CN105985401B - Tripterine derivative, preparation method and application thereof - Google Patents
Tripterine derivative, preparation method and application thereof Download PDFInfo
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- CN105985401B CN105985401B CN201510083099.0A CN201510083099A CN105985401B CN 105985401 B CN105985401 B CN 105985401B CN 201510083099 A CN201510083099 A CN 201510083099A CN 105985401 B CN105985401 B CN 105985401B
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- Prior art keywords
- tripterine
- compound
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- alkyl
- reaction
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 28
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 12
- 125000001041 indolyl group Chemical group 0.000 claims abstract description 10
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
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- 238000000034 method Methods 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
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- 238000003756 stirring Methods 0.000 claims description 8
- 201000011510 cancer Diseases 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
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Abstract
The inventionDiscloses a tripterine derivative, a preparation method and application thereof, the tripterine derivative has a structure shown as a formula I, wherein, R is1Is H, alkyl, halogenated alkyl, unsaturated alkyl or alkyl containing hetero atoms, R2Is alkyl, halogen, alkoxy, nitro, R3Is H or alkyl. In the preparation method of the tripterine derivative, indole or substituted indole group is introduced to 6-position of the tripterine through friedel-crafts reaction, and the reaction condition is mild. The tripterine derivative is used for treating cancers, and has the characteristics of high anticancer activity, low toxicity, small side effect and stable structure.
Description
Technical Field
The invention relates to a tripterine derivative, a preparation method and application thereof.
Background
Cancer is a serious public health problem in the world, and as shown by 2008 statistical data published by the international cancer research institute, about 760 million people die of cancer worldwide each year. The tumor treatment methods commonly used in clinic at present comprise surgery, chemotherapy (chemotherapy), radiotherapy (radiotherapy), biological treatment and the like.
Currently, surgical methods are still the first choice for cancer treatment to completely eradicate the cancer foci. Currently, the categories of tumor therapeutic drugs are mainly 7: alkylating agents, antimetabolites, antibiotics, plants, small molecule targeted therapy drugs and the like. Among many anticancer drugs, plant-derived anticancer drugs have been a major class of products in the international anticancer drug market, camptothecin, paclitaxel, and the like are lead compounds of well-known anticancer drugs, and derivatives thereof have been used clinically as first-line drugs for chemotherapy for cancer. With the increase and change of the incidence of tumors, the development of low-toxicity and high-efficiency antitumor drugs has become an urgent need for cancer treatment.
Tripterine (Celastrol) is a pentacyclic triterpenoid extracted and separated from the root of tripterygium wilfordii and flat plastic vine, and has various biological activities, such as: the anti-inflammatory, anti-tumor, antifungal and antioxidant effects are achieved, and the effect targets are as follows: NF-Kb, Notch, HSP90, Cdc37, p23, IKK β, proteonome, Bcr-Abl, and p-Akt, etc. Since tripterine has various biological activities, a great deal of side effects are brought, and the low solubility of the tripterine limits the clinical application of the tripterine.
The side effects of tripterine mainly come from a quinone methyl structure in the tripterine structure, and the quinone methyl structure can generate addition reaction with cysteine residues widely distributed in vivo, so that different side effects are generated, and therefore, how to effectively maintain the activity of the compound and obtain a safe target compound becomes the research direction of the compound.
Aiming at the side effect and low solubility of the tripterine, the literature reports that different groups are introduced into the 29-position carboxylic acid group of the tripterine to change the solubility of the tripterine. The Chinese patent CN102796254A introduces polyethylene glycol to prepare polyethylene glycol ester, although the water solubility is increased, the activity is only 3-5% of tripterine; chinese patent CN101311187A introduces long-chain alkane to increase its lipid solubility, and prepares long-chain ester at position 29, but its anticancer activity is slightly weaker than that of tripterine (the inhibition rates of tripterine cetyl ester and tripterine on U-14 cervical cancer are 63.2% and 55.3% respectively under the same dosage); wangjiaqiang, etc. are esterified and amidated at position 29, and the activity of the Wangjiaqiang, etc. is found to be weaker than that of tripterine (Chinese herbal medicine, 2009(40) 2: 201-204).
