CN109705187B - Tripterine derivative and preparation method and application thereof - Google Patents
Tripterine derivative and preparation method and application thereof Download PDFInfo
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- CN109705187B CN109705187B CN201910083069.8A CN201910083069A CN109705187B CN 109705187 B CN109705187 B CN 109705187B CN 201910083069 A CN201910083069 A CN 201910083069A CN 109705187 B CN109705187 B CN 109705187B
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- tripterine
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- ethyleneimine
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- KQJSQWZMSAGSHN-JJWQIEBTSA-N celastrol Chemical class C([C@H]1[C@]2(C)CC[C@@]34C)[C@](C)(C(O)=O)CC[C@]1(C)CC[C@]2(C)C4=CC=C1C3=CC(=O)C(O)=C1C KQJSQWZMSAGSHN-JJWQIEBTSA-N 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 229910052700 potassium Inorganic materials 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims 1
- 206010028980 Neoplasm Diseases 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical group C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 11
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 11
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 9
- -1 nitrogen mustard phosphorus oxychloride Chemical class 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 230000001093 anti-cancer Effects 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 229960004961 mechlorethamine Drugs 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 5
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical group ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 5
- 159000000000 sodium salts Chemical class 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002475 indoles Chemical class 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 2
- LFGREXWGYUGZLY-UHFFFAOYSA-N phosphoryl Chemical group [P]=O LFGREXWGYUGZLY-UHFFFAOYSA-N 0.000 description 2
- 239000011736 potassium bicarbonate Substances 0.000 description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulphite Substances [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- ONRREFWJTRBDRA-UHFFFAOYSA-N 2-chloroethanamine;hydron;chloride Chemical group [Cl-].[NH3+]CCCl ONRREFWJTRBDRA-UHFFFAOYSA-N 0.000 description 1
- 229910018894 PSCl3 Inorganic materials 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 241000830536 Tripterygium wilfordii Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229960002868 mechlorethamine hydrochloride Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000002966 pentacyclic triterpenoids Chemical class 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M sodium bicarbonate Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000015398 thunder god vine Nutrition 0.000 description 1
Abstract
A tripterine derivative or its pharmaceutically acceptable salt has a structure shown in formula (I). The tripterine derivative is prepared byThe 3-hydroxy of tripterine is acylated. The invention also relates to the use of said compounds in the treatment of tumors.
Description
Technical Field
The invention relates to a tripterine derivative, a preparation method thereof and application of the tripterine derivative as an anticancer drug.
Background
Tripterine is a pentacyclic triterpenoid extracted and separated from the roots of tripterygium wilfordii and flat plastic vine, and has various physiological activities of anticancer, anti-inflammatory, antifungal, antioxidant, liver protection and the like. However, various side effects and low solubility limit their clinical use. Aiming at the problems of side effect, low solubility and low bioavailability of tripterine, the literature respectively discloses20The carboxyl group at the site being esterified or amidated, by reaction of C3The hydroxyl in the site becomes carboxylic ester to prepare tripterine derivatives, but the anticancer activity of the derivatives is similar to or weaker than that of tripterine. CN105985401A at Tripterine C6Indole or substituted indole is introduced at the position, and the derivative of the indole or substituted indole has high anticancer activity and low toxicity. WO2009067891 in tripterine C6Sodium sulfite is introduced into the site, so that the water solubility of the obtained derivative is increased, and the bioavailability is increased. CN100453551C the tripterine is made into sodium salt or potassium salt, which improves its water solubility, and can be used for preparing powder for injection. The invention takes tripterine as a carrier, introduces pharmacodynamic groups such as nitrogen mustard, ethylimine and the like, synthesizes tripterine derivatives, salifies the derivatives and improves the solubility of the derivatives in water. The compounds have high anticancer activity.
Disclosure of Invention
The invention aims to provide a tripterine derivative or pharmaceutically acceptable salt thereof, which has good anticancer activity and good solubility in water.
The invention also aims to provide a preparation method of the tripterine derivative or the pharmaceutically acceptable salt thereof.
The invention also aims to provide the application of the tripterine derivative or the pharmaceutically acceptable salt thereof.
The present invention is described in detail below.
The invention provides a tripterine derivative with the following general formula (I) or pharmaceutically acceptable salt thereof. The structure is shown as the following formula:
in the formula, R1And R2Each independently is: h, 2-chloroethyl, but not both H; r1And R2Together are CH2CH2X is O and S; m is H, K, Na.
