CN111646941A - Sulfonamide derivative and preparation method and application thereof - Google Patents
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Abstract
The invention relates to a sulfonamide derivative and a preparation method and application thereof. The invention synthesizes and discovers the compounds for the first time, the compounds have certain activity of inhibiting human colon cancer cells (SW480 and HCT116), and have potential value in the aspects of development and application of anti-tumor drugs; meanwhile, the invention carries out the evaluation of the alpha-glucosidase inhibitory activity of the synthesized compound, and the result shows that the compound also has certain alpha-glucosidase inhibitory activity, which indicates that the compound also has wide prospect in the development and application of diabetes treatment medicines.
Description
Technical Field
The invention belongs to the field of synthesis of new compounds and application of medicines, and relates to a sulfonamide derivative, which comprises synthesis, activity evaluation and application.
Background
The sulfonamide derivative has various biological activities, and has important applications in the field of biological medicines, such as anticancer, sterilization, anesthesia and analgesia, human carbonic anhydrase activity inhibition, and the like. In recent years, the research on sulfonamide derivatives is paid more and more attention by scientific researchers, and a plurality of medicines with good curative effects, such as celecoxib for treating rheumatoid arthritis, a hypoglycemic drug glibenclamide and an anti-migraine drug sumatriptan, are developed. It is found that the sulfonamide group is an important functional group, and efficient biomedicine and new functional materials can be developed by accessing different functional groups. Therefore, synthesis and activity studies of sulfonamide derivatives are receiving much attention.
In 1932, Domagk, a German scientist, conducted cellular studies on Bailangduo compounds, and found that sulfonamide groups in the molecules have a proliferation-inhibiting effect on Staphylococcus aureus, Streptococcus pneumoniae, and the like. In 2004, robert synthesized a novel cyclic sulfonamide compound, which was found to effectively inhibit Matrix Metalloproteinases (MMPs), blocking the invasion of primary and secondary tumors. In 2004, building Yong Jun et al, starting from a splicing idea, introduce methanesulfonamide into a benzanilide structure to synthesize an N- (4-benzamidophenyl) methanesulfonamide compound, and research shows that the anti-inflammatory effect of the N- (4-benzamidophenyl) methanesulfonamide compound is obvious. 2006 Guapina et al report a series of flavone sulfonamides compounds, the inhibitory activity of which on human leukemia cells and human cervical cancer cells in an antitumor test is higher than that of the traditional drug 5-fluorouracil. In 2020, Sunwawa et al reported that 1, 4-naphthoquinone derivatives have excellent activity of inhibiting human colon cancer cells (SW480 and HCT116), and the derivative structure thereof has a sulfonamide group.
Disclosure of Invention
The invention aims to provide synthesis of a novel sulfonamide derivative and application of the novel sulfonamide derivative in the aspects of tumor resistance and diabetes resistance.
The purpose of the invention is realized by the following technical scheme:
the invention synthesizes a novel sulfonamide derivative with the following structural general formula I:
wherein R is1Is cyclohexylimino, piperazinyl or 4-piperidyl.
The general structural formula II is as follows:
wherein R is1Is cyclohexylimino or piperazinyl.
Structural formula III is as follows:
structural formula IV is as follows:
the invention has the advantages and beneficial effects that:
1. the reaction of the invention does not need anhydrous and anaerobic operation, has simple and convenient operation, cheap and easily obtained raw materials and reagents, and is suitable for large-scale production and development.
2. The sulfonamide derivative has better activity of resisting human colon cancer cells.
3. The sulfonamide derivative has certain alpha-glucosidase inhibition activity.
Drawings
FIG. 1 is a nuclear magnetic hydrogen spectrum of compound 1 in deuterated dimethyl sulfoxide;
FIG. 2 is a nuclear magnetic hydrogen spectrum of compound 2 in deuterated dimethyl sulfoxide;
FIG. 3 is a nuclear magnetic hydrogen spectrum of compound 3 in deuterated dimethyl sulfoxide;
FIG. 4 is a nuclear magnetic hydrogen spectrum of compound 4 in deuterated trichloromethane;
FIG. 5 is a nuclear magnetic hydrogen spectrum of compound 5 in deuterated trichloromethane;
FIG. 6 is a nuclear magnetic hydrogen spectrum of compound 6 in deuterated trichloromethane;
FIG. 7 is a nuclear magnetic hydrogen spectrum of compound 7 in deuterated trichloromethane;
Detailed Description
For understanding the present invention, the present invention will be further described with reference to the following examples: the following examples are illustrative and not intended to be limiting, and are not intended to limit the scope of the invention.
