CN109912590B - Amino acid and amino n-hexanoic acid modified carboline benzyl carboxylate, and preparation, activity and application thereof - Google Patents
Amino acid and amino n-hexanoic acid modified carboline benzyl carboxylate, and preparation, activity and application thereof Download PDFInfo
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- CN109912590B CN109912590B CN201711316809.5A CN201711316809A CN109912590B CN 109912590 B CN109912590 B CN 109912590B CN 201711316809 A CN201711316809 A CN 201711316809A CN 109912590 B CN109912590 B CN 109912590B
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- carboline
- tetrahydro
- hexanoyl
- benzyl ester
- carboxylic acid
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Abstract
The invention discloses (3S) -N- (6-amino acylamino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxyl with the following structureBenzyl acid ester (wherein AA is selected from the group consisting of L-Phe, L-Gly, L-Ile, L-Val and L-Tyr residues). Discloses a preparation method and an anti-tumor effect thereof, and illustrates the application of the compounds in preparing medicaments with the anti-tumor effect.
Description
Technical Field
The invention relates to (3S) -N- (6-amino acylamino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate with the following structure (AA is selected from L-Phe, L-Gly, L-Ile, L-Val and L-Tyr residues), a preparation method thereof, an anti-tumor effect thereof, and application thereof in preparing medicaments with the anti-tumor effect, belonging to the field of biological medicine.
Technical Field
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. The inventor's prior invention (patent application publication No. CN 106349148A, application No. CN201510409682.6) has disclosed that amino acid benzyl ester substituted bisindole acetic acid alcohol has triple effects of anti-tumor, anti-tumor metastasis and anti-inflammatory at 0.2 mu mol/kg (left formula). The minimum effective dose of benzyl bisindoloethanol amino acid to exert an antitumor effect by the inventors was unsatisfactory at 0.2. mu. mol/kg. The dosage is higher. Over the past two years, the inventors have been searching for compounds with an anti-tumour effect at a minimum effective dose of less than 0.2. mu. mol/kg. Finally, the inventor finds that the 6-amino amido caproic acid modified tetrahydro carboline benzyl carboxylate has an anti-tumor effect at an oral 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. Thus, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention provides benzyl (3S) -N- (6-aminoacyl-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate of the following structure (wherein AA is selected from the group consisting of L-Phe, L-Gly, L-Ile, L-Val and L-Tyr residues).
The second aspect of the present invention provides a process for preparing benzyl (3S) -N- (6-aminoacylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, which comprises:
(1) under the catalysis of dilute sulfuric acid, performing Pictet-Spengler reaction on L-tryptophan benzyl ester and formaldehyde to generate (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(2) 6-aminocaproic acid and di-tert-butyl dicarbonate (Boc) in aqueous sodium hydroxide (2M), mixed solution of water and dioxane2O reaction to produce 6-tert-butyloxycarbonylaminohexanoic acid;
(3) reacting 6-tert-butoxycarbonylamino caproic acid with (3S) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate in anhydrous tetrahydrofuran in the presence of N, N-dicyclohexylcarbodiimide and N-hydroxybenzotriazole to obtain (3S) -N- (6-tert-butoxycarbonylamino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate;
(4) removing Boc from (3S) -N- (6-tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in hydrogen chloride ethyl acetate solution under ice bath to obtain (3S) -N- (6-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(5) reacting (3S) -N- (6-amino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester with Boc-AA (wherein AA is selected from L-Phe, L-Gly, L-Ile, L-Val and L-Tyr) in dry tetrahydrofuran in the presence of N, N-dicyclohexylcarbodiimide and N-hydroxybenzotriazole to obtain (3S) -N- (6-tert-butoxycarbonylamino acylamino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(6) removing Boc from (3S) -N- (6-tert-butoxycarbonylamino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in hydrogen chloride ethyl acetate solution under ice bath to obtain (3S) -N- (6-amino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester.
The third aspect of the present invention is to evaluate the inhibition of tumor growth in S180 mice by (3S) -N- (6-aminoacyl-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester.