The Chinese patent CN101805390A esterifies 3 or 29 sites of tripterine to obtain tripterine derivatives, although the antitumor activity is basically similar to that of tripterine, or the antitumor activity is weaker than that of tripterine (Cel-1-Cel-13 has weaker inhibition effect on C6 cells than that of tripterine).
However, the tripterine derivatives involved in the above studies still have many toxic reactions because the quinone methyl structure of tripterine is still retained.
Sunworli was prepared into oxime with hydroxylamine hydrochloride at position 2 of tripterine (Sunworli, chemical synthesis of tripterine derivatives and its activity study [ D ], river-south university, 2011), although the structure of quinone methyl group was changed, its IC50 was greater than 50 for both PC12 and C6 cells, and anticancer activity was lost.
In the world patent WO2009067891, 6-position of tripterine reacts with sulfite to prepare water-soluble tripterine derivative, and after sodium sulfite is introduced into 6-position of tripterine, the bioavailability is increased due to the increase of the solubility of the tripterine derivative, and the anticancer activity of the tripterine derivative is increased to different degrees. Because the A/B ring of the tripterine is a Michael addition reaction receptor, the tripterine is released in vivo through reverse Michael reaction after sulfite addition is introduced at the 6-position, thereby increasing the activity. However, since the tripterine sulfite has a thioether bond, the thioether bond is unstable and easily oxidized, and the pharmaceutical properties thereof are lowered.
Disclosure of Invention
The invention aims to provide a tripterine derivative, a preparation method and application thereof, wherein indole or substituted indole group is introduced into 6-position of tripterine through friedel-crafts reaction, the reaction condition is mild, and the tripterine derivative has the characteristics of high anticancer activity, reduced toxicity, small side effect and stable structure.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a tripterine derivative has a structure shown in a formula I:
wherein R is1、R2、R3Are independent radicals, the three radicals being identical or different, R2Is one or two substituent groups at any position of nitrogen atom at position 1 and carbon atom at positions 2, 4, 5, 6 and 7 of indole ring;
R1is H, alkyl, haloalkyl, unsaturated alkyl or heteroatom-containing alkyl;
R2is H, alkyl, halogen, alkoxy or nitro;
R3is H or alkyl.
Preferably, the alkyl group has 1 to 6 carbon atoms.
Preferably, R is2H, F, Cl, Br, methoxy, methyl or ethyl.
Preferably, the tripterine derivative is selected from the following compounds:
the invention also provides a preparation method of the tripterine derivative, which comprises the following steps:
1) dissolving tripterine in an organic solvent, adding a Lewis acid catalyst and the compound of the formula A, stirring, and carrying out a friedel-crafts reaction to obtain a compound of the formula B; wherein R in the compound of formula A2Is H, alkyl, halogen, alkoxy or nitro; the molar ratio of the tripterine to the compound of formula a is 1: 2-3;
2) dissolving the compound of formula B in an organic solvent under anhydrous conditions, adding an inorganic base and a halogenated hydrocarbon R1X, stirring to react to obtain a compound of formula I, wherein R1And R3Are each independently of the other R1Is H or alkyl, R3And R1The same;
the reaction route is as follows:
the invention also provides another preparation method of the tripterine derivative, which is characterized by comprising the following steps:
1) dissolving tripterine in organic solvent, adding inorganic base and halogenated hydrocarbon R1X, carrying out nucleophilic substitution to obtain an intermediate compound in a formula C;
2) dissolving the compound shown in the formula C in an organic solvent, adding a Lewis acid catalyst and the compound shown in the formula A, and stirring for reaction to obtain a compound shown in the formula D; wherein R is2Is H, alkyl, halogen, alkoxyOr a nitro group; wherein the molar ratio of the compound of formula C to the compound of formula A is 1: 2-3;
3) dissolving the compound of formula D in an organic solvent under anhydrous conditions, adding an inorganic base and a halogenated hydrocarbon R3X, stirring for reaction to obtain a compound II; wherein R is1And R3Are independently of one another radicals R1Is H, alkyl, halogenated alkyl, unsaturated alkyl or alkyl containing hetero atoms; r3Is H or alkyl, R1And R3The same or different;
the reaction route is as follows:
preferably, the organic solvent is selected from dimethyl sulfoxide, N' N-dimethylformamide, dichloromethane, chloroform or methanol.
