CN111410660B - Substituted perxanthenoxanthene compounds and uses thereof - Google Patents
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Abstract
The present invention discloses substituted xanthenoxanthene compounds of formula I. The substituted xanthenoxanthene compound provided by the invention has high antitumor activity and good prospect in preparing antitumor drugs.
Wherein R is1Selected from H, CN, COOCH3Or CONHCH2CH2OH，R2Selected from CN or COOCH3Or CONHCH2CH2OH。
Description
The technical field is as follows:
the invention relates to a compound with anticancer activity and the application field thereof, in particular to a substituted xanthene compound and the application thereof.
Background art:
photodynamic therapy (PDT) is an emerging medical discipline under research and development for the treatment of tumors and other benign diseases, and is a new therapy for tumors following traditional therapies for tumors such as surgery, radiotherapy, chemotherapy and immunotherapy.
The Xanthenoxanthene (peri-Xanthenoxanthene) is a condensed ring aromatic compound, can emit blue fluorescence, is a compound with strong fluorescence, and is a hole transport material with great potential, can be applied to OLEDs, and is expected to develop applications thereof in other fields.
The invention content is as follows:
the invention aims to provide a substituted xanthenoxanthene compound and application thereof, in particular to synthesis of the substituted xanthenoxanthenoxanthene compound and application thereof in preparing antitumor drugs, wherein the substituted xanthenoxanthenoxanthenoxanthenoxantheno compound has strong in-vitro photoperiod inhibition activity on human cervical cancer cells, human lung cancer cells, human gastric cancer cells and human liver cancer cells, has low dark toxicity, and is expected to be applied to photodynamic therapy of tumors.
The invention is realized by the following technical scheme:
a substituted xanthenoxanthene compound of formula I:
wherein R is1Selected from H, CN, COOCH3Or CONHCH2CH2OH，R2Selected from CN or COOCH3Or CONHCH2CH2OH。
The substituted xanthenoxanthene compounds of formula I are shown in Table 1:
the invention also provides a preparation method of the substituted perxanthene xanthene compound, and the reaction equation is as follows:
the method comprises the following steps: weighing reaction substrate and catalyst Cu (OAc)2Controlling the mass ratio of the reaction substrate to the catalyst to be 2:3, uniformly mixing the reaction substrate and the catalyst, placing the mixture into a small beaker, covering the small beaker by a surface dish, and then placing the small beaker into a container filled with carbon powderPutting the beaker in a microwave oven for reaction; and tracking the reaction by TLC (thin layer chromatography) until a reaction substrate disappears, adding a proper amount of water, filtering, drying filter residues, separating and purifying the obtained filter residues by using silica gel column chromatography, and taking a mixture of petroleum ether and ethyl acetate as an eluent to obtain yellow powdery solid, namely the reaction product.
In the reaction substrate
And
the mass ratio of (A) to (B) is 1: 1.
The 2-naphthol is used as a raw material, a series of novel substituted xanthene is obtained by solid phase synthesis under microwave radiation, and is innovatively applied to anti-tumor research, so that the 2-naphthol has strong in-vitro illumination proliferation inhibition activity on human cervical cancer cells, human lung cancer cells, human gastric cancer cells and human liver cancer cells, has low dark toxicity, and is expected to be applied to photodynamic therapy of tumors.
The invention also protects the application of the substituted xanthenoxanthene compound shown in the formula I in the preparation of antitumor drugs.
Preferably, the use of a substituted xanthenoxanthene compound in the manufacture of a medicament for the treatment of cervical cancer.
Preferably, the use of a substituted perxanthenoxanthene compound in the manufacture of a medicament for the treatment of lung cancer.
Preferably, the use of a substituted perxanthenoxanthene compound in the manufacture of a medicament for the treatment of gastric cancer.
Preferably, the use of a substituted xanthenoxanthene compound in the preparation of a medicament against liver cancer.
