with 75% ethanol. The tumor cell suspension was injected subcutaneously into the mouse axilla with a 1mL sterile syringe in the right hand, 0.2mL each. 10 days after inoculation, the mice developed tumors of 4-5mm in diameter, and the inoculated mice were randomly grouped by the measured tumor volume. Each group had 12 mice. Mice on day 11 of tumor inoculation were orally administered either a 20 μmol/kg/day normal saline solution of the putative anti-tumor metastasis peptide Arg-Gly-Asp-ser (rgds) or a 0.02 μmol/kg/day normal saline solution of compound 3 or a 2 μmol/kg/day normal saline solution or an oral normal saline solution of compound 2 (10 mL/kg/day), 1 dose per day for 12 consecutive days, with tumor volumes measured and recorded every two days. The next day of the last administration, tumor volume was measured, cervical spine was removed by ether anesthesia and sacrificed, tumor of the mice was weighed, lung of the mice was taken and tumor nodules transferred from the lung of the tumor were counted. Statistical analysis of the data was performed using the t-test. The results are shown inTable 1. Compound 3 was not only effective in inhibiting tumor lung metastasis at 0.02 μmol/kg dose, but there was no significant difference in activity from compound 2 at 1000 times higher RGDS than it and at 100 times higher doses than them. These data indicate that the present invention has significant technical effects.
TABLE 1 antitumor metastatic Activity of Compound 3
a) P <0.01 to saline, p >0.05 to RGDS and Compound 2; n-10
EXAMPLE 5 determination of the anti-tumor growth Activity of Compound 3
Doxorubicin was dissolved in physiological saline before the measurement, and compound 2 and compound 3 were dissolved in physiological saline and evaluated using an S180 mouse model. Taking S180 ascites tumor liquid which is inoculated in a male ICR mouse and grows vigorously for 10 days in a sterile environment, diluting the S180 ascites tumor liquid into liquid (1:2) by using normal saline, fully mixing the liquid, dyeing the tumor cell suspension by using freshly prepared 0.2% trypan blue, uniformly mixing the liquid and the liquid, counting the liquid according to a white cell counting method, wherein the blue-dyed cell is a dead cell, and the non-dyed cell is a live cell. The cell concentration is 4-large-grid viable cell number/4 × 104The cell density was calculated as x dilution factor ═ cell number/mL, and the cell survival rate was calculated as live cell number/(live cell number + dead cell number) × 100%. Homogenizing tumor solution with survival rate of more than 90% to density of 2.0 × 107Cell suspension per mL. This cell suspension was inoculated subcutaneously (0.2 mL/mouse) in the right axilla of a mouse to prepare S180 tumor-bearing mice. 24h after inoculation, S180 tumor-bearing mice were intraperitoneally injected daily with a physiological saline solution of doxorubicin (at a dose of 2. mu. mol/kg/day g), or orally administered daily with a physiological saline solution of Compound 2 (at a dose of 5. mu. mol/kg/day), or orally administered daily with a physiological saline solution of Compound 3 (at a dose of 0.02. mu. mol/kg/day). The administration is once daily for 12 days. The day after the last dose, tumor volume was measured, cervical spine was removed under ether anesthesia and sacrificed, then the right axillary tumor growth site of the mouse was fixed with forceps, and the skin was excised and the tumor was blunt-stripped and weighed. The tumor weight (mean + -SD g) is used to express the curative effect,data were analyzed using t-test and variance. The results are shown in Table 2. Compound 3 was not only effective at 0.02 μmol/kg dose in inhibiting tumor growth, but also had no significant difference in activity from compound 2, which was 100-fold higher in dose. These data indicate that the present invention has significant technical effects.
TABLE 2 Effect of Compound 3 on tumor growth in S180 mice
a) P <0.01 to saline, p >0.05 to compound 2; n is 12.