Also preferably, the Lewis acid catalyst is Sc (OTf)3、Ln(OTf)3、Re(OTf)3、Sc(OPf)3The amount of Lewis acid catalyst is 0.1-10 mol%, preferably 2-6 mol% of tripterine or compound of formula C.
And the inorganic base is selected from potassium carbonate, sodium carbonate or cesium carbonate.
The tripterine derivative is applied to the treatment of cancers.
The invention has the beneficial effects that:
1) the tripterine derivative changes both the A ring and the B ring of the tripterine. The indole ring is successfully introduced into the 6 th site of the tripterine, namely the B ring, and the indole ring has a certain anticancer effect because the indole ring has signal pathway inhibition.
2) The side effects of tripterine mainly come from the quinone methyl structure on the A/B ring in the structure, and the quinone methyl structure can generate addition reaction with cysteine residues widely distributed in vivo, thereby generating different side effects. Meanwhile, the tripterine derivative changes the A/B ring of the tripterine, aromatizes the A ring, and alkylates the catechol of the A ring, so that the derivative does not contain a quinone methyl structure which is easy to generate side effects, thereby reducing the toxicity of the tripterine derivative.
3) According to the invention, through a friedel-crafts reaction, indole derivatives are introduced to the 6 th carbon atom of the tripterine, and the indole derivatives are connected to the 6 th carbon atom of the tripterine in a C-C bond form, and the stability of the carbon-carbon bond is superior to that of a carbon-sulfur bond, so that the compound is good in stability.
Detailed Description
For a further understanding of the invention, reference will now be made to the preferred embodiments of the present invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the present invention, and not to limit the scope of the claims.
Route one
Example 1R1＝R2＝R3When H, preparation of compound 1
The reaction formula is as follows:
dissolving tripterine (1.0eq) in anhydrous dichloromethane, adding indole (2.0eq) and catalyst Sc (OTf)3(5 mol%), reacting at normal temperature for 24 hours, detecting the reaction by TLC, after the reaction is finished, drying the solvent by a rotary column chromatography method (petroleum ether/acetone: 3/1) to obtain the compound 1 (yield 78%, purity 99.2%) [ mp114-116 ℃ ], [ α ]]20D-89.78°(MeOH,c＝0.2),1H-NMR(300MHz,CDCl3)7.87(s,1H),7.78(d,J＝7.2Hz,1H),7.34(d,J＝7.5Hz,1H),7.15-7.20(m,2H),6.83(s,1H),6.32(s,1H),6.23(d,J＝6.3Hz,1H),4.94(d,J＝5.7Hz,1H),2.41(d,J＝15.6Hz,1H),2.03-2.11(m,3H),1.95(s,3H),1.40-1.68(m,8H),1.38(s,3H),1.31-1.23(m,2H),1.16(s,3H),1.02(s,3H),0.94-0.89(m,1H),0.75(s,3H).HRMS(ESI-)m/z calcd for C38H46NO6[M+COOH]-612.3331,found 612.3325。
