CN119504483A - Synthesis and antitumor activity of adamantanecarboxylic acid derivatives - Google Patents
Synthesis and antitumor activity of adamantanecarboxylic acid derivatives Download PDFInfo
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Abstract
The invention discloses a novel synthesis of a small molecular formula (1) of a drug containing an adamantane structure and an anti-tumor activity researchWherein R isThe invention takes 3-bromo-1-adamantanecarboxylic acid as an initial raw material, then obtains 5- (adamantane-1-yl) -2-hydroxybenzaldehyde through free radical substitution, oxidation reaction and demethylation reaction, and then obtains a target compound through condensation reaction of 5- (adamantane-1-yl) -2-hydroxybenzaldehyde and amino. CCK-8 experiments are carried out on target compounds, and the conclusion is drawn that the target compounds 8a-8f and 5-fluorouracil are tested at the concentration of 20 mu M, so that the compound 8c has the best inhibition effect on HeLa and A549 cells, and the 8a has better inhibition effect on HepG2 cells. The IC 50 value calculation is carried out on the target compound at each concentration, the value of the 8c on HeLa and A549 cell IC 50 is minimum, the inhibition effect is best, the value of the 8a on HepG2 cell IC 50 is minimum, and the inhibition effect is best.
Description
Technical Field
The invention relates to synthesis of a drug small molecule containing an adamantane structure and anti-tumor activity research.
Background
Cancer is considered the second most fatal disease. According to global cancer report 2021 issued by World Health Organization (WHO) 2021, 2 and 3, the global cancer morbidity and mortality is growing at a striking rate, with an average of 1 death from cancer in every 8 deaths. Reports predict that global cancer cases will continue to grow, from 1400 tens of thousands in 2021 to 1900 tens of thousands in 2025, to 2400 tens of thousands in 2035. Lung cancer, breast cancer, colon cancer and melanoma are all the most common types of cancer in developing and developed countries. Lung and breast cancer are more prevalent in developed countries. Traditional methods of tumor treatment include surgical treatment, radiation treatment, and chemotherapy. However, it is well known that chemotherapy causes a number of adverse effects such as bone marrow depression (cytopenia), gastrointestinal reactions, alopecia, fever, rash, cardiotoxicity, hepatotoxicity, neurotoxicity, urinary tract toxicity, local phlebitis, teratogenesis, mutagenesis, carcinogenesis, etc., and it is imperative to continually find better antitumor drugs.
Adamantane is mainly used for synthesizing anticancer, antitumor and other specific medicines, is alicyclic hydrocarbon with excellent liposolubility, and has non-toxic skeleton and can change its pharmacological activity. According to previous studies, it has been demonstrated that the introduction of an amino moiety into a molecule generally improves water solubility and enhances its anticancer activity, and that the inhibition of tumor cells will also have different effects due to the different physicochemical properties of the different substituents, which in turn determine the properties of the target compound. The study of these compounds will provide valuable information for the synthesis and study of new small molecule anticancer inhibitors.
Disclosure of Invention
The invention discloses a preparation method of a drug small molecule containing an adamantane structure, which uses a CCK-8 method to carry out toxicity experiments on cells and evaluates the antiproliferative effect of a compound on A549, heLa, MCF-7, hep G2 and normal mouse fibroblast L929.
The invention adopts the following technical scheme that the medicine containing adamantane structure has the following structural formula:
In the invention, R is R 1,R2,R3 is H, OCH 3, or C 2H4O2, each alone.
The 3- ((benzyloxy) carbonyl) adamantane-1-yl) phenoxy) acrylic acid is synthesized by taking 3-bromo-1-adamantanecarboxylic acid as a starting material through typical Friedel-crafts reaction and final multi-step reaction such as hydrolysis reaction, and the structural formula is as follows:
In the invention, 3- ((benzyloxy) carbonyl) adamantan-1-yl) phenoxy) acrylic acid and different amine compounds are subjected to coupling reaction to obtain the drug micromolecule containing an adamantan structure, wherein the drug micromolecule contains an adamantan structure represented by the formula (1).
The invention is characterized by nuclear magnetic resonance, high resolution mass spectrum, infrared spectrum and the like, and the result fully proves the synthesis of the compound.
