CN111574582A - Tripterine derivative and preparation method and application thereof - Google Patents
Tripterine derivative and preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a tripterine derivative shown in a formula (I), and a preparation method thereof is as follows: dissolving tripterine (II) in methanol, adjusting pH to 1-2, and stirring at room temperature for 8-16h to obtain a reaction solution containing an intermediate (III); adding amino acid (IV) into the reaction solution, adjusting the pH value to 7-8, stirring and reacting for 8-16h at room temperature, and then carrying out aftertreatment on the reaction solution to obtain a product shown in the formula (I); the tripterine derivative can be applied to preparing antitumor drugs.
Description
Technical Field
The invention relates to a tripterine derivative, a preparation method thereof and application thereof in preparing antitumor drugs.
Background
The natural products are important sources for preventing and treating diseases of human beings, about 30 percent of chemical drugs on the market are from the natural products, and part of the drugs are generated by structural modification and structural modification of the natural products serving as lead compounds. Celastrol (Celastrol), also known as Celastrol, is a natural product with multiple bioactivities, is derived from the root bark of Tripterygium wilfordii hook F, and is a red crystal powder of triterpenes. Tripterine has a certain clinical application prospect as a natural product with multiple activities, but has large toxicity and low bioavailability, so the application of the tripterine is limited. Among the activities of tripterine, the antitumor activity is the most significant, and exceeds some common antitumor drugs in clinic. In the structure modification research, the main idea is to form ester bonds and amido bonds on 29-site carboxyl groups, but the antitumor activity of the tripterine is not obviously improved, and the current situation of insufficient drug properties of the tripterine is not changed.
As early as the 60's of the 20 th century, pharmacologists discovered that tripterine had strong antitumor effects. In 2006, research on anticancer of tripterygium wilfordii, a traditional Chinese medicine, was carried out by cooperation of Wuhan plantations and American scientists at Chinese academy of sciences, and in vivo and in vitro anticancer mechanism research proves that the anticancer active ingredient tripterine in tripterygium wilfordii induces apoptosis of cancer cells by controlling proteasomes of the cancer cells, and can effectively inhibit hyperplasia of prostate cancer in nude mice.
Chinese patent publication No. CN1276209 discloses an application of an extract of centella plant in preventing and treating nervous system diseases, including alzheimer's disease, parkinson's disease, huntington's neurodegenerative disease, spinal cord injury, and lateral sclerosis of spinal cord. The Chinese patent application with the publication number of CN101091713A discloses a tripterine capsule for preventing and treating nerve injury diseases, a preparation method and a use method thereof, wherein the tripterine is used as a main raw material to be compounded with trehalose to be prepared into the capsule for treating the nerve injury diseases. USA patent with application No. 20040220267, "derivatives of pentacyclic demethylated triterpenoid ketone for inflammation, nerve injury and tumor diseases", discloses the use of tripterine and pristimerin derivatives, such as their dihydrogen and acetylate of dihydrogen, for treating inflammation, nerve injury and tumor diseases, and the preparation method of the derivatives. Chinese patent application No. CN201010150428.6 discloses the use of tripterine derivatives as anti-inflammatory, anticancer and central nervous system disease treating drugs.
At present, the research of patents at home and abroad is mainly to form ester bonds and amido bonds on 29-site carboxyl of the tripterine, but the antitumor activity of the tripterine is not obviously improved, and the current situation of insufficient drug properties of the tripterine is not changed.
Disclosure of Invention
The invention discloses a tripterine derivative, a preparation method thereof and application thereof in preparing antitumor drugs.
The technical scheme of the invention is as follows:
a tripterine derivative has a structure shown in formula (I):
in the formula (I), R is hydrogen or C1-C8Alkyl or C substituted by one or more substituents1-C8Alkyl, each of said substituents being independently selected from: fluorine, chlorine, hydroxyl, hydroxymethyl, nitrile group, C1-C6Alkylthio radical, C1-C8Alkoxy radical, C1-C8Amide group, C6-C14Aryl radical, C6-C14An aromatic heterocyclic group, a five-membered heterocyclic ring or a six-membered heterocyclic ring;
preferably, R is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, methyl thiolethyl, 3-methylidene indolyl, 4-methylidene imidazolyl, n-propionamido, p-hydroxyphenylmethyl or benzyl.
