CN111747921A - Preparation method and medical application of daphnetin derivative - Google Patents
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Abstract
The invention belongs to the technical field of medicines. The invention discloses a preparation method of daphnetin derivatives and medical application thereof, and relates to daphnetin derivatives substituted at 8-OH position shown in a structural general formula (I), wherein the derivatives are prepared by performing etherification reaction on daphnetin and 2-bromoethanol to obtain an intermediate II, and performing esterification reaction on the intermediate II and non-steroidal anti-inflammatory drugs. The activity screening test proves that the compound has COX-2 enzyme inhibition effect, the anti-inflammatory activity of the daphnetin derivative is superior to that of daphnetin serving as a raw material, and the daphnetin derivative has a prospect of being developed into a medicament for treating inflammation. The prior art does not disclose the derivative, the preparation method and the medical application thereof.
Description
Technical Field
The invention belongs to the field of natural medicinal chemistry, relates to a novel natural compound derivative, and particularly relates to a daphnetin derivative, and a preparation method and medical application thereof.
Background
Inflammation is a common clinical disease worldwide, and seriously threatens human health. Having become a major challenge for the public health system, while many scientists have been working on developing new treatments for treating various inflammations, it remains a clinical hotspot and difficulty of global concern. In recent years, a large number of anti-inflammatory drugs have been developed, most of which are natural products or derivatives thereof.
Daphnetin, also known as daphnetin A, is an effective component extracted from daphne giraldii nitsche, mainly exists in daphne plants, and has pharmacological effects of diminishing inflammation and relieving pain. However, daphnetin has the limitations of poor water solubility, low bioavailability, poor stability and the like, so that the application of daphnetin in medicines is limited. Therefore, the invention determines to use the effective components in natural plants as leads to carry out structural modification, and carries out structural modification on daphnetin so as to obtain the compound with stronger anti-inflammatory activity and higher bioavailability.
The daphnetin is structurally modified to obtain a series of derivatives. The purpose is basically achieved through preliminary pharmacological experiments, and the compound is expected to become a candidate drug for treating inflammation and has good application prospect.
Disclosure of Invention
One of the purposes of the invention is to provide a daphnetin derivative.
The invention also aims to provide a preparation method of the daphnetin derivative.
Still another object of the present invention is to provide a medical use of the aforementioned daphnetin derivative.
In order to realize the purpose, the invention provides a daphnetin derivative with 8-OH substituted position shown in a structural general formula (I), and screening of COX-2 enzyme inhibitory activity shows that most compounds have good in vitro activity and can be used as precursor compounds for further development into COX-2 enzyme inhibitors.
The 8-OH substituted daphnetin derivative provided by the invention is represented by a structural general formula (I):
in the general formula (I), R is selected from non-steroidal anti-inflammatory drugs with anti-inflammatory and analgesic effects, such as ibuprofen, diclofenac, flurbiprofen, indomethacin, naproxen, ketoprofen, and the like.
Wherein R is preferably flurbiprofen, indomethacin, naproxen and ketoprofen.
The compounds of the invention are preferably the following:
compound 1:
chemical combinationAn object 2:
compound 3:
compound 4:
the preparation method of the 8-OH substituted daphnetin derivative comprises the following steps: etherification reaction and esterification reaction.
The invention also provides a preparation method of the daphnetin 8-OH derivative, which comprises the following operation steps:
step a, performing etherification reaction on daphnetin and 2-bromoethanol to obtain an intermediate II shown in the following structural formula;
and step b, the intermediate II and the non-steroidal anti-inflammatory drug are subjected to esterification reaction to prepare the compound with the general structural formula (I).
Preferably, the etherification reaction conditions in step a include: potassium iodide is used as a catalyst, potassium carbonate is used as an alkali, and the reaction temperature is 85-90 ℃.
More preferably, step a comprises: firstly, dissolving daphnetin (1eq), potassium carbonate (3eq) and potassium iodide (0.1eq) in anhydrous DMF, uniformly stirring, adding 2-bromoethanol (2eq) into the solution, carrying out reflux reaction at 85-90 ℃, and detecting the reaction process by TLC (thin layer chromatography); after the reaction is finished, adding a proper amount of diluted hydrochloric acid, stirring and neutralizing until the mixture is acidic, extracting for three times by using ethyl acetate, and combining organic layers; the organic layer was washed with distilled water and saturated brine three times, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the residue was purified by column chromatography to give intermediate II.