Drawings
FIG. 1 is a synthetic route;
FIG. 2 is a target product of a synthetic route;
FIG. 3 is a hydrogen spectrum of an intermediate compound;
FIGS. 4-9 are hydrogen and carbon spectra of target compounds;
FIG. 10 is the inhibition of various cancer cells by a target compound and 5-fluorouracil at 20 micromolar concentrations;
FIG. 11 is a graph of IC50 values of target compounds;
Detailed Description
The following detailed description of the embodiments of the present invention is provided on the premise of the technical solution of the present invention, and the detailed implementation manner and specific operation process are provided, and it should be noted that, for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered as the protection scope of the present invention.
EXAMPLE 1 Synthesis of 3- ((benzyloxy) carbonyl) adamantan-1-yl) phenoxy) acrylic acid
(1) Synthesis of benzyl-3- (4- (3-methoxy-3-oxoprop-1-en-1-yl) oxy) phenyl) adamantane-1-carboxylate (intermediate Compound 5)
Taking a 100mL single-port bottle, sequentially adding 0.1g of benzyl-3- (4-hydroxyphenyl) adamantane-1-carboxylate, adding 0.14g of triphenylphosphine, adding quantitative toluene to dissolve the solution, adding 100 mu L of methyl propiolate, transferring the whole reaction system into a 115 ℃ oil pot, connecting a straight condensing tube, introducing nitrogen, and reacting for 3 hours. After the reaction, cooling to room temperature, concentrating, eluting with eluent (V petroleum ether: V ethyl acetate=5:1) by column chromatography, and after eluting, spinning out the solvent by a rotary evaporator, and drying the residue in a vacuum drying oven to obtain white solid. Yield is good ：55％.1H NMR(400MHz,Chloroform-d)δ7.80(d,J＝12.2Hz,1H),7.34(s,7H),7.01(d,J＝8.6Hz,2H),5.54(d,J＝12.2Hz,1H),5.12(s,2H),3.73(s,3H),2.25(s,2H),2.04(s,2H),1.97(s,4H),1.87(s,4H),1.74(s,2H).
(2) Synthesis of 3- (4- (3- ((benzyloxy) carbonyl) adamantan-1-yl) phenoxy) acrylic acid
Taking a 100mL single-port bottle, sequentially adding 0.1g of benzyl-3- (4- ((-3-methoxy-3-oxo-prop-1-en-1-yl) oxy) phenyl) adamantane-1-carboxylate, adding 1.47g of sodium hydroxide, adding 10mL of water and quantitatively taking absolute ethyl alcohol as a reaction solvent, transferring the whole reaction system into an oil pan at 80 ℃, connecting a condenser tube, protecting by nitrogen, and refluxing for 4 hours. And cooling the reaction product to room temperature after the reaction is finished, taking out the rotor, removing ethanol, adding diluted concentrated hydrochloric acid to enable the pH value to be acidic, separating out flocculent precipitate, filtering, and drying a filter cake in a vacuum drying oven for one night to obtain white solid. The yield thereof was found to be 98%.
1H NMR(400MHz,Chloroform-d)δ7.88(d,J＝12.2Hz,1H),7.37(s,2H),7.35(s,5H),7.03(d,J＝8.5Hz,2H),5.51(d,J＝12.2Hz,1H),5.12(s,2H),2.25(s,2H),2.04(s,2H),1.96(d,J＝5.8Hz,4H),1.88(s,4H),1.74(s,2H).
EXAMPLE 2 Synthesis of target Compounds 8a-8f
(1) Synthesis of benzyl-3- (4- ((3-oxo-3- (phenylamino) prop-1-en-1-yl) oxy) phenyl) adamantane-1-carboxylate (Compound 8 a)
A100 mL single-necked flask was taken, 0.1g of 3- (4- (3- ((benzyloxy) carbonyl) adamantan-1-yl) phenoxy) acrylic acid was sequentially added at normal temperature, 0.13g of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) and 0.09g of 1-hydroxybenzotriazole (HOBt) were added, N-Diisopropylethylamine (DIPEA). Mu.L were dissolved by adding a fixed amount of dichloromethane and ultra-dry tetrahydrofuran, and the whole reaction system was transferred to a magnetic stirrer and reacted at room temperature under nitrogen protection for 1 hour. After 1 hour, 42. Mu.L of aniline was added, and the reaction was continued for 12 hours. After the reaction, the mixture was washed with saturated NaCl solution and dichloromethane several times, dried over anhydrous magnesium sulfate for one hour, suction-filtered after the drying was completed, the filtrate was concentrated, eluted by column chromatography using an eluent (V dichloromethane: V ethyl acetate=30:1), the solvent was removed after elution, and the residue was dried in a vacuum oven overnight to give a white solid. Yield is good ：32％.1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),7.73(d,J＝12.0Hz,1H),7.62(d,J＝8.0Hz,2H),7.42(d,J＝8.7Hz,2H),7.38–7.26(m,7H),7.14(d,J＝8.6Hz,2H),7.02(t,J＝7.3Hz,1H),5.84(d,J＝12.0Hz,1H),5.10(s,2H),2.17(s,2H),1.97(d,J＝16.1Hz,3H),1.84(dd,J＝20.8,11.0Hz,9H),1.68(s,2H).