Particularly preferred tripterine derivatives of the invention are the compounds shown in examples 3 a-3 k.
Unless otherwise indicated, the terms used in the present invention have the following definitions:
"alkyl" means a saturated or unsaturated, substituted or unsubstituted, straight or branched alkane chain, such as in particular: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 2-methylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 2-trimethylpropyl, 1,2, 2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl.
"aryl" represents an aromatic hydrocarbon group, preferably an aryl group of 6 to 14 carbon atoms, and specifically includes, for example: phenyl, tolyl, xylyl, biphenyl, naphthyl, indenyl, anthryl, phenanthryl, more preferably phenyl or naphthyl, most preferably phenyl.
"aromatic heterocyclic group" means a heteroaryl group containing 1 to 4 oxygen atoms, nitrogen atoms or sulfur atoms, and specifically for example: furyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazolyl, tetrazolyl.
"five-or six-membered heterocyclic ring" means a heterocyclic group containing 1 to 4 oxygen atoms, sulfur atoms or nitrogen atoms, and specifically for example: morpholinyl, piperazinyl, substituted piperazinyl, pyrrolidinyl, piperidinyl.
The invention provides a preparation method of a tripterine derivative shown as a formula (I), which comprises the following steps:
dissolving tripterine (II) in methanol, adjusting pH to 1-2 (adjusting with hydrochloric acid with pH of 1), and stirring at room temperature (20-30 deg.C) for 8-16h (TLC tracking monitoring) to obtain reaction solution containing intermediate (III); adding amino acid (IV) into the reaction solution, adjusting the pH to 7-8 (adjusting with sodium carbonate), stirring and reacting for 8-16h at room temperature (TLC tracking monitoring), and then carrying out aftertreatment on the reaction solution to obtain a product shown in the formula (I);
the volume dosage of the methanol is 30-50mL/mmol based on the amount of the tripterine (II);
the mass ratio of the tripterine (II) to the amino acid (IV) is 1: 2-3;
the amino acid (IV) may be a D-type or L-type amino acid, and the pH of the reaction mixture is adjusted to about 8 with sodium carbonate after the addition of a basic amino acid, to about 7 to 8 with sodium carbonate after the addition of a neutral or acidic amino acid; r in formula (IV) is as defined for formula (I);
the post-treatment method comprises the following steps: after the reaction is finished, adjusting the pH value of the reaction solution to be 7, extracting with ethyl acetate, washing the extract with saturated saline solution, drying with anhydrous sodium sulfate, performing suction filtration, and concentrating the filtrate to be dry to obtain a crude product; and (3) separating the obtained crude product by silica gel column chromatography, wherein the volume ratio is 6:1 or a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 30:1, collecting eluent containing the target compound, evaporating the solvent under reduced pressure, and drying to obtain the product tripterine derivative (I).
The tripterine derivative shown in the formula (I) can be used for preparing antitumor drugs.
Specifically, the medicine is a pharmaceutical composition of the tripterine derivative, a pharmaceutically acceptable solid or liquid carrier, and pharmaceutically acceptable auxiliary agents and excipients.
The pharmaceutical compositions may be prepared using standard and conventional techniques, for example: the tripterine derivative is combined with a solid or liquid carrier acceptable in pharmaceutics, and is optionally combined with auxiliary agents and excipients acceptable in pharmaceutics to prepare particles or microspheres. The solid dosage forms include tablets, dispersible granules, capsules, sustained-release tablets, sustained-release pellets and the like. A solid carrier can be at least one substance that can act as a diluent, flavoring agent, solubilizing agent, lubricant, suspending agent, binder, disintegrant, and encapsulating agent. Inert solid carriers include magnesium phosphate, magnesium stearate, lactose, pectin, propylene glycol, polysorbate 80, dextrin, starch, gelatin, cellulosic materials (e.g., methyl cellulose, microcrystalline cellulose), low melting paraffins, polyethylene glycols, mannitol, cocoa butter, and the like. Liquid dosage forms include solvents, suspensions, such as injections, powders, and the like.