The tripterine derivative is specifically shown in the formula (I) as follows:
the invention also provides a preparation method of the compound with the general formula (I), which comprises the following steps:
in the formula, R1And R2Each independently is H, 2-chloroethyl, but not both; r1And R2Together are CH2CH2X is O and S; m is K, Na; the base is NaHCO3And KHCO3。
The tripterine derivative or the pharmaceutically acceptable salt thereof has obvious anticancer effect, and the salt thereof has better water solubility.
The present invention is further illustrated by the following examples, but it should be noted that the scope of the present invention is not limited in any way by these examples.
Detailed Description
Example 1
Preparation of ethyleneimine phosphoryl dichloride or thioethyleneimine phosphoryl dichloride:
0.43g (0.01mol) of ethyleneimine and 1.11g (0.011mol) of Et3N was dissolved in 15mL of dichloromethane, cooled to 0 ℃ and 1.52g (0.01mol) of POCl was added dropwise3Or 1.68g (0.01mol) of PSCl3Reacting with 5mL of dichloromethane solution at room temperature for 3 hours after the dropwise addition, concentrating, distilling under reduced pressure to obtain ethyleneimine phosphoryl dichloride or thioethyleneimine phosphoryl dichloride,the yields were 79% and 81%, respectively.
Example 2
Preparation of compound (1) and its sodium salt:
1.77g (0.01mol) of mechlorethamine hydrochloride are dissolved in 10mL of dichloromethane, and 2.22g (0.022mol) of Et are added3And N, cooling to 0 ℃, stirring for 15min, dropwise adding a solution of 1.66g (0.01mol) of ethyleneimine phosphoryl dichloride and 5mL of dichloromethane, reacting at room temperature for 3 hours after dropwise adding, concentrating, and distilling under reduced pressure to obtain ethyleneimine nitrogen mustard phosphoryl chloride.
Dissolving 4.50g (0.01mol) tripterine in 10mL dichloromethane, adding 1.11g (0.011mol) Et3N, cooled to 0 ℃, added with 2.90g (0.011mol) of ethylene imine nitrogen mustard phosphoryl chloride, reacted at room temperature for 12 hours, concentrated, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound (1) with a yield of 72%. Elemental analysis (C)35H49Cl2N2O5P) theoretical value: c, 61.85; h, 7.27; cl, 10.43; n, 4.12; p, 4.56. Measured value: c, 61.82; h, 7.28; cl, 10.41; n, 4.11; p, 4.53.
678mg (1mmol) of Compound (1) were dissolved in 5mL of ethanol, and 88.2mg (1.05mmol) of NaHCO were added3And (2) stirring the aqueous solution, dropwise adding a small amount of water to dissolve the solution clearly, stirring the solution at room temperature for 4 hours, evaporating the solution to dryness under reduced pressure, dissolving the residue in absolute ethyl alcohol, filtering the solution, dropwise adding ethyl acetate into the filtrate until the filtrate is turbid, refrigerating the filtrate at the temperature of 5 ℃ for 24 hours, separating out a solid, filtering the solid, and drying the solid under reduced pressure to obtain the sodium salt of the compound (1), wherein the yield is 77%.
Example 3
Preparation of compound (2) and its sodium salt:
compound (2) and its sodium salt were prepared in 68% and 79% yields, respectively, by substituting ethyleneimine nitrogen mustard phosphorus oxychloride in example 1 with thioethyleneimine nitrogen mustard phosphorus oxychloride and by following the same procedure as in example 1. Elemental analysis (C)35H49Cl2N2O4PS) theoretical value: c, 60.42; h, 7.10; cl, 10.19; n, 4.03; p, 4.45; s, 4.61. Measured value: c, 60.44; h, 7.11; cl, 10.16; n, 4.00; p, 4.44; and S, 4.60.
Example 4
Preparation of compound (3) and its potassium salt:
the nitrogen mustard hydrochloride from example 1 was replaced with 2-chloroethylamine hydrochloride to prepare ethyleneimine 2-chloroethylamine phosphoryl chloride. Replacing ethyleneimine nitrogen mustard phosphoryl chloride with ethyleneimine 2-chloroethylamine phosphoryl chloride, and substituting NaHCO with ethyleneimine 2-chloroethylamine phosphoryl chloride3With KHCO3Alternatively, the compound (3) and its potassium salt were obtained in the same manner as in example 1 in yields of 73% and 81%, respectively. Elemental analysis (C)33H46ClN2O5P) theoretical value: c, 64.22, H, 7.51, Cl, 5.74, N, 4.54 and P, 5.02. Measured value: c, 64.20, H, 7.50, Cl, 5.75, N, 4.56 and P, 5.03.