Example 2R1＝R3＝H，R2＝-CH3，R2Preparation of Compound 2 when H in position 7 of the indole Ring is substituted
The reaction formula is as follows:
the reaction conditions were the same as in example 1 except that the indole in example 1 was replaced with 7-methylindole, to give Compound 2 (yield 65%, purity 98.5%) < mp92-94 ℃ >]20D-78.39°(MeOH,c＝0.2),1H-NMR(300MHz,CDCl3)7.72(s,1H),6.62(d,J＝7.8Hz,1H),6.99-7.10(m,2H)，6.84(s,1H),6.33(d,J＝1.8Hz,1H),6.21(d,J＝6.3Hz,1H),4.93(d,J＝6.3Hz,1H),2.46(s,3H),2.39-2.43(dd,J＝15.0Hz,0.6Hz,1H),2.03-2.06(m,3H),1.96(s,3H),1.46-1.73(m,9H),1.38(s,3H),1.16(s,3H),1.02(s,3H),1.01(s,3H),0.88-0.93(m,1H),0.73(s,3H).HRMS(ESI)m/zcalcd for C38H47NO4Na[M+Na]+604.3396,found 604.3397。
Example 3 parallel reaction
Referring to the preparation method of the compound 1 in the example 1, the corresponding substituted indole is used as a reaction substrate to carry out a reaction, so as to obtain compounds 3-11, wherein the structural formula is as follows:
data for analysis of partial compounds:
compound 4 at mp96-98 deg.C and α]20D-66.31°(MeOH,c＝0.2),1H-NMR(300MHz,CDCl3)7.94(s,1H),7.87(s,1H),7.22(m,3H),6.83(s,1H),6.32(s,1H),6.14(d,J＝6.2Hz,1H),4.86(d,J＝5.8Hz,1H),2.41(m,2H),2.15–1.96(m,2H),1.93(s,3H),1.80–1.41(m,8H),1.37(s,3H),1.31-1.22(m,2H),1.17(s,3H),1.04(s,3H),1.02(s,3H),0.98–0.87(m,1H),0.73(s,3H).HRMS(ESI)m/z calcd for C37H44FNO4Na[M+Na]+608.3147,found 608.3141.
Compound 6 at mp90-92 deg.C and α ℃]20D-90.36°(MeOH,c＝0.2),1H-NMR(300MHz,CDCl3)7.85(s,1H),7.62(dd,J＝8.6,5.3Hz,1H),7.06–6.78(m,3H),6.29(d,J＝1.1Hz,1H),6.17(d,J＝6.3Hz,1H),4.89(d,J＝6.1Hz,1H),2.40(d,J＝15.1Hz,2H),2.10-2.01(m,3H),1.95(s,3H),1.78–1.39(m,9H),1.35(s,3H),1.32–1.24(m,1H),1.15(s,3H),1.02(s,3H),1.01(s,3H),0.94–0.85(m,1H),0.72(s,3H).HRMS(ESI)m/z calcd for C38H47NO5Na[M+Na]+620.3344,found 620.3346.
Compound 10 at mp98-100 deg.C (α)]20D-69.71°(MeOH,c＝0.2),1H-NMR(300MHz,CDCl3)7.82(s,1H),7.62(d,J＝8.4Hz,1H),7.32(s,1H),7.10(d,J＝8.3Hz,1H),6.83(s,1H),6.33(s,1H),6.16(d,J＝6.4Hz,1H),4.89(d,J＝6.2Hz,3H),2.40(d,J＝15.3Hz,1H),2.10-2.04(m,3H),1.95(s,3H),1.68-1.43(m,9H),1.35(s,3H),1.26-1.22(m,3H),1.16(s,3H),1.03(s,3H),1.00(s,3H),0.90-0.87(m,2H),0.72(s,3H).HRMS(ESI)m/z calcd forC37H44ClNO4Na[M+Na]+624.2861,found 624.2851。
Example 4R1＝R3＝-CH3，R2＝-CH3And R is2Preparation of Compound 12 when H is substituted in position 2 of the indole Ring
The reaction formula is as follows:
dissolving Compound 3(1.0eq) in anhydrous DMF and adding K2CO3(4.0eq) and MeI (3.6eq), reacting at room temperature overnight under the protection of nitrogen, detecting by TLC, adding water after the reaction is finished, precipitating a solid, filtering by suction, dissolving the solid by methanol, and purifying by column chromatography (petroleum ether/acetone) to obtain a compound 12.