The amount of the active ingredient (compound of the present invention) contained in the pharmaceutical composition and unit dosage form may be specifically applied depending on the condition of the patient and the condition diagnosed by the doctor, and the amount or concentration of the compound used is adjusted within a wide range, and generally, the active compound is contained in an amount of 0.5 to 90 wt%, preferably 0.5 to 70 wt%, based on the total weight of the pharmaceutical composition.
Compared with the prior art, the invention has the beneficial effects that:
according to the structure-activity relationship of the tripterine derivative in the aspect of antitumor activity, the 2-position and 3-position rings of the tripterine are synthesized into an oxazole ring structure through structure modification, so that the water solubility of the tripterine derivative is increased, the cytotoxic activity of the tripterine derivative is reduced, the antitumor activity of the prepared tripterine derivative is superior to that of a positive control medicament cisplatin, and the antitumor activity of part of the tripterine derivative is superior to that of the tripterine derivative, so that the tripterine derivative can be used for developing antitumor medicaments.
Detailed Description
The present invention is further illustrated by the following specific examples, but the scope of the invention is not limited thereto.
Example 1: synthesis of tripterine derivative Ia
Methanol (4mL) and tripterine (45.0mg,0.1mmol) were added to a 25mL two-necked flask, and hydrochloric acid (1mL) having a pH of 1 was added thereto with stirring at room temperature, and the pH of the reaction solution was 1-2. Reacting for 12 hours under stirring at room temperature, adding glycine (15.0mg,0.2mmol), adding sodium carbonate to adjust the pH to about 8, continuing to react for 8 hours, detecting by TLC, adding water (5mL) after the reaction is finished, stirring to dissolve the sodium carbonate solid, adding hydrochloric acid to adjust the pH of the reaction solution to about 7, extracting for three times by ethyl acetate (10mL), combining organic phases, washing for 2 times by saturated saline solution, drying by anhydrous magnesium sulfate, then carrying out suction filtration, and concentrating the filtrate to dryness to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: ethyl acetate: 6:1), and the product was vacuum dried to give a white tripterine derivative Ia in 12.7mg, 27.6% yield.
The spectrum analysis of the tripterine derivative Ia is as follows:
1H NMR(500MHz，CD3COCD3)8.36(s,1H,1’-H),7.48(s,1H,H-1),6.72(d,J＝10.0Hz,1H,H-6),6.49(d,J＝10.0Hz,1H,H-7),5.72(dd,J＝6.75,1.73Hz,1H,H-11),2.47(s,3H,4-CH3),1.23(s,3H,9-CH3),1.12(s,3H,20-CH3),1.11(s,3H,17-CH3),1.04(s,3H,14-CH3),1.03(s,3H,13-CH3),MS(ESI)m/z458.3(M-H)-.
example 2: synthesis of tripterine derivative Ib
Methanol (4mL) and tripterine (45.0mg,0.1mmol) were added to a 25mL two-necked flask, and hydrochloric acid (1mL) having a pH of 1 was added thereto under stirring at room temperature, and the pH of the reaction solution was about 1-2. The reaction was carried out at room temperature for 12 hours with stirring, alanine (17.8mg,0.2mmol) was added, sodium carbonate was added to adjust the pH to about 8, the reaction was continued for 8 hours, TLC detection was carried out, after the reaction was completed, water (5mL) was added, the sodium carbonate solid was dissolved with stirring, hydrochloric acid was added to adjust the pH of the reaction solution to about 7, extraction was carried out three times with ethyl acetate (10mL), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, followed by suction filtration, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: ethyl acetate: 6:1), and the product was vacuum dried to give a yellow tripterine derivative Ib of 42.9mg, in 90.7% yield.