The invention also protects the application of a pharmaceutically acceptable pharmaceutical composition or preparation formed by the substituted xanthenoxanthene compound and pharmaceutically acceptable salts thereof in preparing antitumor drugs. A pharmaceutical composition comprising as active ingredient at least one substituted perxanthenoxanthene compound of formula I, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
The invention has the beneficial effects that:
(1) the substituted xanthenoxanthene compound has high antitumor activity and good prospect in preparing antitumor drugs.
(2) The preparation method of the substituted perixanthenoxanthene compound is simple, the reaction condition is mild, the speed is high, and the yield is high.
The specific implementation mode is as follows:
the following is a further description of the invention and is not intended to be limiting. Unless otherwise specified, the experimental materials and reagents in the invention are all conventional commercial products in the technical field.
When the substituted xanthenoxanthene is a mono-substituted xanthenoxanthene, the reaction equation is:
R1＝H，R2＝CN，COOCH3，CONHCH2CH2OH；
when the substituted xanthenoxanthene is a disubstituted xanthenoxanthene, the reaction equation is:
R1＝R2＝CN，COOCH3，CONHCH2CH2OH。
the substituted xanthenoxanthene compounds are prepared as follows: weighing reaction substrate and catalyst Cu (OAc)2Controlling the mass ratio of the mass sum of the reaction substrate to the catalyst to be 2:3,
and
is mixed evenly and placed in the mixture according to the mass ratio of 1:1The small beaker is covered by a watch glass, and then put into a big beaker filled with carbon powder to be put into a microwave oven for reaction. And tracking the reaction by TLC (thin layer chromatography) until the raw materials disappear, adding a proper amount of water, filtering, drying the filter residue, separating and purifying the obtained filter residue by using a silica gel column chromatography, and taking a mixture of petroleum ether and ethyl acetate as an eluent to obtain a yellow powdery solid, namely the reaction product.
Example 1: 3-Cyanoxanthenoxanthene (Compound 1)
The structural formula of the product is as follows:
the reaction time was 8.0min, the product was a yellow solid, and the yield was 57.8% as in the above preparation procedure.
mp 323.6℃；1H NMR(500MHz,DMSO-d6)δ:7.88(s,1H),7.65-7.63(d,J＝9.5Hz,1H),7.57-7.55(d,J＝9.5Hz,1H),7.30-7.21(m,4H),7.16-7.14(d,J＝9Hz,1H),7.08(s,1H),6.83-6.81(d,J＝7.5Hz,1H).IR(KBr)ν:3444.5,3053.1,2930.9,1637.4,1465.8,1270.4,1246.8,1077.6,821.6,775.9,614.6cm-1.HRMS calcd for C21H9NO2[M+H]+307.06333,found 307.06258。
Example 2: 3-Methoxycarbonylphenoxanthenoxanthene (Compound 2)
The structural formula of the product is as follows:
the reaction time was 6.0min, the product was a yellow solid, the yield was 61.2% as in the above preparation.
mp 272.2℃；1H NMR(500MHz,DMSO-d6)δ:7.99(s,1H),7.75-7.73(d,J＝9Hz,1H),7.55-7.53(d,J＝9Hz,1H),7.30-7.28(d,J＝8Hz,1H),7.23-7.20(q,J＝16Hz,2H),7.15-7.13(d,J＝10.5Hz,1H),6.82-6.80(d,J＝7Hz,1H),3.88(s,3H).IR(KBr)ν:2375.7,1716.9,1466.5,1302.5,1206.0,1071.0,806.3,729.5,588.5cm-1.HRMS calcd for C22H12O4[M+H]+340.07356,found 340.07283。
Example 3: 3- (N-hydroxyethyl carboxamido) xanthenoxanthene (Compound 3)
The structural formula of the product is as follows:
the reaction time was 9.0min, the product was a yellow solid, and the yield was 55.3% as in the above preparation procedure.