(2) Synthesis of benzyl-3- (4- (E) -3- ((2-methoxyphenyl) amino) -3-oxoprop-1-en-1-yl) oxy) phenyl) adamantane-1-carboxylate (Compound 8 b)
A100 mL single-necked flask was taken, 0.1g of 3- (4- (3- ((benzyloxy) carbonyl) adamantan-1-yl) phenoxy) acrylic acid was sequentially added at normal temperature, 0.13g of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) and 0.09g of 1-hydroxybenzotriazole (HOBt) were added, N-Diisopropylethylamine (DIPEA). Mu.L were dissolved by adding a fixed amount of dichloromethane and ultra-dry tetrahydrofuran, and the whole reaction system was transferred to a magnetic stirrer and reacted at room temperature under nitrogen protection for 1 hour. After 1 hour, 80. Mu.L of o-methoxyaniline was added thereto, and the reaction was continued for 12 hours. After the reaction, the mixture was washed with saturated NaCl solution and dichloromethane several times, dried over anhydrous magnesium sulfate for one hour, suction-filtered after the drying was completed, the filtrate was concentrated, eluted by column chromatography using an eluent (V dichloromethane: V ethyl acetate=30:1), the solvent was removed after elution, and the residue was dried in a vacuum oven overnight to give a white solid. Yield is good ：32％.1H NMR(400MHz,Chloroform-d)δ7.85(d,J＝11.7Hz,1H),7.40(d,J＝18.5Hz,2H),7.33(d,J＝8.7Hz,7H),7.14(s,1H),7.01(d,J＝8.6Hz,2H),6.85(d,J＝8.8Hz,2H),5.66(d,J＝11.7Hz,1H),5.12(s,2H),3.78(s,3H),2.24(s,2H),2.04(s,2H),1.96(d,J＝6.8Hz,4H),1.88(s,4H),1.74(s,2H).
(3) Synthesis of benzyl-3- (4- (E) -3- ((3-methoxyphenyl) amino) -3-oxoprop-1-en-1-yl) oxy) phenyl) adamantane-1-carboxylate (Compound 8 c)
A100 mL single-necked flask was taken, 0.1g of 3- (4- (3- ((benzyloxy) carbonyl) adamantan-1-yl) phenoxy) acrylic acid was sequentially added at normal temperature, 0.13g of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) and 0.09g of 1-hydroxybenzotriazole (HOBt) were added, N-Diisopropylethylamine (DIPEA). Mu.L were dissolved by adding a fixed amount of dichloromethane and ultra-dry tetrahydrofuran, and the whole reaction system was transferred to a magnetic stirrer and reacted at room temperature under nitrogen protection for 1 hour. After 1 hour, 80. Mu.L of m-methoxyaniline was added thereto, and the reaction was continued for 12 hours. After the reaction, the mixture was washed with saturated NaCl solution and dichloromethane several times, dried over anhydrous magnesium sulfate for one hour, suction-filtered after the drying was completed, the filtrate was concentrated, eluted by column chromatography using an eluent (V dichloromethane: V ethyl acetate=30:1), the solvent was removed after elution, and the residue was dried in a vacuum oven overnight to give a white solid. Yield is good ：32％.1H NMR(400MHz,DMSO-d6)δ9.90(s,1H),7.73(d,J＝12.0Hz,1H),7.42(d,J＝8.7Hz,2H),7.35(p,J＝7.3Hz,6H),7.16(dd,J＝17.3,8.4Hz,4H),6.61(d,J＝9.7Hz,1H),5.81(d,J＝12.0Hz,1H),5.10(s,2H),3.72(s,3H),2.17(s,2H),1.95(s,2H),1.90–1.80(m,8H),1.69(s,2H).