Drawings
FIG. 1A synthetic route for (3S) -N- (6-Aminoacylamido-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester i) HCHO, H2O,H2SO4(ii) a ii) N, N-Dicyclohexylcarbodiimide (DCC), N-hydroxybenzotriazole (HOBt), N-methylmorpholine, tetrahydrofuran; iii) dioxane, aqueous sodium hydroxide solution, di-tert-butyl dicarbonate (Boc)2O; iv) a solution of hydrogen chloride in ethyl acetate (4M).
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 benzyl (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (1)
To 300mL of water under ice bath was slowly added 1.5mL of concentrated H2SO4And stirring for 3 min. Thereafter 5.00g (15.1mmol) L-tryptophan benzyl ester hydrochloride and 6mL formaldehyde solution (40%) were added. After stirring at room temperature for 72h, TLC showed disappearance of L-tryptophan benzyl ester hydrochloride. The reaction solution was adjusted to pH 7 with concentrated ammonia water in an ice bath and filtered. The filter cake was dissolved in 100mL of ethyl acetate, and the resulting solution was washed with a saturated aqueous solution of sodium chloride (40 mL. times.3), followed by drying over anhydrous sodium sulfate. Filtering, and concentrating the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 90:1) to give 1.9g (41%) of the title compound as yellowAn oily solid. ESI-MS (m/e): 307[ M + H]+。
EXAMPLE 2 preparation of 6-tert-Butoxycarbonylaminohexanoic acid (2)
5.00g (38.2mmol) 6-aminocaproic acid (EACA) were suspended in 50mL distilled water. The resulting suspension was added with 10mL of aqueous sodium hydroxide (2M) under ice-bath and stirred until dissolved. To the resulting solution was added 9.2g (42.2 mmol) (Boc)2A solution of O and 20mL dioxane was adjusted to pH 9 with aqueous sodium hydroxide (2M) and stirred for 30 min. The ice bath was removed and stirred at room temperature until TLC showed disappearance of 6-aminocaproic acid. The reaction solution was saturated KHSO in ice bath4The pH of the aqueous solution was adjusted to 7 and the dioxane was removed by concentration under reduced pressure. The reaction solution was saturated KHSO in ice bath4The pH of the aqueous solution was adjusted to 2, and the mixture was extracted with ethyl acetate (50 mL. times.3). The ethyl acetate layer was then washed with saturated aqueous NaCl solution (40 mL. times.3), and was dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate under reduced pressure gave 8.0g (91%) of the title compound as a colorless oil. ESI-MS (m/e): 232[ M + H ]]+。
EXAMPLE 3 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (3)
Dissolving 4.15g (18mmol) of tert-butoxycarbonyl-6-aminocaproic acid in 80mL of anhydrous tetrahydrofuran, adding 2.46g (18.2mmol) of N-hydroxybenzotriazole (HOBt) and 4.04g (19.6mmol) of N, N-Dicyclohexylcarbodiimide (DCC) under ice bath, stirring for 60 min, adding a solution of 5.06g (16.5mmol) of (3S) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate and 80mL of anhydrous tetrahydrofuran to the obtained reaction solution, adjusting pH of the reaction mixture to 9 with N-methylmorpholine (NMM) under ice bath, stirring at room temperature for 24 h, TLC (3S) -2,3,4, 9-tetrahydro- β -carboline-3-benzyl carboxylate disappearance, filtering the filtrate, concentrating the filtrate under reduced pressure, adding ethyl acetate to the residue to dissolve the solution, and sequentially