Preferably, the esterification reaction conditions in step b comprise: 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) is used as a condensing agent, 4-Dimethylaminopyridine (DMAP) is used as a catalyst, and the reaction is carried out at normal temperature.
More preferably, step b comprises: firstly, dissolving the non-steroidal anti-inflammatory drug (1.5eq) and 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine hydrochloride (EDCI) (2eq) and 4-Dimethylaminopyridine (DMAP) (0.4eq) in dichloromethane, stirring and mixing uniformly, adding the intermediate II (1eq) into a reaction system, stirring and reacting at normal temperature, and detecting the reaction progress by TLC; after the reaction was completed, the organic layer was washed three times with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the residue was purified by column chromatography to obtain the objective compound.
The daphnetin derivative substituted at the 8-OH position prepared by the invention is developed into a COX-2 enzyme inhibitor and used for preventing and treating diseases such as inflammation, and the anti-inflammatory activity of the compound is evaluated by taking screening of COX-2 enzyme inhibitory activity as a carrier.
Screening for COX-2 enzyme inhibitory Activity of Compounds COX-2 inhibitor screening kit (purchased from Biyuntian Biotech Co., Ltd.) was used.
The daphnetin derivative substituted at the 8-OH position prepared by the invention still shows more obvious inhibitory activity under the concentration of 20 mu mol/L by COX-2 enzyme activity screening.
According to the present invention, other various modifications, substitutions and alterations can be made without departing from the technical spirit of the present invention in accordance with the common technical knowledge and conventional means in the field.
The above-mentioned contents are further explained by way of examples, but it should not be construed that the scope of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The invention is better illustrated by the following examples. However, the present invention is not limited to the following examples.
The process flow is as follows, and the room temperature or the rt in the preparation method are both referred to as the normal temperature:
example 1
Synthesis of Compound 1
(1) Synthesis of intermediate II
Weighing daphnetin (1g, 5.6mmol), anhydrous potassium carbonate (2.3g, 16.8mmol) and potassium iodide (0.092g, 0.56mmol), adding DMF (N, N-dimethylformamide) as solvent (12ml), adding 2-bromoethanol (796. mu.l, 11.2mmol), refluxing at 85 deg.C for over 72h, adding a drying tube or a nitrogen protection device at the top of the refluxing device, detecting the reaction with TLC plate, stopping the reaction after the reaction is finished, slowly cooling the reaction mixture at room temperature, diluting with 20ml cold water, adding 3mol/L diluted hydrochloric acid to adjust the solution to acidity, extracting with ethyl acetate, collecting the ethyl acetate layer, washing with distilled water, washing with saturated common salt water, collecting the organic layer, drying with anhydrous sodium sulfate, recovering the solvent by suction filtration to obtain a crude product, performing chromatography with petroleum ether ethyl acetate 2: 1 (V: V) to obtain an eluent, 13%).
(2) Synthesis of Compound 1
Putting the solid (40mg, 0.18mmol) into a 50ml round bottom flask, adding 10ml dichloromethane for dissolving, adding 1-ethyl- (3-dimethylaminopropyl) carbonyl diimine hydrochloride (EDCI) (69mg, 0.36mmol) and 4-Dimethylaminopyridine (DMAP) (8.8mg, 0.07mmol), ibuprofen (56mg, 0.27mmol), stirring at room temperature for 4-5 h, detecting the reaction progress by a TLC plate, adding distilled water for washing after the reaction is finished, adding a saturated saline for washing, collecting an organic layer, drying by anhydrous sodium sulfate, and carrying out suction filtration to recover the solvent to obtain a crude product. And (3) carrying out column chromatography by using an eluent of petroleum ether and ethyl acetate which are 3: 1 (V: V) to obtain a pure white solid product. Total yield: 48.8%, melting point: 76-78 ℃. GF254Spreading a thin layer of nm silica gel plate to a point, ultraviolet lamp UV254Dark spots at nm, UV365Blue fluorescence at nm.1H-NMR(500MHz，CDCl3，ppm)7.60(d，J＝9.5Hz，1H)，7.21(d，J＝8.1Hz，2H)，7.10(dd，J＝8.3，4.1Hz，3H)，6.86(d，J＝8.5Hz，1H)，6.21(d，J＝9.5HZ，1H)，4.71(m，4H)，3.78(q，J＝7.1Hz，1H)，2.43(d，J＝7.2Hz，2H)，1.83(dp，J＝13.5，6.8Hz，1H)，1.52(d，J＝7.2Hz，3H)，0.88(d，J＝6.6Hz，6H)；13C-NMR(125Hz，CDCl3，ppm)175.24，160.31，152.84，147.42，144.22，140.87，137.32，132.55，129.60，127.18，123.70，112.99，72.81，63.79，45.25，45.11，30.23，22.46，18.60；ESI-MS m/z433.2[M+Na]+(calcd forC24H26O6，410).