(4) Synthesis of benzyl-3- (4- (E) -3- ((4-methoxyphenyl) amino) -3-oxoprop-1-en-1-yl) oxy) phenyl) adamantane-1-carboxylate (Compound 8 d)
A100 mL single-necked flask was taken, 0.1g of 3- (4- (3- ((benzyloxy) carbonyl) adamantan-1-yl) phenoxy) acrylic acid was sequentially added at normal temperature, 0.13g of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) and 0.09g of 1-hydroxybenzotriazole (HOBt) were added, N-Diisopropylethylamine (DIPEA). Mu.L were dissolved by adding a fixed amount of dichloromethane and ultra-dry tetrahydrofuran, and the whole reaction system was transferred to a magnetic stirrer and reacted at room temperature under nitrogen protection for 1 hour. After 1 hour, 0.09g of p-anisole was added and the reaction was continued for 12 hours. After the reaction, the mixture was washed with saturated NaCl solution and dichloromethane several times, dried over anhydrous magnesium sulfate for one hour, suction-filtered after the drying was completed, the filtrate was concentrated, eluted by column chromatography using an eluent (V dichloromethane: V ethyl acetate=5:1), the solvent was removed after elution, and the residue was dried in a vacuum oven overnight to give a white solid. Yield is good ：32％.1H NMR(400MHz,DMSO-d6)δ9.79(s,1H),7.70(d,J＝11.9Hz,1H),7.53(d,J＝8.7Hz,2H),7.44–7.28(m,7H),7.13(d,J＝8.5Hz,2H),6.87(d,J＝8.9Hz,2H),5.81–5.76(m,1H),5.10(s,2H),3.71(s,3H),2.17(s,2H),1.94(s,2H),1.84(dd,J＝21.0,11.3Hz,8H),1.69(s,2H).
(5) Benzyl-3- (4- ((3- ((3- (methoxycarbonyl) phenyl) amino) -3-oxoprop-1-en-1-yl) oxy) phenyl) adamantane-1-carboxylate (compound 8 e)
A100 mL single-necked flask was taken, 0.1g of 3- (4- (3- ((benzyloxy) carbonyl) adamantan-1-yl) phenoxy) acrylic acid was sequentially added at normal temperature, 0.13g of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) and 0.09g of 1-hydroxybenzotriazole (HOBt) were added, N-Diisopropylethylamine (DIPEA). Mu.L were dissolved by adding a fixed amount of dichloromethane and ultra-dry tetrahydrofuran, and the whole reaction system was transferred to a magnetic stirrer and reacted at room temperature under nitrogen protection for 1 hour. After 1 hour, 0.14g of methyl 2-aminobenzoate was added, and the reaction was continued for 12 hours. Washing with saturated NaCl solution and dichloromethane for several times after the reaction, drying with anhydrous magnesium sulfate for one hour, suction filtering after the drying, concentrating the filtrate, eluting by column chromatography with eluent (V petroleum ether: V ethyl acetate=5:1), removing the solvent after eluting, and drying the residue in a vacuum drying oven for one night to obtain white solid. Yield is good ：35％.1H NMR(400MHz,Chloroform-d)δ8.06(s,1H),7.90(d,J＝11.7Hz,2H),7.77(d,J＝7.5Hz,1H),7.34(s,8H),7.03(d,J＝8.5Hz,2H),5.66(d,J＝11.7Hz,1H),5.12(s,2H),3.90(s,3H),2.24(s,2H),2.04(s,2H),1.96(d,J＝8.4Hz,4H),1.88(s,4H),1.73(s,2H).
(5) Benzyl-3- (4- ((3- ((2- (methoxycarbonyl) phenyl) amino) -3-oxoprop-1-en-1-yl) oxy) phenyl) adamantane-1-carboxylate (compound 8 f)
A100 mL single-necked flask was taken, 0.1g of 3- (4- (3- ((benzyloxy) carbonyl) adamantan-1-yl) phenoxy) acrylic acid was sequentially added at normal temperature, 0.13g of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) and 0.09g of 1-hydroxybenzotriazole (HOBt) were added, N-Diisopropylethylamine (DIPEA). Mu.L were dissolved by adding a fixed amount of dichloromethane and ultra-dry tetrahydrofuran, and the whole reaction system was transferred to a magnetic stirrer and reacted at room temperature under nitrogen protection for 1 hour. After 1 hour, 0.14g of methyl 2-aminobenzoate was added, and the reaction was continued for 12 hours. Washing with saturated NaCl solution and dichloromethane for several times after the reaction, drying with anhydrous magnesium sulfate for one hour, suction filtering after the drying, concentrating the filtrate, eluting by column chromatography with eluent (V petroleum ether: V ethyl acetate=5:1), removing the solvent after eluting, and drying the residue in a vacuum drying oven for one night to obtain white solid. Yield is good ：28％.1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),8.31(s,1H),7.89(d,J＝8.1Hz,1H),7.78(d,J＝12.0Hz,1H),7.62(d,J＝7.7Hz,1H),7.35(s,8H),7.13(d,J＝8.6Hz,2H),5.83(d,J＝12.0Hz,1H),5.09(s,2H),3.84(s,3H),2.15(s,2H),1.94(s,2H),1.86(s,4H),1.81(d,J＝11.7Hz,4H),1.66(s,2H).