The spectrum analysis of the tripterine derivative Ib is as follows:
1H NMR(500MHz，CD3COCD3)7.34(s,1H,H-1),6.66(d,J＝10.0Hz,1H,H-6),6.45(d,J＝10.0Hz,1H,H-7),5.68(dd,J＝6.50,1.50Hz,1H,H-11),2.59(s,3H,1’-CH3),2.41(s,3H,4-CH3),1.24(s,3H,9-CH3),1.11(s,6H,20,17-CH3),1.04(s,3H,14-CH3),1.03(s,3H,13-CH3),MS(ESI)m/z 472.3(M-H)-.
example 3: synthesis of tripterine derivative Ic
Methanol (4mL) and tripterine (45.0mg,0.1mmol) were added to a 25mL two-necked flask, and hydrochloric acid (1mL) having a pH of 1 was added thereto under stirring at room temperature, and the pH of the reaction solution was about 1-2. Reacting for 12 hours under stirring at room temperature, adding valine (23.4mg,0.2mmol), adding sodium carbonate to adjust the pH to about 7, continuing to react for 8 hours, detecting by TLC, adding water (5mL) after the reaction is finished, stirring to dissolve the sodium carbonate solid, adding hydrochloric acid to adjust the pH of the reaction solution to about 7, extracting with ethyl acetate (10mL) for three times, combining organic phases, washing with saturated saline solution for 2 times, drying with anhydrous magnesium sulfate, performing suction filtration, and concentrating the filtrate to dryness to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: ethyl acetate: 6:1), and the product was vacuum dried to give a pale yellow tripterine derivative Ic of 19.7mg, with a yield of 39.0%.
The spectral analysis of tripterine derivative Ic is as follows:
1H NMR(500MHz，CD3COCD3)7.37(s,1H,H-1),6.65(d,J＝10.0Hz,1H,H-6),6.44(d,J＝10.0Hz,1H,H-7),5.69(dd,J＝6.70,1.4Hz,1H,H-11),2.42(s,3H,4-CH3),1.43(d,J＝6.95Hz,6H,2’,3’-CH3),1.24(s,3H,9-CH3),1.11(s,6H,20,17-CH3),1.03(s,3H,14,13-CH3),MS(ESI)m/z 500.3(M-H)-.
example 4: synthesis of tripterine derivative Id
Methanol (4mL) and tripterine (45.0mg,0.1mmol) were added to a 25mL two-necked flask, and hydrochloric acid (1mL) having a pH of 1 was added thereto under stirring at room temperature, and the pH of the reaction solution was about 1-2. Reacting for 12 hours under stirring at room temperature, adding methionine (29.8mg,0.2mmol), adding sodium carbonate to adjust the pH to about 8, continuing to react for 8 hours, detecting by TLC, adding water (5mL) after the reaction is finished, stirring to dissolve the sodium carbonate solid, adding hydrochloric acid to adjust the pH of the reaction solution to about 7, extracting for three times by ethyl acetate (10mL), combining organic phases, washing by saturated saline water, drying by anhydrous magnesium sulfate, then carrying out suction filtration, and concentrating the filtrate to dryness to obtain a crude product. The crude product is separated and purified by a flash column chromatography (petroleum ether: ethyl acetate: 6:1), and the product is dried in vacuum to obtain a light yellow tripterine derivative Id of 21.0mg, and the yield is 38.7%.