A sulfonamide derivative I is obtained by the following synthetic route:
the preparation of the sulfonamide derivative I specifically comprises the following steps:
(1) adding triethylamine (3.0eq.) and sulfonyl chloride (1.2eq.) into a dichloromethane (10mL) solution of a primary amine or secondary amine raw material (1.0eq.), reacting at room temperature for about 4-8h, monitoring by Thin Layer Chromatography (TLC), after the reaction is completed, diluting with dichloromethane (10mL), washing with water and saturated common salt water, and using anhydrous Na for an organic layer2SO4Drying, filtering, evaporating the solvent to dryness, and purifying by silica gel column chromatography to obtain a product V.
(2) Dissolving the product V obtained in the step (1) in methanol, adding an aqueous sodium hydroxide solution (5M, 3eq.) into the methanol, refluxing the mixture for about 2 to 4 hours, monitoring the reaction by Thin Layer Chromatography (TLC), concentrating the reaction mixture under reduced pressure after the reaction is completed, diluting the concentrated reaction mixture with dichloromethane (10mL), washing the diluted reaction mixture with water and saturated brine, and using anhydrous Na as an organic layer2SO4Drying, filtering, evaporating the solvent to dryness, and purifying by silica gel column chromatography to obtain a product VI.
The specific preparation examples provided by the invention are as follows:
example 1
A process for preparing the sulfonamide derivatives of claim 1, comprising the steps of:
reacting a primary amine or secondary amine raw material with p-acetamido-benzenesulfonyl chloride to obtain V, removing an acetyl protecting group of an amino group under an alkaline condition to obtain VI, and reacting the VI with 1, 4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester to obtain a sulfonamide derivative, wherein the reaction formula is as follows:
in particular to the synthesis of a compound 1.
A solution of cycloheximide (2mL, 17.8mmol) in dichloromethane (50mL) was added triethylamine (7.4mL, 53.5mmol) and p-acetamidobenzenesulfonyl chloride (5g, 21.4mmol) and reacted at room temperature for about 8h, monitored by Thin Layer Chromatography (TLC), after completion of the reaction, diluted with dichloromethane (10mL), washed with water and saturated brine, and the organic layer was washed with anhydrous Na2SO4Drying, filtering, evaporating the solvent, and purifying by silica gel column chromatography (20: 1-2: 1v/v petroleum ether: ethyl acetate) to obtain the product VII.
Dissolving the product VII (600mg, 2.02mmol) obtained in the step (1) in methanol, adding aqueous sodium hydroxide (5M, 3eq.) to the solution, refluxing the mixture for about 4 hours, monitoring by Thin Layer Chromatography (TLC), concentrating the reaction mixture under reduced pressure after the reaction is completed, diluting the concentrated reaction mixture with dichloromethane (30mL), washing the diluted reaction mixture with water and saturated brine respectively, and using anhydrous Na as an organic layer2SO4Drying, filtering, evaporating solvent, and purifying by silica gel column Chromatography (CH)2Cl2MeOH ═ 100: 1 to 10: 1v/v) to give product VIII.
example 2
Synthesis of Compound 2.
The synthesis of example 2 is the same as that of compound 1 above.
Yield: 63%; structural parameters are as follows:1H-NMR(400MHz，DMSO-d6)12.24(s，1H)，8.48(d，J＝8.8Hz，2H)，8.09(d，J＝6.4Hz，2H)，8.04(d，J＝8.4Hz，2H)，7.69(t，J＝7.2Hz，1H)，7.58(d，J＝8.4Hz，1H)，7.37(t，J＝7.2Hz，1H)，3.70(s，2H)，3.32(s，2H)，3.06(s，4H)；13C-NMR(100MHz，DMSO-d6)173.3，166.1，150.7，141.5，141.2，139.8，132.7，129.6，126.2，125.8，125.3，124.6，119.1，117.2，46.8，46.3.HRMS(ESI-TOF)m/z calcd.for C20H20N4O4S[M+Na]+：435.1097，found 435.1098.
example 3
Synthesis of Compound 3.
The synthesis of example 3 was the same as that of compound 1 above.