mp 253.4℃；1H NMR(500MHz,DMSO-d6)δ:8.42(s,1H),7.75(d,J＝1Hz,1H),7.55-7.53(d,J＝9.5Hz,1H),7.47-7.45(d,J＝9Hz,1H),7.17-7.15(d,J＝8Hz,1H),7.12-7.05(m,4H),6.74-6.73(d,J＝7Hz,1H),4.70(s,1H),350-3.48(d,J＝6Hz,2H).IR(KBr)ν:3398.8,3346.5,1629.7,1547.9,1466.0,1335.7,1252.2,1077.6,1053.0,811.6,759.8,525.9cm-1.HRMS calcd for C23H15NO4[M+H]+370.10794,found 370.10896。
Example 4: 3, 9-Dicyanofexanxanthene (Compound 4)
The structural formula of the product is as follows:
the reaction time was 10.0min, the product was a yellow solid, and the yield was 89.6% as in the above preparation procedure.
mp>400℃；1H NMR(500MHz,DMSO-d6)δ:7.81-7.80(d,J＝7Hz,2H),7.52-7.50(d,J＝9Hz,2H),7.09-7.07(d,J＝9Hz,2H),6.87(s,2H).IR(KBr)ν:3423.6,2365.1,1618.8,1499.7,1460.5,1264.1,1076.8,807.2,668.5,569.4cm-1.HRMS calcd for C22H8N2O2[M+H]+332.05858,found 332.05804。
Example 5: 3, 9-Dimethoxycarbonyl-s-xanthenoxanthene (Compound 5)
The structural formula of the product is as follows:
the reaction time is 12.0min, the product is yellow solid, and the yield is 85.3 percent.
mp 261.0℃；1H NMR(500MHz,DMSO-d6)δ:8.21(s,2H),7.98-7.96(d,J＝8.5Hz,2H),7.31-7.29(d,J＝9Hz,2H),6.87-6.85(d,J＝9Hz,2H).3.89(s,6H).IR(KBr)ν:2958.2,1642.4,1394.1,1286.1,1214.7,1092.0,1075.5,996.6,808.1,759.5,539.8cm-1.HRMS calcd for C24H14O6[M+H]+398.07904,found 398.07823。
Example 6: 3, 9-bis (N-hydroxyethyl carboxamido) xanthenoxanthene (Compound 6)
The structural formula of the product is as follows:
the reaction time was 12.0min, the product was a yellow solid, and the yield was 84.2% as in the above preparation procedure.
mp 251.6℃；1H NMR(500MHz,DMSO-d6)δ:8.41-8.40(d,J＝5.5Hz,2H),7.81(s,2H),7.63-7.61(d,J＝9Hz,2H),7.20-7.18(d,J＝9Hz,4H),4.67-4.65(t,J＝11.5Hz,1H),3.56-3.53(dd,J＝63Hz,4H),3.38-3.35(t,J＝12Hz,2H).IR(KBr)ν:3347.7,1712.5,1654.6,1500.41,287.9,1251.8,1076.7,810.4,759.1,543.6cm-1.HRMS calcd for C26H20N2O6[M+H]+456.13214,found 456.13172。
Example 7: test for antitumor Activity of substituted Comxanthoxanthene Compound 1-6
MTT assay was used to detect the inhibition of tumor cell growth in vitro by the substituted xanthenoxanthene compounds obtained in examples 1-6.
Dark toxicity test: respectively selectScreening human cervical cancer cell strain HeLa, human lung cancer cell A549, human gastric cancer cell strain SGC-7901 and human hepatoma cell Bel-7402. The specific method comprises the following steps: each tumor cell strain in logarithmic growth phase is expressed by 8 multiplied by 104Inoculating the cell amount of each well into a 96-well plate, placing the plate in an incubator for incubation for 24h, changing culture solution, and adding each drug with concentration gradient to make the final concentration of the drug be 10-6～10-4And (3) mol/L, setting 3 parallel multiple holes in each group, and setting a culture solution blank control hole. Then, the mixture was incubated in an incubator for 48 hours, 90. mu.L of a serum-free medium and 10. mu.L of MTT solution at a concentration of 5mg/mL were added to each well, and then the mixture was incubated in the incubator for 4 hours, added to a 100. mu.L DMSO micro-shaker, and shaken for 15 minutes, and then the absorbance was measured at 490nm using a microplate reader. Cell survival was calculated as follows: cell survival (%) × 100% (experimental)/blank). Drawing a cell growth curve by the concentration of each group of medicines and the corresponding cell survival rate, and reading out the concentration of a compound corresponding to the cell survival rate of 50%, wherein the concentration is IC50Values (Dark), see table 2.