Example 3 in vitro cytotoxicity evaluation results
The invention carries out CCK-8 experimental test on target compounds 8a-8f, expresses HeLa, A549, hepG2 and L929, and tests the target compounds 8a-8f and 5-fluorouracil at the concentration of 20 mu M. From the graph, the 8c containing the amine compound structure with the methoxy group grafted at the tail end of the benzene ring of the adamantane structure has the best inhibition effect on HeLa cells and HepG2 cells, the inhibition rates are 66.88% and 70.14%, and the inhibition rates of 5-fluorouracil on HeLa cells and HepG2 cells are 58.85% and 46.66%, respectively. The 8a containing the amine compound structure with the benzene ring end of the adamantane structure grafted with no substituent has the best inhibition effect on the A549 cells, the inhibition rate is 48.33%, and the inhibition rate of 5-fluorouracil on the A549 cells is 41.13%.
The invention calculates the IC50 values of the compounds 8a-8f on HeLa, A549 and HepG2 cells at the concentrations of 40 mu M, 20 mu M, 10 mu M and 5 mu M, wherein the IC50 values of the compounds 8a and 8c on the HepG2 cells are lower, the IC50 values of the compounds 8c on the HeLa cells are lower, and the IC50 values of the compounds 8a on the A549 cells are lower. For amine compounds with benzene ring terminal connected with different groups at the 3 rd position, the drug effect of the compound containing methoxy in HeLa cells and HepG2 cells is obviously better than that of the compound containing methyl benzoate. In contrast, in a549 cells, the compounds without substituents were more potent than the compounds with methyl benzoate, while all the target compounds were non-toxic to L929 cells. FIG. 11 shows the IC50 values of the target compounds 8a-8f for different cells.
Claims (5)
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130237542A1 (en) * | 2010-10-20 | 2013-09-12 | Dongguk University Industry-Academic Cooperation Foundation | Aryloxy phenoxy acrylic compound having hif-1 inhibition activity, method for preparing same, and pharmaceutical composition containing same as an active ingredient |
| US20200031764A1 (en) * | 2017-03-09 | 2020-01-30 | Dongguk University Gyeongju Campus Industry-Academy Cooperation Foundation | Novel compound having malate dehydrogenase inhibitory activity and pharmaceutical composition for preventing or treating cancer comprising same as active ingredient |
| CN115003650A (en) * | 2020-01-23 | 2022-09-02 | 万可真株式会社 | Disubstituted adamantyl derivatives, pharmaceutically acceptable salts thereof, and pharmaceutical compositions for inhibiting cancer growth comprising the same as active ingredients |
| CN118515580A (en) * | 2023-10-24 | 2024-08-20 | 长春工业大学 | Synthesis and anti-tumor activity research of novel adamantane structure-containing drug small molecules |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20130237542A1 (en) * | 2010-10-20 | 2013-09-12 | Dongguk University Industry-Academic Cooperation Foundation | Aryloxy phenoxy acrylic compound having hif-1 inhibition activity, method for preparing same, and pharmaceutical composition containing same as an active ingredient |
| US20200031764A1 (en) * | 2017-03-09 | 2020-01-30 | Dongguk University Gyeongju Campus Industry-Academy Cooperation Foundation | Novel compound having malate dehydrogenase inhibitory activity and pharmaceutical composition for preventing or treating cancer comprising same as active ingredient |
| CN115003650A (en) * | 2020-01-23 | 2022-09-02 | 万可真株式会社 | Disubstituted adamantyl derivatives, pharmaceutically acceptable salts thereof, and pharmaceutical compositions for inhibiting cancer growth comprising the same as active ingredients |
| CN118515580A (en) * | 2023-10-24 | 2024-08-20 | 长春工业大学 | Synthesis and anti-tumor activity research of novel adamantane structure-containing drug small molecules |
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