The spectrum analysis of the tripterine derivative Id was as follows:
1H NMR(500MHz，CD3COCD3)7.38(s,1H,H-1),6.67(d,J＝10.0Hz,1H,H-6),6.44(d,J＝10.0Hz,1H,H-7),5.69(dd,J＝6.77,1.53Hz,1H,H-11),3.25(t,J＝7.35Hz,2H,H-1’),3.04(t,J＝7.35Hz,2H,H-1’),2.41(s,3H,4-CH3),2.16(s,3H,4’-CH3),1.24(s,3H,9-CH3),1.11(s,6H,20,17-CH3),1.04(s,3H,14-CH3),1.03(s,3H,13-CH3),MS(ESI)m/z 532.3(M-H)-.
example 5: synthesis of tripterine derivative Ie
Methanol (4mL) and tripterine (45.0mg,0.1mmol) were added to a 25mL two-necked flask, and hydrochloric acid (1mL) having a pH of 1 was added thereto with stirring at room temperature, and the pH of the reaction solution was 1-2. The reaction was carried out at room temperature for 12 hours with stirring, isoleucine (26.2mg,0.2mmol) was added, sodium carbonate was added to adjust the pH to about 8, the reaction was continued for 8 hours, TLC detection was carried out, after the reaction was completed, water (5mL) was added, the sodium carbonate solid was dissolved with stirring, hydrochloric acid was added to adjust the pH of the reaction solution to about 7, extraction was carried out three times with ethyl acetate (10mL), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, followed by suction filtration, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: ethyl acetate: 6:1), and the product was vacuum dried to give a pale yellow tripterine derivative Ie 17.8mg, with a yield of 34.4%.
The spectrum analysis of the tripterine derivative Ie is as follows:
1H NMR(500MHz，CD3COCD3)7.40(s,1H,H-1),6.65(d,J＝10.0Hz,1H,H-6),6.32(d,J＝10.0Hz,1H,H-7),5.60(dd,J＝6.50,1.50Hz,1H,H-11),3.08(m,1H,H-1’),2.40(s,3H,4-CH3),1.43(d,J＝7.26Hz,3H,2’-CH3),1.28(s,3H,9-CH3),1.09(s,3H,20-CH3),1.03(s,3H,17-CH3),1.01(s,6H,14,13-CH3),0.95(t,J＝7.41Hz,3H,4’-CH3),MS(ESI)m/z514.3(M-H)-.
example 6: synthesis of tripterine derivative If
Methanol (4mL) and tripterine (45.0mg,0.1mmol) were added to a 25mL two-necked flask, and hydrochloric acid (1mL) having a pH of 1 was added thereto with stirring at room temperature, and the pH of the reaction solution was 1-2. Reacting for 12 hours under stirring at room temperature, adding leucine (26.2mg,0.2mmol), adding sodium carbonate to adjust the pH to about 8, continuing to react for 8 hours, detecting by TLC, adding water (5mL) after the reaction is finished, stirring to dissolve the sodium carbonate solid, adding hydrochloric acid to adjust the pH of the reaction solution to about 7, extracting with ethyl acetate (10mL) for three times, combining organic phases, washing with saturated saline solution for 2 times, drying with anhydrous magnesium sulfate, then performing suction filtration, and concentrating the filtrate to dryness to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: ethyl acetate: 6:1), and the product was vacuum dried to obtain 37.6mg of white tripterine derivative If, with a yield of 72.9%.
The spectrum analysis of the tripterine derivative If is as follows:
1H NMR(500MHz，CD3COCD3)7.37(s,1H,H-1),6.65(d,J＝10.0Hz,1H,H-6),6.41(d,J＝10.0Hz,1H,H-7),5.68(dd,J＝6.65,1.40Hz,1H,H-11),2.81(d,J＝7.15Hz,2H,H-1’),2.38(s,3H,4-CH3),1.24(s,3H,9-CH3),1.11(s,6H,20,17-CH3),1.04(d,J＝6.5Hz,6H,3’,4’-CH3),1.03(s,6H,14,13-CH3),MS(ESI)m/z 514.3(M-H)-.
example 7: synthesis of tripterine derivative Ig
Methanol (4mL) and tripterine (45.0mg,0.1mmol) were added to a 25mL two-necked flask, and hydrochloric acid (1mL) having a pH of 1 was added thereto with stirring at room temperature, and the pH of the reaction solution was 1-2. The reaction was carried out at room temperature for 12 hours with stirring, glutamine (23.4mg,0.2mmol) was added, sodium carbonate was added to adjust the pH to about 7, the reaction was continued for 8 hours, TLC detection was carried out, after the reaction was completed, water (5mL) was added, the sodium carbonate solid was dissolved with stirring, hydrochloric acid was added to adjust the pH of the reaction solution to about 7, extraction was carried out three times with ethyl acetate (10mL), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, suction filtration was carried out, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: ethyl acetate: 6:1), and the product was vacuum dried to give a white tripterine derivative Ig of 36.7mg, with a yield of 69.2%.