Example 2
Synthesis of Compound 2
Referring to example 1, step 2 using diclofenac instead of ibuprofen and the other conditions were the same as in example 1, a white solid product was obtained. Total yield: 50.7%, melting point: 146 ℃ and 148 ℃. GF254Spreading a thin layer of nm silica gel plate to a point, ultraviolet lamp UV254Dark spots at nm, UV365Blue fluorescence at nm.1H-NMR(500MHz，CDCl3，ppm)7.59(d，J＝9.6Hz，1H)，7.32(d，J＝8.0Hz，2H)，7.13(td，J＝7.8，1.6Hz，1H)，7.09(d，J＝8.5Hz，1H)，7.02(d，J＝3.7Hz，1H)，6.97(m，2H)，6.87(d，J＝8.5Hz，1H)，6.74(s，1H)，6.55(d，J＝7.9Hz，1H)，6.22(d，J＝9.6Hz，1H)，4.51(m，4H)，3.91(s，2H)；13C NMR(125MHz，CDCl3，ppm)172.84，160.30，152.72，147.37，144.21，142.81，137.85，132.70，131.06，129.66，128.97，128.34，124.23，123.93，123.77，122.31，118.50，113.09，112.70，112.59，72.84，64.47，38.59；ESI-MS m/z522.2[M+Na]+(calcd for C25H19Cl2NO6，410).
Example 3
Synthesis of Compound 3
Referring to example 1, step 2 using flurbiprofen instead of ibuprofen and the other conditions were the same as in example 1, a light green oil was obtained in total yield: 28.2%, GF254Spreading a thin layer of nm silica gel plate to a point, ultraviolet lamp UV254Dark spots at nm, UV365Blue fluorescence at nm.1H-NMR(500MHz，CDCl3，ppm)7.60(d，J＝9.5Hz，1H)，7.52(m，2H)，7.40(m，4H)，7.15(m，2H)，7.10(d，J＝8.5Hz，1H)，6.87(d，J＝8.6Hz，1H)，6.22(d，J＝9.5Hz，1H)，4.46(m，4H)，3.85(q，J＝7.2Hz，1H)，1.58(d，J＝7.2Hz，3H)；13C NMR(125MHz，CDCl3，ppm)174.56，160.28，152.69，147.35，144.24，141.31，135.53，132.59，131.14，131.11，129.08，129.05，128.55，127.82，123.77，123.62，123.59，115.46，115.27，113.10，112.72，112.54，72.87，64.16，45.17，18.51；ESI-MS m/z 471.2[M+Na]+(calcd for C26H21FO6，448).
Example 4
Synthesis of Compound 4
Referring to example 1, step 2 using indomethacin instead of ibuprofen and the other conditions were the same as in example 1, a yellow solid was prepared in total yield: 19.8%, melting point: 68-70 ℃. GF254Spreading a thin layer of nm silica gel plate to a point, ultraviolet lamp UV254Dark spots at nm, UV365Blue fluorescence at nm.1H-NMR(600MHz，CDCl3，ppm)7.68(d，J＝8.5Hz，2H)，7.61(d，J＝9.5Hz，1H)，7.46(d，J＝8.5Hz，2H)，7.11(d，J＝8.5Hz，1H)，6.96(d，J＝2.5Hz，1H)，6.84(dd，J＝10.8，8.7Hz，3H)，6.65(dd，J＝9.0，2.5Hz，1H)，6.22(d，J＝9.5Hz，1H)，4.49(m，2H)，4.45(m，2H)，3.81(s，3H)，3.78(s，2H)，2.40(s，3H)；13C NMR(150MHz，CDCl3，ppm)171.48，168.42，160.26，156.18，152.64，147.37，144.23，139.41，136.32，133.95，132.52，131.35，130.93，130.53，129.24，123.84，115.15，113.12，112.77，112.50，111.97，111.89，101.21，72.84，64.12，55.81，30.44，13.47.ESI-MS m/z 584.2[M+Na]+(calcd forC30H24ClNO8，561).