Example 5
Preparation of compound (4) and its potassium salt:
the procedure of example 4 was otherwise the same as that of example 4 except that ethyleneimine 2-chloroethylamine phosphoryl chloride in example 4 was replaced with thioethyleneimine 2-chloroethylamine phosphoryl chloride, to obtain compound (4) and its potassium salt in yields of 69% and 80%, respectively. Elemental analysis (C)33H46ClN2O4PS) theoretical value: c, 62.59, H, 7.32, Cl, 5.60, N, 4.42, P, 4.89 and S, 5.06. Measured value: c, 62.56, H, 7.31, Cl, 5.62, N, 4.41, P, 4.87 and S, 5.05.
Example 6
Preparation of compound (5) and its potassium salt:
compound (5) and its potassium salt were obtained in 68% and 79% yields, respectively, by substituting ethyleneimine 2-chloroethylamine phosphoryl chloride in example 4 with diethyleneimine phosphoryl chloride and by following the same procedure as in example 4. Elemental analysis (C)33H45N2O5P) theoretical value: c, 68.26, H, 7.81, N, 4.82 and P, 5.33. Measured value: c, 68.23, H, 7.80, N, 4.80 and P, 5.31.
Example 7
Preparation of compound (6) and its potassium salt:
compound (6) and its potassium salt were obtained in yields of 70% and 78%, respectively, by substituting thiodiethyieneiminophosphorochloridate for diethyieneiminophosphorochloridate in example 6 and by following the same procedure as in example 6. Elemental analysis (C)33H45N2O4PS) theoretical value: c, 66.42, H, 7.60, N, 4.69, P, 5.19 and S, 5.37. Measured value: c, 66.40, H, 7.60, N, 4.68, P, 5.18 and S, 5.35.
Example 8
Antitumor Activity test and results of typical Compounds of the present invention
Bel7402 cell strain, A549 cell strain, SMMC-7721 cell strain, MCF-7 cell strain, PC12 cell strain and C6 cell strain (3X 10)4cell/mL) were inoculated into 96-well plates (100 uL/well), incubated at 37 ℃ with 5% CO2Culturing in incubator for 4 hr, and adding tripterine derivative and positive control drugs including carboplatin and tripterine. Placing at 37 ℃ and 5% CO2The temperature in the incubator at the saturated humidity of (3) was maintained for 48 hours. Adding 5mg/mL MTT (20 uL/well), mixing, and adding 5% CO at 37 deg.C2Incubate under conditions for 4 hours. DMSO (150 uL/well) was added to the reaction solution to dissolve the mixture, and the absorbance (OD value) was measured using a microplate reader. The inhibition rate of the compound on cells, IC50 (uM), was calculated.
Inhibition = (control mean OD value-administration mean OD value)/control mean OD value × 100%
The results show that the tripterine derivatives and salts thereof have good inhibitory effects on 6 kinds of cancer cells compared with carboplatin and tripterine (Table 1).
Claims (3)
1. A tripterine derivative and a salt (I) thereof are characterized in that: has the following general formula:
in the formula, R1And R2Each independently is H, 2-chloroethyl, but not both; r1And R2Together are CH2CH2(ii) a X is O and S; m is H, K, Na.
2. The tripterine derivative and the salt (I) thereof according to claim 1, wherein: the compounds of formula (I) are specifically as follows:
in the formula, M is K and Na.
3. The use of the tripterine derivative and the salt (I) thereof according to claim 1 in the preparation of anticancer drugs.
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| CN101805390B (en) * | 2010-04-13 | 2012-07-18 | 暨南大学 | Tripterine derivate and use thereof |
| WO2012024893A1 (en) * | 2010-08-23 | 2012-03-01 | Suzhou Neupharma Co., Ltd. | Certain chemical entities, compositions, and methods |
| CN102432663B (en) * | 2011-10-27 | 2014-12-03 | 浙江工业大学 | Celastrol derivative and preparation method thereof and application of celastrol derivative to preparation of antitumor medicine |
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