The spectrum analysis of the tripterine derivative Ig is as follows:
1H NMR(500MHz，CD3COCD3)7.33(s,1H,H-1),6.55(d,J＝10.0Hz,1H,H-6),6.29(d,J＝10.0Hz,1H,H-7),5.58(d,J＝6.0Hz,1H,H-11),3.25(m,2H,H-2’),3.0(m,1H,H-2a’),2.8(m,1H,H-2b’),2.33(s,3H,4-CH3),1.34(s,3H,9-CH3),1.11(s,6H,20-CH3),1.03(s,6H,17,14-CH3),1.00(s,3H,13-CH3),MS(ESI)m/z 531.3(M+H)+.
example 8: synthesis of tripterine derivative Ih
Methanol (4mL) and tripterine (45.0mg,0.1mmol) were added to a 25mL two-necked flask, and hydrochloric acid (1mL) having a pH of 1 was added thereto with stirring at room temperature, and the pH of the reaction solution was 1-2. The reaction was carried out at room temperature for 12 hours with stirring, tyrosine (36.2mg,0.2mmol) was added, sodium carbonate was added to adjust the pH to about 8, the reaction was continued for 8 hours, TLC detection was carried out, after the reaction was completed, water (5mL) was added, the sodium carbonate solid was dissolved with stirring, hydrochloric acid was added to adjust the pH of the reaction solution to about 7, extraction was carried out three times with ethyl acetate (10mL), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, suction filtration was carried out, and the filtrate was concentrated to dryness to obtain a crude product. The crude product is separated and purified by a flash column chromatography (petroleum ether: ethyl acetate: 6:1), and the product is dried in vacuum to obtain the yellow tripterine derivative Ih, which is 24.7mg and the yield is 43.7%.
The spectrum analysis of the tripterine derivative Ih is as follows:
1H NMR(500MHz，CD3COCD3)7.37(s,1H,H-1),7.24(d,J＝8.5Hz,2H,H-3’,7’),6.82(d,J＝8.5Hz,2H,H-4’,6’),6.65(d,J＝10.0Hz,1H,H-6),6.43(d,J＝10.0Hz,1H,H-7),5.68(dd,J＝6.65,1.4Hz,1H,H-11),4.18(s,2H,H-1’),2.38(s,3H,4-CH3),1.23(s,3H,9-CH3),1.10(s,6H,20,17-CH3),1.03(s,3H,14-CH3),1.02(s,3H,13-CH3),MS(ESI)m/z564.3(M-H)-.
example 9: synthesis of tripterine derivative Ii
Methanol (4mL) and tripterine (45.0mg,0.1mmol) were added to a 25mL two-necked flask, and hydrochloric acid (1mL) having a pH of 1 was added thereto with stirring at room temperature, and the pH of the reaction solution was 1-2. Reacting for 12 hours under stirring at room temperature, adding phenylalanine (33.0mg,0.2mmol), adding sodium carbonate to adjust the pH to about 8, continuing to react for 8 hours, detecting by TLC, adding water (5mL) after the reaction is finished, stirring to dissolve the sodium carbonate solid, adding hydrochloric acid to adjust the pH of the reaction solution to about 7, extracting for three times by using ethyl acetate (10mL), combining organic phases, washing twice by using saturated saline solution, drying by anhydrous magnesium sulfate, filtering, and concentrating the filtrate to dryness to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: ethyl acetate: 6:1), and the product was vacuum dried to give a pale yellow tripterine derivative Ii 29.4mg, 53.5% yield.