Example 5
Synthesis of Compound 5
Referring to example 1, step 2 using naproxen instead of ibuprofen and the other conditions were the same as in example 1, a cream white solid was obtained with an overall yield: 161%, melting point: 58-60 ℃. GF254Spreading a thin layer of nm silica gel plate to a point, ultraviolet lamp UV254Dark spots at nm, UV365Blue fluorescence at nm.1H-NMR(500MHz，CDCl3，ppm)7.69(m，3H)，7.58(d，J＝9.5Hz，1H)，7.41(dd，J＝8.5，1.9Hz，1H)，7.13(dd，J＝8.9，2.5Hz，1H)，7.10(d，J＝2.6Hz，1H)，7.08(d，J＝8.5Hz，1H)，6.92(s，1H)，6.83(d，J＝8.5Hz，1H)，6.20(d，J＝9.5Hz，1H)，4.44(m，3H)，4.36(m，1H)，3.94(q，J＝7.1Hz，1H)，3.91(s，1H)，1.61(d，J＝7.1Hz，3H)；13C-NMR(125Hz，CDCl3，ppm)175.28，160.32，157.82，152.75，147.35，144.23，135.18，133.90，132.59，129.43，129.07，127.51，126.17，126.09，123.71，119.20，113.02，112.66，112.54，105.69，72.97，63.96，55.45，45.61，18.67；ESI-MS m/z 457.2[M+Na]+(calcd forC25H22O7，434).
Example 6
Synthesis of Compound 6
Referring to example 1, step 2 using ketoprofen instead of ibuprofen and the other conditions were the same as in example 1, a dark green oil was obtained in total yield: 58.2%, GF254Spreading a thin layer of nm silica gel plate to a point, ultraviolet lamp UV254Dark spots at nm, UV365Blue fluorescence at nm.1H-NMR(600MHz，CDCl3，ppm)7.79(m，2H)，7.77(t，1.8Hz，1H)，7.67(m，1H)，7.60(d，9.5Hz，1H)，7.56(m，3H)，7.46(dt，J＝15.5，7.7Hz，3H)，7.09(d，J＝8.5Hz，1H)，6.96(s，1H)，6.83(d，8.5Hz，1H)，6.21(d，9.5Hz，1H)，4.43(m，4H)，3.89(q，7.1Hz，1H)，1.57(d，7.2Hz，3H)；13C-NMR(150MHz，CDCl3，ppm)196.69，174.65，160.32，152.73，147.38，144.25，140.47，138.16，137.47，132.71，132.57，131.57，130.23，129.37，129.24，128.83，128.43，123.76，113.04，112.67，112.58，72.79，64.15，45.52，18.61；ESI-MS m/z 481.1[M+Na]+(calcd for C27H22O7，458).
Example 7
Determination of daphnetin derivative COX-2 enzyme inhibitory Activity
The experimental principle is as follows: in the presence of a Cofactor (Cofactor), COX-2 epoxidizes a substrate such as Arachidonic Acid (Arachidonic Acid) to produce an intermediate such as PGG2 using its Cyclooxygenase (COX) activity, and COX-2 catalyzes an intermediate such as PGG2 to produce a final product such as PGH2 using its peroxidase (peroxidase) activity, while a COX-2 Probe (Probe) having almost no fluorescence catalyzes the production of a Probe having strong fluorescence (Ex560/Em 590). Thus, the enzyme activity of COX-2 can be detected very sensitively by fluorescence detection. When COX-2 Inhibitor (Inhibitor) is added to the reaction, the generation of fluorescence is suppressed, and the fluorescence intensity is inversely proportional to the inhibitory effect of the Inhibitor, so that the inhibitory effect of the Inhibitor can be detected. The maximum excitation wavelength of the strong fluorescent probe generated by the reaction is 571nm, the maximum emission wavelength is 585nm, the recommended excitation wavelength during detection is 560nm, and the emission wavelength is 590 nm.