dissolving the saturated NaHCO in saturated NaHCO solution3Washing with an aqueous solution (40 mL. times.3), washing with a saturated aqueous NaCl solution (40 mL. times.3), and saturating KHSO4Aqueous solution (40 mL. times.3), saturated aqueous NaCl solution (40 mL. times.3), saturated aqueous NaHCO solution3The resulting mixture was washed with an aqueous solution (40 mL. times.3) and with a saturated aqueous NaCl solution (40 mL. times.3). Anhydrous Na for ethyl acetate layer2SO4Drying, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column chromatography (dichloromethane: methanol ═ methanol)160:1) 5.43g (64%) of the expected compound are obtained as a yellow oily solid. ESI-MS (m/e): 520 [ M + H ]]+。
EXAMPLE 4 preparation of benzyl (3S) -N- (6-amino-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (4)
3.4g (6.6mmol) of benzyl (3S) -N- (tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate were dissolved in 40mL of hydrogen chloride in ethyl acetate (4M) under ice-bath, stirred for 3 hours, TLC showed disappearance of benzyl (3S) -N- (tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, the reaction mixture was concentrated to dryness under reduced pressure with stirring, the residue was dissolved in anhydrous ethyl acetate, the solution was concentrated to dryness under reduced pressure, the operation was repeated three times, the residue was washed well with anhydrous ether to give 2.8g (94%) of the title compound as a tan solid, ESI-MS (M/e):420[ M + H ] (M + H): 420]+；Mp 223-226℃。1H NMR(300MHz,DMSO-d6:δ/ppm＝10.963(d,J＝11.4Hz,1H),7.894(s,3H),7.458(d,J＝7.5Hz,1H),7.327(t,J＝7.5Hz,1H),7.204(dd,J1＝1.5Hz,J2＝7.2Hz,1H), 7.158-6.972(m,6H),5.607(d,J＝4.7Hz,1H),5.059(s,2H),4767(d,J＝15.6Hz,1H),4.610(d, J＝17.4Hz,1H),3.426(m,1H),3.021(m,1H),2.754(m,2H),2.613(m,1H),2.389(m,1H), 1.568-1.546(m,4H),1.399-1.323(m,2H)。
EXAMPLE 5 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylphenylalanylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5a)
Dissolving 1.60g (6.0mmol) of Boc-Phe and 0.82g (6.1mmol) of N-hydroxybenzotriazole (HOBt) in 30mL of anhydrous tetrahydrofuran, adding 1.36g (6.6mmol) of N, N-Dicyclohexylcarbodiimide (DCC) under ice bath, stirring for 40 minutes, adding a solution of 2.50g (5.5mmol) of (3S) -N- (6-amino-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester and 30mL of anhydrous tetrahydrofuran to the obtained reaction solution, adjusting pH to 8 with N-methylmorpholine (NMM) under ice bath, stirring at room temperature for 12 hours, TLC showing that (3S) -N- (6-amino-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester, filtering the reaction solution, concentrating the filtrate under reduced pressure, adding 100mL of ethyl acetate to dissolve the residue, and sequentially using saturated NaHCO3Aqueous solution (40 mL. times.3), saturated NaCl aqueous solution (40 mL. times.3), and saturatedKHSO4Aqueous solution (40 mL. times.3), saturated aqueous NaCl solution (40 mL. times.3), saturated aqueous NaHCO solution3The resulting mixture was washed with an aqueous solution (40 mL. times.3) and with a saturated aqueous NaCl solution (40 mL. times.3). Anhydrous Na for ethyl acetate layer2SO4Drying, filtration, concentration of the filtrate under reduced pressure and purification of the residue by silica gel column chromatography (dichloromethane: methanol ═ 60:1) gave 2.21g (61%) of the title compound as a pale yellow solid. ESI-MS (M/z):667[ M + H]+。