Phototoxicity test: respectively selecting and screening a human cervical cancer cell strain HeLa, a human lung cancer cell A549, a human gastric cancer cell strain SGC-7901 and a human hepatoma cell Bel-7402. The specific method comprises the following steps: each tumor cell strain in logarithmic growth phase is expressed by 8 multiplied by 104Inoculating the cell amount of each well into a 96-well plate, placing the plate in an incubator for incubation for 24h, changing culture solution, and adding each drug with concentration gradient to make the final concentration of the drug be 10-6～10-4And (3) mol/L, setting 3 parallel multiple holes in each group, and setting a culture solution blank control hole. The cells were irradiated with white light for 1h, incubated in an incubator for 48h, and 90. mu.L of serum-free medium and 10. mu.L of 5mg/mL MTT solution were added to each well, followed by incubation in an incubator for 4h, shaking in a 100. mu.L DMSO micro shaker for 15min, and then absorbance was measured at 490nm using a microplate reader. Cell survival was calculated as follows: cell survival (%) × 100% (experimental)/blank). Plotting the concentration of each group of drugs and the corresponding cell survival rate to obtain a cell growth curve, and reading out the compound concentration corresponding to the cell survival rate of 50%, which isThe concentration is IC50Values (Light), see table 2 for results.
TABLE 2 in vitro cytotoxicity (IC) of substituted xanthenoxanthene Compounds 1-650，μmol/L)
As can be seen from Table 2, the IC of compounds 1-6 on four tumor cells50Values (Dark) are all>100. mu. mol/L, which indicates that they have extremely low dark toxicity; meanwhile, the compounds 1 to 6 show high phototoxicity to four tumor cells, particularly the compound 3, and the phototoxicity to Heal and Bel-7402 is 0.091 mu mol/L and 0.074 mu mol/L respectively. The results show that the compounds 1-6 are potential PDT antitumor drugs.
The detailed description is specific to possible embodiments of the invention, which are not intended to limit the scope of the invention, but rather are intended to include equivalent implementations or modifications within the scope of the invention.
Claims (4)
1. A substituted xanthenoxanthene compound of formula I:
wherein R is1Selected from H, CN, COOCH3Or CONHCH2CH2OH，R2Selected from CN, COOCH3Or CONHCH2CH2OH。
2. The substituted xanthenoxanthene compound of claim 1 wherein said substituted xanthenoxanthene compound of formula i is as shown in the table:
3. the process for preparing a substituted xanthenoxanthene compound of claim 1 wherein the reaction equation is as follows:
the method comprises the following steps: weighing reaction substrate and catalyst Cu (OAc)2Controlling the mass ratio of the reaction substrate to the catalyst to be 2:3, uniformly mixing the reaction substrate and the catalyst, placing the mixture into a reaction container, placing the reaction container into a container filled with carbon powder, placing the container into a microwave oven for reaction, tracking the reaction by TLC until the raw materials disappear, adding water for filtration, separating and purifying the obtained filter residue by using a silica gel column chromatography, and obtaining yellow powdery solid, namely the reaction product, by using a mixture of petroleum ether and ethyl acetate as an eluent.
4. The use of the substituted perxanthenoxanthene compound according to claim 1 or 2 for the preparation of an anti-cervical cancer drug, an anti-lung cancer drug, an anti-gastric cancer drug or an anti-liver cancer drug.
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| CN1372467A (en) * | 1999-08-13 | 2002-10-02 | 福托金公司 | Improved topical medicaments and methods for photodynamic treatment of disease |
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| CN101490208A (en) * | 2006-07-28 | 2009-07-22 | 默克专利有限公司 | Novel materials for organic electroluminescent devices |
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