Example 5 parallel reaction
Referring to the preparation method of compound 12 in example 4, alkylation reaction is performed by using a corresponding reaction substrate to obtain compounds 13 to 21, wherein the structural formula is as follows:
data for analysis of partial compounds:
compound 13, mp142-144 ℃ [ α ]]20D-72.37°(MeOH,c＝0.2),1H-NMR(300MHz,CDCl3)7.80(s,1H),7.64-7.60(m,1H),7.00(d,J＝9.9Hz,1H),6.96–6.81(m,2H),6.28-6.27(m,1H),6.18(d,J＝5.9Hz,1H),4.88(d,J＝6.0Hz,1H),3.91(s,3H),3.75(s,3H),3.55(s,3H),2.42(d,J＝16.2Hz,1H),2.16–2.01(m,3H),1.98(s,3H),1.81–1.42(m,8H),1.41(s,3H),1.38-1.25(m,1H),1.16(s,3H),1.04(s,3H),1.02(s,3H),0.98–0.80(m),0.63(s,3H).HRMS(ESI)m/z calcd for C40H50FNO4Na[M+Na]+650.8175,found 650.8169。
Compound 15 at mp111-113 deg.C and α]20D-85.77°(MeOH,c＝0.2),1H-NMR(300MHz,CDCl3)7.64(d,J＝8.1Hz,2H),7.14(s,1H),7.00(d,J＝7.8Hz,1H),6.85(s,1H),6.22(d,J＝6.0Hz,2H),4.90(d,J＝6.1Hz,1H),3.91(s,3H),3.75(s,3H),3.56(s,3H),2.47(s,3H),2.45–2.40(m,1H),2.19–2.02(m,4H),1.99(s,3H),1.77-1.49(m,8H),1.42(s,3H),1.38–1.26(m,2H),1.17(s,3H),1.04(s,3H),1.02(s,3H),0.98–0.92(m,1H),0.64(s,3H).HRMS(ESI)m/z calcd for C41H53NO4Na[M+Na]+646.3865,found 646.3867。
Compound 18, mp108-110 ℃ [ α ]]20D-93.86°(MeOH,c＝0.2),1H-NMR(300MHz,CDCl3)7.70(s,1H),7.22(d,J＝8.9Hz,1H),7.14(d,J＝1.9Hz,1H),6.87-6.84(m,2H),6.32(d,J＝2.2Hz,1H),6.20(d,J＝6.2Hz,1H),4.88(d,J＝5.9Hz,1H),3.91(s,3H),3.89(s,3H),3.75(s,3H),3.56(s,3H),2.45-2.41(m,1H),2.14–2.10(m,3H),1.99(s,3H),1.83–1.50(m,8H),1.43(s,3H),1.39-1.26(m,2H),1.17(s,3H),1.05(s,3H),1.04(s,3H),0.97-0.92(m,1H),0.65(s,3H).HRMS(ESI)m/z calcd for C41H53NO5Na[M+Na]+662.3836,found 662.3816。
The compound 21, mp84-86 deg.C, [ α ]]20D-76.73°(MeOH,c＝0.2),1H-NMR(300MHz,CDCl3)7.81(s,1H),7.65-7.60(m,1H),7.01(d,J＝9.5Hz,1H),6.90(dd,J＝19.1,7.8Hz,2H),6.28(d,J＝1.1Hz,1H),6.19(d,J＝6.1Hz,1H),4.89(d,J＝5.9Hz,1H),3.91(s,3H),3.76(s,3H),3.56(s,3H),2.43(d,J＝15.5Hz,1H),2.14-2.04(m,3H),1.99(s,3H)1.69–1.49(m,8H),1.41(s,3H),1.37-1.26(m,1H),1.17(s,3H),1.05(s,3H),1.03(s,3H),0.97-0.93(m,1H),0.64(s,3H).HRMS(ESI)m/z calcd for C40H51FNO4[M+H]-628.3797,found 628.3786。
Route two
Example 6R1＝-CH2CH3，R2＝H，R3Preparation of compound 22 when ═ H
The reaction formula is as follows:
tripterine (1eq) is dissolved in DMF, sodium carbonate (5eq) is added, 1-iodoethane (5eq) is added, reaction is carried out at room temperature overnight, water and ethyl acetate are added, an organic layer is separated, the organic layer is washed by saturated sodium chloride, dried by anhydrous sodium sulfate, spin-dried and purified by column chromatography (ethyl acetate/n-hexane), and the intermediate compound 22-1 is obtained.