EXAMPLE 6 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylglycylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5b)
According to the method of example 5, from 2.20g (4.8mmol) of benzyl (3S) -N- (6-aminon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 0.93g (5.3mmol) of Boc-Gly, 0.83g (30%) of the title compound was obtained as a light yellow solid ESI-MS (M/z):577[ M + H: (M/z):577]+。
EXAMPLE 7 preparation of benzyl (3S) -N- (tert-butoxycarbonylisoleucyl-aminoamido-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5c)
Following the procedure of example 5, from 2.60g (5.7mmol) of benzyl (3S) -N- (6-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 1.45g (6.3mmol) of Boc-Ile, 1.19g (33%) of the title compound was obtained as a light yellow solid ESI-MS (M/z):633[ M + H ]: 633]+。
EXAMPLE 8 preparation of benzyl (3S) -N- (6-tert-butoxycarbonylvalylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5d)
Following the procedure of example 5, from 3.5g (7.7mmol) of benzyl (3S) -N- (6-aminon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 1.83g (8.4mmol) of Boc-Val 2.52g (53%) of the title compound were obtained as a light yellow solid ESI-MS (M/z):619[ M + H)]+。
EXAMPLE 9 preparation of benzyl (3S) -N- (6-tert-butoxycarbonyltyrosylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (5e)
Following the procedure of example 5, from 2.7g (5.9mmol) of benzyl (3S) -N- (6-aminon-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate and 1.83g (6.5mmol) of Boc-Tyr, 1.40g (35%) of the title compound was obtained as a pale yellow solid ESI-MS (M/z):683[ M + H): 683]+。
EXAMPLE 10 preparation of benzyl (3S) -N- (6-phenylalanylamino-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6a)
1020mg of (3S) -N- (6-tert-butoxycarbonylphenylalanyl-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester were added in an ice bath to 16mL of a solution of hydrogen chloride in ethyl acetate (4M) and stirred for 2h, TLC (ethyl acetate: water: glacial acetic acid ═ 3: 1: 1.2) showed disappearance of (3S) -N- (di-tert-butoxycarbonyllysylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester, the reaction solution was concentrated under reduced pressure to dryness, the residue was dissolved in anhydrous ethyl acetate and then concentrated under reduced pressure to dryness18Column chromatography purification (methanol: water ═ 30:70) and lyophilization gave 670mg (77%) of the title compound as a pale yellow solid. ESI-MS (M/e):567[ M + H]+；Mp 122-123 ℃；1H NMR(300MHz,DMSO-d6:δ/ppm＝11.020(d,J＝19.2Hz,1H),8.511(m,1H),8.353 (s,3H),7.457(d,J＝7.5Hz,1H),7.362-7.184(m,6H),7.155-7.074(m,7H),5.603(d,J＝4.8 Hz,1H),5.058(s,2H),4773(d,J＝15.6Hz,1H),4.635(d,J＝17.4Hz,1H),3.973(dd,J1＝5.4 Hz,J2＝12.0Hz 1H),3.456(m,1H),3.147-2.875(m,5H),2.575(m,1H),2.368(m,1H),1.486 (m,2H),1.295(m,2H),1.169(m,2H)。
EXAMPLE 11 preparation of benzyl (3S) -N- (6-glycylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6b)
Following the procedure of example 10, from 1000mg of benzyl (3S) -N- (6-tert-butoxycarbonylglycylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, 670mg (81%) of the title compound was obtained as a pale yellow solid ESI-MS (M/e):477 [ M + H ] ESI]+.Mp 112-113℃；1H NMR(300MHz,DMSO-d6:δ/ppm＝10.995(d,J＝14.4Hz,1H),8.465(m,1H),8.150(s,3H),7.455(d,J＝7.8Hz,1H),7.330(t,J＝7.8Hz,1H),7.204(dd,J1＝2.1Hz,J2＝7.5Hz,1H),7.162-7.073(m,6H),5.602(d,J＝4.5Hz,1H),5.059(s,2H),4771 (d,J＝15.6Hz,1H),4.632(d,J＝17.4Hz,1H),3.516(s,2H),3.450(m,1H),3.128-2.917(m, 3H),2.578(m,1H),2.423(m,1H),1.554(m,2H),1.450(m,2H),1.344(m,2H)。