Yield: 60 percent; structural parameters are as follows:1H-NMR(400MHz，DMSO-d6)12.97(s，1H)，8.91(s，1H)，8.34(d，J＝7.6Hz，1H)，7.97(d，J＝8.8Hz，2H)，7.82(t，J＝7.6Hz，1H)，7.77(s，1H)，7.72(d，J＝8.8Hz，2H)，7.55(t，J＝7.6Hz，1H)，3.66(d，J＝11.2Hz，2H)，2.41(s，4H)，2.23(t，J＝11.2Hz，3H)，1.75(d，J＝11.6Hz，2H)，1.44(s，6H)，1.35(d，J＝5.2Hz，2H)，1.23(s，1H)；13C-NMR(100MHz，DMSO-d6)176.8，164.1，145.5，143.4，140.2，133.5，129.6，129.4，126.5，125.9，125.8，120.3，119.9，110.4，61.1，50.0，46.3，27.1，26.2，24.7.HRMS(ESI-TOF)m/zcalcd.for C26H30N4O4S[M+Na]+：517.1880，found 517.1881.
the preparation method of the sulfonamide derivative II comprises the following steps:
wherein the preparation of the sulfonamide derivative II specifically comprises the following steps:
(1) adding triethylamine (3.0eq.) and sulfonyl chloride (1.2eq.) into a dichloromethane (10mL) solution of a primary amine or secondary amine raw material (1.0eq.), reacting at room temperature for about 4-8h, monitoring by Thin Layer Chromatography (TLC), after the reaction is completed, diluting with dichloromethane (10mL), washing with water and saturated common salt water, and using anhydrous Na for an organic layer2SO4Drying, filtering, evaporating the solvent to dryness, and purifying by silica gel column chromatography to obtain a product V.
(2) Dissolving the product V obtained in the step (1) in methanol, adding an aqueous sodium hydroxide solution (5M, 3eq.) into the methanol, refluxing the mixture for about 2 to 4 hours, monitoring the reaction by Thin Layer Chromatography (TLC), concentrating the reaction mixture under reduced pressure after the reaction is completed, diluting the concentrated reaction mixture with dichloromethane (10mL), washing the diluted reaction mixture with water and saturated brine, and using anhydrous Na as an organic layer2SO4DryingFiltering, evaporating the solvent, and purifying by silica gel column chromatography to obtain a product VI.
(3) Dissolving the product (1.0eq.) of step (2) in DMF, adding 5, 6-dichlorouracil (1.5eq.), heating at 180 ℃ for 4-6h, monitoring by Thin Layer Chromatography (TLC), concentrating the reaction mixture under reduced pressure after the reaction is complete, diluting with dichloromethane (10mL), washing with water and saturated brine, washing the organic layer with anhydrous Na2SO4Drying, filtering, evaporating the solvent to dryness, and purifying by silica gel column chromatography to obtain a product II.
The specific preparation examples provided by the invention are as follows:
example 4
Synthesis of Compound 4.
The synthesis of example 4 is as described above for the compound.
Yield: 19 percent; structural parameters are as follows:1H-NMR(400MHz，CDCl3)8.00(s，1H)，7.70(d，J＝7.6Hz，2H)，7.57(d，J＝7.6Hz，2H)，3.28(t，J＝4.8Hz，4H)，1.75-1.72(m，4H)，1.62-1.60(m，4H)，1.43(s，1H)；13C-NMR(100MHz，CDCl3)161.1，150.7，145.4，130.1，129.8，119.1，112.7，110.6，44.8，27.3，26.6.HRMS(ESI-TOF)m/z calcd.for C16H19ClN4O4S[M+H]+：399.0888，found 399.2422.
example 5
Synthesis of Compound 5.
The synthesis of example 5 is as described above for the compound.
Yield: 66 percent; structural parameters are as follows:1H-NMR(400MHz，CDCl3)8.41(d，J＝8.8Hz，2H)，8.00(s，1H)，7.95(d，J＝8.8Hz，2H)，3.68(t，J＝5.2Hz，2H)，3.51(t，J＝5.2Hz，2H)，3.14(t，J＝5.2Hz，2H)，3.09(t，J＝5.2Hz，2H)；13C-NMR(100MHz，CDCl3)160.6，141.7，128.8，124.6，46.5，45.5，44.9，39.3.HRMS(ESI-TOF)m/z calcd.for C14H16ClN5O4S[M+H]+：386.0684，found 385.1827.
example 6
Synthesis of Compound 6.