EXAMPLE 6 determination of anti-inflammatory Activity of Compound 3
Since xylene-induced ear swelling in mice is recognized as an acute inflammation model, the present invention measures the therapeutic effect of compound 3 on a xylene-induced ear swelling model in mice. Because aspirin is a positive drug for treating acute inflammation, aspirin is selected as a positive control in the present invention. ICR male mice (body weight 20 ± 2g) were allowed to rest for 2 days at 22 ℃ with free access to water and food. Thereafter, 12 mice were randomly divided into a saline group (dose of 0.2 mL/mouse), an aspirin group (dose of 1.11mmol/kg), a compound 2 group (dose of 2. mu. mol/kg) and a compound 3 group (dose of 0.02. mu. mol/kg), each group. The mice were tested either orally with normal saline, orally with aspirin, orally with Compound 2, or orally with Compound 3, as indicated. After 30min of administration, the left auricle of the mouse was evenly smeared with 30 μ L of xylene, and after 2h, the mouse was subjected to ether anesthesia, the neck was cut off, the left and right ears were cut off, round ears were taken at the same positions of the two ears by a 7mm punch, and the difference in swelling between the two ears was weighed and found to be the swelling degree. Namely swelling degree, namely the weight of the right ear disk to the weight of the left ear disk. The results are shown in Table 3. Compound 3 was not only effective in inhibiting xylene-induced ear swelling in mice at the 0.02 μmol/kg dose, but also had no significant difference in activity from compound 2, which was 100-fold higher than the dose. These data indicate that the present invention has significant technical effects.
TABLE 3 Effect of Compound 3 on xylene-induced ear swelling in mice
a) P <0.01 to saline, p >0.05 to compound 2; n is 12.
Claims (5)
1.1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole of the formula,
2. a process for the preparation of 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole according to claim 1 which comprises:
1) indole ethanol and ethyl bromoacetate react in tetrahydrofuran at 80 ℃ under the catalysis of sodium hydride to generate 1-ethoxycarbonylmethyl-3-ethoxycarbonylmethoxyethyl-indole (compound 1);
2) saponifying the compound 1 in a 2N NaOH aqueous solution to obtain 1-carboxymethyl-3-carboxymethoxyethyl indole (compound 2);
3) the compound 2 reacts with Met-OBzl in anhydrous tetrahydrofuran in the presence of dicyclohexylcarbodiimide and N-hydroxybenzotriazole to generate 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole.
3. Use of the 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole according to claim 1 for the preparation of a medicament against tumor metastases.
4. Use of the 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole according to claim 1 for the preparation of an anti-ascites tumor medicament.
5. Use of the 1- (acetyl-Met-OBzl) -3- (ethoxyacetyl-Met-OBzl) indole according to claim 1 for the preparation of an anti-inflammatory medicament.
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| CN102146081A (en) * | 2010-02-09 | 2011-08-10 | 首都医科大学 | Indoleacetic acid derivatives and preparation method and application thereof |
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| CN105315332A (en) * | 2014-07-03 | 2016-02-10 | 首都医科大学 | CIPPC-AA-OBzl, and preparation, nano structure, activity and application thereof |
| CN106279357A (en) * | 2015-06-24 | 2017-01-04 | 首都医科大学 | Double [(acetyl-Lys (AA)-OBzl) indole] ethane, it prepares, activity and application |
| CN106349148A (en) * | 2015-07-13 | 2017-01-25 | 首都医科大学 | Novel indoles compound having anti-tumor metastasis activity and anti-inflammatory activity, as well as synthesis and application of novel indoles compound |
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| CN102146081A (en) * | 2010-02-09 | 2011-08-10 | 首都医科大学 | Indoleacetic acid derivatives and preparation method and application thereof |
| CN105218637A (en) * | 2014-06-11 | 2016-01-06 | 首都医科大学 | The indoles quinolizine that LPNISKP modifies, its preparation, nanostructure, active and application |
| CN105315332A (en) * | 2014-07-03 | 2016-02-10 | 首都医科大学 | CIPPC-AA-OBzl, and preparation, nano structure, activity and application thereof |
| CN106279357A (en) * | 2015-06-24 | 2017-01-04 | 首都医科大学 | Double [(acetyl-Lys (AA)-OBzl) indole] ethane, it prepares, activity and application |
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