EXAMPLE 12 preparation of benzyl (3S) -N- (6-isoleucylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6c)
Following the procedure of example 10, from 840mg of benzyl (3S) -N- (6-tert-butoxycarbonylisoleucylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate, 560mg (79%) of the title compound were obtained as a pale yellow solid ESI-MS (M/e):533 [ M + H ] 533]+.Mp 121-122℃；1H NMR(300MHz,DMSO-d6:δ/ppm＝10.997(d,J＝13.2Hz,1H), 8.541(m,1H),8.240(s,3H),7.454(d,J＝7.5Hz,1H),7.329(t,J＝7.8Hz,1H),7.205(dd, J1＝2.1Hz,J2＝5.7Hz,1H),7.162-7.104(m,6H),5.602(d,J＝4.8Hz,1H),5.058(s,2H),4769 (d,J＝15.6Hz,1H),4.637(d,J＝17.4Hz,1H),3.586(m,1H),3.422(m,1H),3.196(m,1H), 3.028(m,1H),2.566(m,1H),2.417(m,1H),1.815(m,1H),1.592-1.310(m,6H),1.113(m, 2H),0.911-0.840(m,6H)。
EXAMPLE 13 preparation of benzyl (3S) -N- (6-valylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6d)
Following the procedure of example 10, from 1000mg of benzyl (3S) -N- (6-tert-butoxycarbonylvalylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate 460mg (55%) of the title compound was obtained as a pale yellow solid ESI-MS (M/e):519 [ M + H ] 519]+.Mp 132-134℃；1H NMR(300MHz,DMSO-d6:δ/ppm＝10.977(d,J＝10.8Hz,1H),8.527(m,1H),8.186(s,3H),7.457(d,J＝7.8Hz,1H),7.328(d,J＝7.5Hz,1H),7.210-6.971(m, 7H),5.604(d,J＝4.9Hz,1H),5.057(s,2H),4765(d,J＝15.8Hz,1H),4.628(d,J＝17.1Hz, 1H),3.526(d,J＝3Hz,1H),3.448(m,1H),3.211(m,1H),3.049-2.932(m,2H),2.584(m,1H), 2.419(m,1H),2.062(m,1H),1.565-1.335(m,6H),0.928(d,J＝6.6Hz,6H)。
EXAMPLE 14 preparation of benzyl (3S) -N- (6-tyrosylamino-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate (6e)
Following the procedure of example 10, from 1080mg of (3S) -N- (6-tert-butoxycarbonyltyrosylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester 630mg (68%) of the title compound were obtained as a pale yellow solid ESI-MS (M/e):583 [ M + H ] ESI-MS (M/e)]+.Mp 136-137℃；1H NMR(300MHz,DMSO-d6:δ/ppm＝10.983(d,J＝16.2Hz,1H),9.424(d,J＝2.1Hz,1H),8.421(m,1H),8.237(s,3H),7.456(d,J＝7.8Hz,1H),7.330(t,J＝7.8 Hz,1H),7.199(dd,J1＝1.5Hz,J2＝7.2Hz,1H),7.154-6.972(m,8H),6.732(d,J＝2.4Hz,1H), 6.704(d,J＝2.1Hz,1H),5.601(d,J＝4.5Hz,1H),5.056(s,2H),4.776(d,J＝15.6Hz,1H), 4.631(d,J＝17.4Hz,1H),3.852(m,1H),3.455(m,1H),3.143-2.896(m,5H),2.562(m,1H), 2.405(m,1H),1.509(m,2H),1.337(m,2H),1.212(m,2H)。
Experimental example 1 evaluation of antitumor Activity of Compounds 6a-e
1) The compounds 6a-e were dissolved in physiological saline, doxorubicin was dissolved in physiological saline as a positive control, and physiological saline as a negative control;
2) the oral dose of the compounds 6a-e is 0.02 mu mol/kg, the oral dose of the compound 4 is 0.2 mu mol/kg, the oral dose of physiological saline is 0.2mL/20g, and the intraperitoneal injection dose of adriamycin is 2 mu mol/kg. The administration was started 5 days after tumor inoculation and continued for 10 days for a total of 10 administrations.
3) The experimental animals were ICR male mice (clean grade) weighing 20 + -2 g, 12 mice per group.
4) The tumor source is mouse S180 sarcoma purchased from animal experiment center of department of medicine of Beijing university and maintained by self passage.