Reacting cycloheximide with p-acetamido-benzenesulfonyl chloride to obtain VII, removing acetyl protecting group of amino group under alkaline condition to obtain VIII, reacting VIII with 6-chloro-1, 3-dimethyl uracil, heating to 180 deg.C, reacting for 4-6 hr, monitoring by Thin Layer Chromatography (TLC), concentrating the reaction mixture under reduced pressure after reaction is completed, diluting with dichloromethane (10mL), washing with water and saturated saline solution, and washing organic layer with anhydrous Na2SO4Drying, filtering, evaporating the solvent to dryness, and purifying by silica gel column chromatography to obtain yellow powder product. Yield: 44%; structural parameters are as follows:1H-NMR(400MHz，CDCl3)7.63(d，J＝8.4Hz，2H)，7.19(d，J＝8.4Hz，2H)，6.68(s，1H)，5.14(s，1H)，3.57(s，3H)，3.33(s，3H)，3.27(t，J＝5.6Hz，4H)，1.75-1.72(m，4H)，1.62-1.60(m，4H)；13C-NMR(100MHz，CDCl3)163.2，151.9，141.8，135.6，128.3，123.7，80.5，48.3，30.1，29.1，28.0，26.8.HRMS(ESI-TOF)m/z calcd.for C18H24N4O4S[M+H]+：393.1591，found 393.1591.
example 7
Synthesis of Compound 7.
Reacting 4-piperidyl piperidine with p-acetamido-benzenesulfonyl chloride to obtain IX, removing acetyl protecting group of amino under alkaline condition to obtain X, reacting X with 2, 3-dichloro-1, 4-naphthoquinone, and reacting at 160 deg.CMicrowave reaction for 1h, monitoring by Thin Layer Chromatography (TLC), after completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with dichloromethane (10mL), washed with water and saturated brine, and the organic layer was washed with anhydrous Na2SO4Drying, filtering, evaporating solvent, and purifying by silica gel column Chromatography (CH)2Cl2MeOH: 100: 1-20: 1) to give the product as a red powder. Yield: 57 percent; structural parameters are as follows:1H-NMR(400MHz，CDCl3)8.22(d，J＝7.6Hz，1H)，8.15(d，J＝6.8Hz，1H)，7.81(t，J＝3.8Hz，1H)，7.69-7.76(m，2H)，7.51-7.53(m，1H)，7.13(d，J＝8.4Hz，2H)，4.30(t，J＝6.8Hz，2H)，2.49(s，4H)，2.31(t，J＝11.2Hz，4H)，1.59(s，4H)，1.41-1.47(m，4H)，0.83-0.88(m，1H)；13C-NMR(100MHz，CDCl3)178.6，178.3，151.5，145.3，135.1，131.6，130.2，129.7，126.8，112.6，70.6，58.2，44.6，27.2，26.3，24.6.HRMS(ESI-TOF)m/z calcd.for C26H28ClN3O4S[M+H]+：514.1567，found 514.1088.
experiment for inhibiting tumor cell proliferation by compound
The culture medium for culturing cells (SW480, HCT116) is 1% penicillin-streptomycin solution, 10% IMDM cell culture medium containing fetal calf serum, and culture conditions are 37 deg.C and 5% CO2The constant temperature incubator.
Taking SW480 and HCT116 cells in logarithmic growth phase, adjusting cell concentration to 5 × 104cells/mL were seeded in 96-well plates at 100. mu.L per well, with blank and control wells. At 37 ℃ with 5% CO2After 24h incubation in an incubator, 0.5 μ L of compound was added to each well at final concentrations of 0.001, 0.01, 0.1, 1, 10 μ M, 3 wells per drug concentration. Blank wells were medium-only wells containing no cells, DMSO, and compound. Control wells were prepared by adding complete medium containing the same concentration of DMSO alone to the cells. Standing at 37 deg.C for 5% CO2After 6h, 12h, 24h and 48h in the incubator, 20. mu.L of 5mg/mL MTT solution (prepared with PBS and sterilized by filtration through a 0.22 μm filter) was added to each well, and the mixture was incubated at 37 ℃ with 5% CO2Continued incubation in a constant temperature incubatorAnd 4h, terminating the culture. The adherent cell treatment method carefully removes culture supernatant in each hole, adds 100 mu LDMSO into each hole, and the suspension cell treatment method is that 100 mu L hydrochloric acid-isopropanol solution is continuously added into each hole to repeatedly blow, beat and mix evenly, after standing for 10min at 37 ℃, purple crystals are fully dissolved, an enzyme labeling instrument (490nm, 630nm) is used for measuring the absorbance (OD) value of each hole, and the cell inhibition rate is calculated according to the following formula.
Cell viability (%) - (experimental OD-blank OD)/(control OD-blank OD). times.100%
IC50: i.e., the concentration of the drug at which the cell viability is 50%, also known as the half maximal effective inhibitory concentration. Solving a linear regression equation according to the MTT result and calculating the IC of each compound50The value is obtained.
The results of in vitro antitumor activity of compounds 1-7 and the positive control camptothecin are shown in table 1.
TABLE 1 in vitro antitumor Activity of Compounds 1-7 and Positive control camptothecin
The results in table 1 show that the compounds have certain inhibitory activity on human colon cancer cells.