Dissolving the intermediate compound 22-1(1.0eq) in anhydrous dichloromethane, adding indole (2.0eq) and the catalyst Sc (OTf)3(5 mol%) and reacting at normal temperature for 24 hours, detecting the reaction by TLC, after the reaction is finished, drying the solvent by spinning, and obtaining the compound 22 by a column chromatography method (petroleum ether/acetone).
Example 7 parallel reaction
Referring to the preparation method of the intermediate compound 22-1 in example 6, a nucleophilic substitution reaction is performed using a corresponding reaction substrate to obtain intermediate compounds 23-1 to 27-1, which have the following structural formula:
referring to the preparation method of compound 22 in example 6, friedel-crafts reaction was performed using the corresponding reaction substrates to obtain compounds 28 to 36.
Data for analysis of partial compounds:
compound 23-1: MS (EI) [ M + H ]]+m/z 493.6,1H-NMR(CDCl3,400MHz)7.03(1H,dd),6.60(IH,d),6.36(IH,d),3.95(2H,m),1.85(1H,m),1.73(1H,m),2.23(3H,s),1.48(3H,s),1.25(3H,s),1.20(3H,s),1.10(3H,s),0.95(3H,s),0.91(3H,s).HRMS(m/z):[M+H]+calcd forC32H45O4,493.3240,found 493.3235。
Compound 25-1: MS (EI) [ M + H ]]+m/z 542.0.1H-NMR(CDCl3,400MHz)7.62(2H,m),7.25(3H,m),6.96(1H,d),6.29(1H,d),5.43(1H,m),4.97(1H,d),4.85(1H,d),2.10(3H,s),1.53(3H,s),1.36(3H,s),1.14(3H,s),1.04(3H,s),0.45(3H,s).HRMS(m/z):[M+H]+calcd forC36H44O4,540.5350,found,540.5351。
Compound 28: MS (EI) [ M + H ]]+m/z 624.9.1H-NMR(300MHz,CDCl3)7.71(s,1H),6.63(d,J＝7.8Hz,1H),6.89-7.11(m,2H)，6.85(s,1H),6.34(d,J＝1.8Hz,1H),6.21(d,J＝6.3Hz,1H),4.93(d,J＝6.3Hz,1H),3.91(2H,m),2.46(s,3H),2.39-2.43(dd,J＝15.0Hz,0.6Hz,1H),2.03-2.05(m,3H),1.95(s,3H),1.46-1.71(m,9H),1.34(s,3H),1.15(s,3H),1.05(s,3H),1.01(s,3H),0.88-0.93(m,1H),0.63(s,3H).HRMS(m/z):[M+H]+calcd forC36H44O4,624.3975,found,624.3974。
Compound 33:1H-NMR(300MHz,CDCl3)7.87～7.38(m,4H),7.64(dd,J＝8.6,5.3Hz,1H),7.04–6.85(m,3H),6.33(s,1H),6.21(d,J＝6.2Hz,1H),4.92(d,J＝6.1Hz,1H),2.45–2.41(m,2H),2.15–2.02(m,2H),1.93(s,3H),1.37(s,3H),1.28–1.25(m,1H),1.16(s,3H),1.07(s,3H),1.01(s,3H),0.95–0.90(m,1H),0.75(s,3H).HRMS(ESI-)m/z calcd forC44H49FNO4[M-H]-674.3722,found674.3734。
example 8R1＝-CH2CH3，R2＝-CH3And R is2H, R substituted in position 2 of indole ring3＝-CH3Preparation of Compound 37
The reaction formula is as follows:
intermediate 36-1 was synthesized by a reaction conducted with reference to 22-1 in example 6, and compound 36 was synthesized by a reaction conducted with reference to the preparation of compound 22 in example 6. Referring again to the reaction conditions of compound 12 in example 4, an alkylation reaction was carried out to obtain compound 37.