5) Inoculating S180 ascites tumor liquid which grows vigorously under aseptic condition, diluting the liquid into liquid (1:2) by using normal saline, fully mixing, staining tumor cell suspension by using freshly prepared 0.2% trypan blue, uniformly mixing, counting according to a white cell counting method, wherein the blue stained cells are dead cells, and the non-stained cells are live cells. The cell concentration is 4-large-grid viable cell number/4 × 104The cell concentration was calculated by x dilution factor ═ cell number/mL. The cell survival rate was calculated as the number of live cells/(number of live cells + number of dead cells) × 100%.
Preparing tumor solution with survival rate of more than 90% into 2.0 × 10 by homogenizing method7One cell/mL of the cell suspension was inoculated subcutaneously to the mouse axilla, and 0.2 mL/mouse was prepared as S180 tumor-bearing mice. Tumor inoculation was administered 5 days later. The mice in the treatment group were dosed orally with compound 4 at 0.2. mu. mol/kg or compound 6a-e at 0.02. mu. mol/kg per day. The daily oral physiological saline dose of the blank group of mice is 0.2mL/20 g. Positive control group is smallThe daily dose of the intraperitoneal injection adriamycin in the mice is 2 mu mol/kg. The administration was continued for ten days, and on the eleventh day, the mice were weighed, anesthetized with ether, sacrificed by removing the cervical vertebrae, then the right axillary tumor growth sites of the mice were fixed with forceps, the skin was cut open, the tumors were exposed, blunt-stripped, and weighed. Experimental data were expressed as (mean ± SD g) tumor weights using t-test and analysis of variance. The results are shown in Table 1. As can be seen from Table 1, compounds 6a-e were effective in inhibiting tumor regrowth in mice at an oral dose of 0.02 μmol/kg. The invention has obvious technical effect.
TABLE 1 antitumor Activity of Compounds 6a-e
a) P <0.05 in the saline group; b) p <0.01 to saline group; n is 12.
Claims (3)
1.(3S) -N- (6-aminoacyl-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester compound with the following structure,
wherein AA is selected from L-Phe or L-Gly or L-Ile or L-Val or L-Tyr residue.
2. A process for preparing a benzyl (3S) -N- (6-aminoacylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate compound of the structure of claim 1, which comprises the steps of:
(1) under the catalysis of dilute sulfuric acid, performing Pictet-Spengler reaction on L-tryptophan benzyl ester and formaldehyde to generate (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(2) 6-aminocaproic acid and di-tert-butyl dicarbonate (Boc) in a 2M aqueous solution of sodium hydroxide, a mixed solution of water and dioxane2O reaction to produce 6-tert-butyloxycarbonylaminohexanoic acid;
(3) reacting 6-tert-butoxycarbonylaminocaproic acid with (3S) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in anhydrous tetrahydrofuran in the presence of N, N-Dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole (HOBt) to obtain (3S) -N- (6-tert-butoxycarbonylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(4) removing Boc from (3S) -N- (6-tert-butoxycarbonylamino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in 4M hydrogen chloride ethyl acetate solution under ice bath to obtain (3S) -N- (6-amino N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester;
(5) reacting (3S) -N- (6-amino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester with Boc-AA in the presence of N, N-Dicyclohexylcarbodiimide (DCC) and N-hydroxybenzotriazole (HOBt) in dry Tetrahydrofuran (THF) to obtain (3S) -N- (6-tert-butoxycarbonylaminoacylamido-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester, wherein AA is selected from L-Phe or L-Gly or L-Ile or L-Val or L-Tyr residue;
(6) removing Boc from (3S) -N- (6-tert-butoxycarbonylamino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester in 4M hydrogen chloride ethyl acetate solution under ice bath to obtain (3S) -N- (6-amino-acylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester.
3. The use of a (3S) -N- (6-aminoacylamino-N-hexanoyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid benzyl ester compound of the structure of claim 1 in the preparation of an anti-tumor medicament.
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