The spectrum analysis of the tripterine derivative Ii is as follows:
1H NMR(500MHz，CD3COCD3)7.29-7.43(m,5H, H-benzene ring), 7.38(s,1H, H-1),6.66(d, J ═ 10.0Hz,1H, H-6),6.43(d, J ═ 10.0Hz,1H, H-7),5.68(dd, J ═ 6.8,1.65Hz,1H, H-11),4.30(s,2H, H-1 '), 2.38(s,3H, 4-CH-1'), and so on3),1.24(s,3H,9-CH3),1.10(s,6H,20,17-CH3),1.03(s,3H,14-CH3),1.02(s,3H,13-CH3),MS(ESI)m/z 548.3(M-H)-.
Example 10: synthesis of tripterine derivative Ij
Methanol (4mL) and tripterine (45.0mg,0.1mmol) were added to a 25mL two-necked flask, and hydrochloric acid (1mL) having a pH of 1 was added thereto with stirring at room temperature, and the pH of the reaction solution was 1-2. The reaction was carried out at room temperature for 12 hours with stirring, tryptophan (40.8mg,0.2mmol) was added, sodium carbonate was added to adjust the pH to about 8, the reaction was continued for 8 hours, TLC detection was carried out, after the reaction was completed, water (5mL) was added, the sodium carbonate solid was dissolved with stirring, hydrochloric acid was added to adjust the pH of the reaction solution to about 7, extraction was carried out three times with ethyl acetate (10mL), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, suction filtration was carried out, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: ethyl acetate: 6:1), and the product was vacuum dried to give a yellow tripterine derivative Ij in 18.5mg, 31.5% yield.
The spectrum analysis of the tripterine derivative Ij is as follows:
1H NMR(500MHz，CD3COCD3)7.31-7.97(m,5H, indole ring), 7.63(s,1H, H-1),6.91(d, J ═ 10.0Hz,1H, H-6),6.68(d, J ═ 10.0Hz,1H, H-7),5.94(dd, J ═ 6.73,1.47Hz,1H, H-11),4.68(s,2H, H-1 '), 2.64(s,3H, 4-CH-1'), and so on3),1.40(s,3H,9-CH3),1.37(s,6H,20,17-CH3),1.29(s,3H,14-CH3),1.27(s,3H,13-CH3),MS(ESI)m/z 587.3(M-H)-.
Example 11: synthesis of tripterine derivative Ik
Methanol (4mL) and tripterine (45.0mg,0.1mmol) were added to a 25mL two-necked flask, and hydrochloric acid (1mL) having a pH of 1 was added thereto with stirring at room temperature, and the pH of the reaction solution was 1-2. The reaction was carried out at room temperature for 12 hours with stirring, histidine (31.0mg,0.2mmol) was added, sodium carbonate was added to adjust the pH to about 7, the reaction was continued for 8 hours, TLC detection was carried out, after the reaction was completed, water (5mL) was added, the sodium carbonate solid was dissolved with stirring, hydrochloric acid was added to adjust the pH of the reaction solution to about 7, extraction was carried out three times with ethyl acetate (10mL), the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, suction filtration was carried out, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was separated and purified by flash column chromatography (chloroform: methanol: 30:1), and the product was vacuum dried to give 5.5mg of yellow tripterine derivative Ik, 10.2% yield.
The spectrum analysis of the tripterine derivative Ik is as follows:
1H NMR(500MHz，CD3COCD3)7.89(s,1H,H-4’),7.62(s,1H,H-1),7.37(s,H-6’),6.93(d,J＝10.0Hz,1H,H-6),6.70(d,J＝10.0Hz,1H,H-7),5.94(dd,J＝6.7,1.5Hz,1H,H-11),4.51(s,2H,H-1’),2.66(s,3H,4-CH3),1.49(s,3H,9-CH3),1.37(s,6H,20,17-CH3),1.29(s,6H,14,13-CH3),MS(ESI)m/z 538.3(M-H)-.
example 12: the tripterine derivative synthesized by the invention adopts an MTT method to measure the antiproliferative effect of the tripterine and the tripterine derivative on A549 cells.