Example 9 parallel reaction
Referring to the synthesis of the compound 37 in example 8, the preparation of the corresponding intermediate compound is performed first, and then the alkylation reaction is performed to obtain the compounds 38 to 44.
Structural data of partial compound
Compound 38:1H-NMR(300MHz,CDCl3)1H-NMR(300MHz,CDCl3)7.71(s,1H),7.21(m,1H),7.14(d,J＝1.9Hz,1H),6.87-6.83(m,2H),6.35(d,J＝2.2Hz,1H),6.20(d,J＝6.2Hz,1H),4.88(d,J＝5.9Hz,1H),3.91(s,3H),3.89(s,3H),2.45-2.41(m,1H),2.14–2.10(m,3H),1.99(s,3H),1.83–1.50(m,10H),1.43(s,3H),1.39-1.26(m,2H),1.17(s,3H),1.05(s,3H),1.04(s,3H),0.97-0.92(m,1H),0.71(s,3H),0.65(s,3H).HRMS(ESI)m/z calcd forC42H55FNO4[M+H]+656.4035,found 656.4033。
compound 42:1H-NMR(300MHz,CDCl3)7.73(s,1H),7.22(d,J＝8.9Hz,1H),7.11(d,J＝1.9Hz,1H),6.87-6.83(m,2H),6.32(d,J＝2.2Hz,1H),6.21(d,J＝6.2Hz,1H),4.89(d,J＝5.9Hz,1H),3.91(s,3H),3.84(s,3H),3.77(s,3H),2.45-2.48(m,1H),2.14–2.120(m,3H),2.01(s,3H),1.83–1.54(m,10H),1.41(s,3H),1.39-1.26(m,2H),1.17(s,3H),1.05(s,3H),1.04(s,3H),0.97-0.92(m,1H),0.75(s,3H),0.65(s,3H).13.HRMS(ESI-)m/z calcdfor C42H56NO5[M+H]+653.9087,found 653.9085。
example 10 verification of the inhibitory Effect of Tripterine derivatives of the present invention on tumor cells
Culturing human liver cancer cell strain Bel7402 and human brain glioma cell strain H4 in vitro, collecting cells after the cells grow to logarithmic growth phase, centrifuging at 1000rpm for 5 minutes, discarding supernatant, suspending with appropriate amount of culture medium, and adjusting cell concentration to 3.5 × 104And/ml. The cell suspension was inoculated into a 96-well cell culture plate at 100. mu.l per well, and after culturing in a cell culture chamber (37 ℃ C., 5% CO2) for 24 hours, the drug to be tested was added, and the negative control group was added with DMSO at a final concentration of 0.5%, each group was provided with 3 duplicate wells. After 72 hours of incubation in an incubator, 20. mu.l of MTT was added at 5mg/ml per well and left in the incubator (37 ℃ C., 5% CO2) for 4 hours. Mu.l DMSO was added to each well, and the absorbance (OD) was measured at 492nm/620nm with shaking at 37 ℃ for 5 minutes. IC50 values were calculated using prism graphpad statistical software and the results are shown in table 1.
TABLE 1
As can be seen from the data in Table 1, some of the compounds of the present invention were more potent than tripterine (compounds 17, 40), or comparable in activity to tripterine (8, 11, 15, 37, 42). The tripterine derivative changes the A ring and the B ring of the tripterine, removes side effects generated by the action of quinone methyl structure and cysteine residues widely distributed in vivo, and reduces toxicity; and the indole ring is introduced, and the anticancer activity of the tripterine is increased or maintained by utilizing the signal path inhibition effect of the indole ring.