Evaluation of alpha-glucosidase inhibitory activity of compound
A microplate screening model is adopted, p-nitrophenyl-alpha-D-glucopyranose is taken as a substrate, and the inhibition activity of alpha-glucosidase of the compound under different concentrations is tested. The experiment is divided into a blank group, a control group without inhibitor and a sample group to be tested. The alpha-glucosidase inhibitor acarbose used clinically is taken as a positive control drug. The inhibitor and the acarbose are dissolved in DMSO, and the content of the DMSO solution in an enzyme test system is 5 percent; the buffer was phosphate buffer (pH 6.8, 0.05M) and p-nitrophenyl- α -D-glucopyranose was dissolved in phosphate buffer.
(1) Blank group: buffer was added in a total volume of 200. mu.L.
(2) Control group: buffer (190. mu.L) and different concentrations of test sample (10. mu.L) were added without inhibitor.
(3) Control group: buffer (150. mu.L), alpha-glucosidase (0.04U, 20. mu.L) and aqueous solution of the substrate p-nitrophenyl-alpha-D-glucopyranose (0.5M, 30. mu.L) were added.
(4) Group of samples to be tested: buffer (140. mu.L), alpha-glucosidase (0.04U, 20. mu.L), DMSO solution of the test sample (10. mu.L) and p-nitrophenyl-alpha-D-glucopyranose substrate (0.5M, 30. mu.L) were added.
Respectively adding buffer solution, samples to be detected with different concentrations, alpha-glucosidase and DMSO solution of the samples to be detected into a 96-well plate according to different experimental groups, warm-laying for 5min at 37 ℃, adding a substrate p-nitrophenyl-alpha-D-glucopyranose, warm-laying for 30min, measuring absorbance at the wavelength of 405nm of an enzyme labeling instrument, and calculating the inhibition rate of the inhibitor on the alpha-glucosidase.
Inhibition (%) > 100- [ sample to be tested OD value-control OD value)/(control OD value-blank OD value ] x 100
The OD value is the absorbance value measured by a microplate reader.
The results of α -glucosidase inhibitory activity of compounds 1-7 and the positive control acarbose are shown in table 2.
TABLE 2 alpha-glucosidase inhibitory Activity of Compounds 1-7(5 and 50. mu.M) and Positive control acarbose (250. mu.M)
In Table 2, the inhibition rate of acarbose was 250. mu.M.
As can be seen from the results in Table 2, the compounds have certain inhibitory activity on alpha-glucosidase at the concentrations of 50 μ M and 5 μ M.
Claims (9)
1. A sulfonamide derivative characterized by: the structural formula is as follows:
2. a process for producing the sulfonamide derivative according to claim 1, characterized in that: the method comprises the following steps:
RNHR1reacting with p-acetamido-benzenesulfonyl chloride to obtain V, removing an acetyl protecting group of an amido group under an alkaline condition to obtain VI, and reacting the VI with 1, 4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester to obtain a sulfonamide derivative I, wherein the reaction route is as follows:
wherein, RNHR1Is composed of
3. A sulfonamide derivative characterized by: the structural formula is as follows:
4. a process for producing the sulfonamide derivative according to claim 3, characterized in that: the method comprises the following steps:
RNHR1reacting with p-acetamido-benzenesulfonyl chloride to obtain V, removing acetyl protecting group of amido under alkaline condition to obtain VI, reacting VI with 5, 6-dichlorouracil to obtain sulfonamide derivative II, wherein the reaction route is as follows:
wherein, RNHR1Is composed of
5. A sulfonamide derivative characterized by: the structural formula is as follows:
6. the process for producing sulfonamide derivatives according to claim 5, wherein: the method comprises the following steps:
reacting cycloheximide with p-acetamido-benzenesulfonyl chloride to obtain VII, removing acetyl protecting group of amido under alkaline condition to obtain VIII, reacting VIII with 6-chloro-1, 3-dimethyl uracil to obtain sulfonamide derivative III, wherein the reaction route is as follows:
7. a sulfonamide derivative characterized by: the structural formula is as follows:
8. a process for producing the sulfonamide derivative according to claim 7, characterized in that: the method comprises the following steps:
4-piperidyl piperidine reacts with p-acetamido-benzenesulfonyl chloride to obtain IX, an acetyl protecting group of amido is removed under an alkaline condition to obtain X, and the X reacts with 2, 3-dichloro-1, 4-naphthoquinone to obtain a sulfonamide derivative IV, wherein the reaction route is as follows:
9. use of sulfonamide derivatives according to claim 1, 3, 5 or 7 for the preparation of a medicament for the treatment of tumors and diabetes.
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