A549 cells in logarithmic phase are taken by MTT method to prepare cell suspension, and the cell suspension is respectively inoculated in 96-well culture (190 mu L/well), and 5000 cells in each well wait for adherent growth. Placing at 37 ℃ and 5% CO2Culturing in incubator for 24 hr, adding 10 μ L compound culture solution with different concentrations to make drug concentration of 96-well plate 5, 2.5, 1.25, 0.625, 0.3125 μ g/mL, selecting part of wells containing cells, addingEqual amounts of drug-free medium were included as blanks, 3 parallel wells for each concentration. After the medicine is added, the mixture is continuously placed at 37 ℃ and 5 percent CO2Culturing in an incubator. After 48h incubation, 20. mu.L of MTT solution (5mg/mL) was added to each well, mixed by gentle shaking, and returned to the incubator for further incubation for 4 h. After the culture was completed, the culture medium in the 96-well plate was aspirated, DMSO was added to each well in an amount of 150. mu.L, the mixture was gently shaken to completely dissolve the crystals, and the OD value at a wavelength of 490nm was measured using a microplate reader. The inhibition ratio of each well was calculated as follows.
IC was calculated using Graph pad prism 5 software based on the obtained inhibition50The value is obtained.
The results are shown in Table 1:
TABLE 1 in vitro antitumor Activity of Tripterine and its derivatives
As can be seen from Table 1, the tripterine derivatives of the invention all have good antitumor activity, the activity is obviously stronger than that of the positive control drug cisplatin, and the antitumor activity of part of the derivatives is better than that of the tripterine.
Claims (6)
1. A tripterine derivative has a structure shown in formula (I):
in the formula (I), R is hydrogen or C1-C8Alkyl or C substituted by one or more substituents1-C8Alkyl, each of said substituents being independently selected from: fluorine, chlorine, hydroxyl, hydroxymethyl, nitrile group, C1-C6Alkylthio radical, C1-C8Alkoxy radical, C1-C8Amide group, C6-C14Aryl radical, C6-C14An aromatic heterocyclic group, a five-membered heterocyclic ring or a six-membered heterocyclic ring.
2. The tripterine derivative of claim 1, wherein in the formula (I), R is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, methyl thiolethyl, 3-methylidene indolyl, 4-methylidene imidazolyl, n-propionamido, p-hydroxyphenylmethyl, or benzyl.
3. The method for preparing a tripterine derivative according to claim 1, wherein the preparation method comprises:
dissolving tripterine (II) in methanol, adjusting pH to 1-2, and stirring at room temperature for 8-16h to obtain a reaction solution containing an intermediate (III); adding amino acid (IV) into the reaction solution, adjusting the pH value to 7-8, stirring and reacting for 8-16h at room temperature, and then carrying out aftertreatment on the reaction solution to obtain a product shown in the formula (I);
the mass ratio of the tripterine (II) to the amino acid (IV) is 1: 2-3;
r in formula (IV) is as defined for formula (I);
4. the method for preparing a tripterine derivative according to claim 3, wherein the volume usage of the methanol is 30-50mL/mmol based on the amount of the tripterine (II) substance.
5. The method for preparing a tripterine derivative according to claim 3, wherein the post-treatment comprises: after the reaction is finished, adjusting the pH value of the reaction solution to be 7, extracting with ethyl acetate, washing the extract with saturated saline solution, drying with anhydrous sodium sulfate, performing suction filtration, and concentrating the filtrate to be dry to obtain a crude product; and (3) separating the obtained crude product by silica gel column chromatography, wherein the volume ratio is 6:1 or a mixed solution of petroleum ether and ethyl acetate in a volume ratio of 30:1, collecting eluent containing the target compound, evaporating the solvent under reduced pressure, and drying to obtain the product tripterine derivative (I).
6. The use of the tripterine derivative of claim 1 in the preparation of an anti-tumor medicament.
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