Claims (10)
1. A tripterine derivative is characterized in that: has a structure shown in formula I:
wherein R is1、R2、R3Are independent radicals, the three radicals being identical or different, R2Is one or two substituent groups at any position of nitrogen atom at position 1 and carbon atom at positions 2, 4, 5, 6 and 7 of indole ring;
R1is H, alkyl, haloalkyl or heteroatom-containing alkyl;
R2h, F, Cl, methoxy, methyl or ethyl;
R3is H or alkyl;
R1and/or R3The alkyl group has 1 to 6 carbon atoms.
2. A tripterine derivative is characterized in that the tripterine derivative is selected from the following compounds:
3. a preparation method of tripterine derivatives is characterized by comprising the following steps:
1) dissolving tripterine in an organic solvent, adding a Lewis acid catalyst and the compound of the formula A, stirring, and reacting to obtain a compound of the formula B; wherein R in the compound of formula A2H, F, Cl, methoxy, methyl or ethyl; the molar ratio of the tripterine to the compound of the formula A is 1: 2-3;
2) dissolving the compound of formula B in an organic solvent under anhydrous conditions, adding an inorganic base and a halogenated hydrocarbon R1X, stirring to react to obtain a compound of formula I, wherein R1And R3Are each independently of the other R1Is H or alkyl, R3And R1Same as R1And/or R3The alkyl group has 1 to 6 carbon atoms;
the reaction route is as follows:
4. the method for preparing a tripterine derivative according to claim 1, comprising the steps of:
1) dissolving tripterine in organic solvent, adding inorganic base and halogenated hydrocarbon R1X, nucleophilic substitution to obtain a compound of formula C;
2) dissolving the compound shown in the formula C in an organic solvent, adding a Lewis acid catalyst and the compound shown in the formula A, and stirring for reaction to obtain a compound shown in the formula D; wherein R is2H, F, Cl, methoxy, methyl or ethyl; wherein the molar ratio of the compound shown in the formula C to the compound shown in the formula A is 1: 2-3;
3) dissolving the compound of formula D in an organic solvent under anhydrous conditions, adding an inorganic base and a halogenated hydrocarbon R3X, stirring for reaction to obtain a compound of a formula II; wherein R is1And R3Are independently of one another radicals R1Is H, alkyl, halogenated alkyl or alkyl containing hetero atoms; r3Is H or alkyl, R1And R3Identical or different, R1And/or R3The alkyl group has 1 to 6 carbon atoms;
the reaction route is as follows:
5. the method according to claim 3 or 4, wherein the organic solvent is selected from dimethyl sulfoxide, N' N-dimethylformamide, dichloromethane, chloroform or methanol.
6. The process according to claim 3 or 4, wherein the Lewis acid catalyst is selected fromFrom Sc (OTf)3Ln (OTf)3, Re (OTf)3 or Sc (OPf) 3.
7. The method according to claim 3 or 4, wherein the amount of the Lewis acid catalyst is 0.1 mol% to 10 mol% of the tripterine.
8. The method according to claim 3 or 4, wherein the Lewis acid catalyst is used in an amount of 2 mol% to 6 mol% based on the tripterine.
9. A preparation process according to claim 3 or 4, characterized in that the inorganic base is chosen from potassium carbonate, sodium carbonate or cesium carbonate.
10. Use of a tripterine derivative according to claim 1 or 2 in the preparation of a medicament for the treatment of cancer.
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| CN101624415A (en) * | 2008-07-10 | 2010-01-13 | 朱永亮 | Tripterine and tripterine derivatives for treating cancer, inflammation and central nervous system diseases |
| CN102432663A (en) * | 2011-10-27 | 2012-05-02 | 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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| CN101624415A (en) * | 2008-07-10 | 2010-01-13 | 朱永亮 | Tripterine and tripterine derivatives for treating cancer, inflammation and central nervous system diseases |
| CN101352444A (en) * | 2008-09-11 | 2009-01-28 | 中国科学院广州生物医药与健康研究院 | New application of tripterine in pharmacy |
| CN102432663A (en) * | 2011-10-27 | 2012-05-02 | 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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