The determination method comprises the following steps: according to COX-2 inhibitor screening kit, the inhibitory activity of each COX-2 ligand is detected, COX-2 assay buffer (75 μ L), COX-2 cofactor working solution (5 μ L), COX-2 working solution (5 μ L) and test compound (5 μ L) are added to a 96-well blackboard, and incubated at 37 deg.C for 10 min. After incubation was complete, 5 μ L of COX-2 probe was added to each well, followed by rapid addition of 5 μ L of COX-2 substrate to all wells. After incubation for 5min at 37 ℃ protected from light, the fluorescence of each well was measured using an excitation wavelength of 560nm and an emission wavelength of 590 nm. Celecoxib, a known COX-2 inhibitor, is used as a positive drug group, 5 microliter DMSO replaces test solution in a 100% enzyme activity control group, and compared with the 100% enzyme activity control group, a blank control group adopts COX-2 auxiliary buffer solution to replace COX-2 auxiliary factor working solution. Finally, the inhibitory activity of each sample was calculated by the following equation:
inhibitory Activity (%) - (A)1-A2)/A1-A3]×100％
Wherein A is1Fluorescence values for 100% enzyme activity control; a. the2Fluorescence values for the sample set; a. the3Fluorescence values for the blank control group.
Continuously selecting 5 concentrations for compound samples with better inhibition rate to determine the inhibition rate, setting 3 multiple holes on each concentration level of each compound sample, and calculating the IC of the compound samples by adopting GraphPad Prism 5 software50The value is obtained.
Table 1: measurement results of COX-2 enzyme inhibitory Activity
| Name (R) | Inhibition ratio (%) of 50. mu. mol/L | IC50(μmol/L) |
| Daphnetin | 31.45 | ＞50 |
| Example 1 | 5.10 | ＞50 |
| Example 2 | 9.61 | ＞50 |
| Example 3 | 78.00 | 7.25±0.23 |
| Example 4 | 95.69 | 2.41±0.52 |
| Examples5 | 65.99 | 26.62±3.23 |
| Example 6 | 86.57 | 6.80±0.67 |
Wherein the positive drug celecoxib IC50About 30nm
The determination result shows that part of the compounds disclosed by the invention have better inhibition effect on COX-2 enzyme, and the activity is superior to daphnetin.
The purpose of the above embodiments is to specifically describe the material of the present invention, but it should be understood by those skilled in the art that the scope of the present invention should not be limited to the above embodiments.
Claims (7)
1. A daphnetin 8-OH derivative has the following structural formula:
in the general formula (I), R is selected from non-steroidal anti-inflammatory drugs with anti-inflammatory and analgesic effects, such as ibuprofen, diclofenac, flurbiprofen, indomethacin, naproxen, ketoprofen, and the like.
2. The process for the preparation of daphnetin 8-OH derivatives according to claim 1, comprising the steps of:
step a, performing etherification reaction on daphnetin and 2-bromoethanol to obtain an intermediate II shown in the following structural formula;
and step b, the intermediate II and the non-steroidal anti-inflammatory drug are subjected to esterification reaction to prepare the compound with the general structural formula (I).
3. The method according to claim 2, wherein the etherification reaction conditions in step a include: potassium iodide is used as a catalyst, potassium carbonate is used as an alkali, and the reaction temperature is 85-90 ℃.
4. The method of claim 3, wherein step a comprises: firstly, dissolving daphnetin, potassium carbonate and potassium iodide in anhydrous DMF (dimethyl formamide), uniformly stirring, adding 2-bromoethanol, carrying out reflux reaction at 85-90 ℃, and detecting the reaction process by TLC (thin layer chromatography); after the reaction is finished, adding a proper amount of diluted hydrochloric acid, stirring and neutralizing until the mixture is acidic, extracting for three times by using ethyl acetate, and combining organic layers; the organic layer was washed with distilled water and saturated brine three times, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the residue was purified by column chromatography to give intermediate II.
5. The method according to claim 2, wherein the esterification reaction in step b comprises reacting 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) as a condensing agent and 4-Dimethylaminopyridine (DMAP) as a catalyst at room temperature.
6. The method of claim 5, wherein step b comprises: firstly, dissolving the non-steroidal anti-inflammatory drug and 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and 4-Dimethylaminopyridine (DMAP) in dichloromethane, stirring and mixing uniformly, dissolving an intermediate II in dichloromethane, stirring and reacting at normal temperature, and detecting the reaction process by TLC; after the reaction was completed, the organic layer was washed three times with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried under reduced pressure, and the residue was purified by column chromatography to obtain the objective compound.
7. The medical use of the daphnetin 8-OH derivative of claim 1 for the preparation of an anti-inflammatory medicament.
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| CN113717143A (en) * | 2021-07-19 | 2021-11-30 | 中国药科大学 | Synthetic method and application of daphnetin derivatives |
| CN115181084A (en) * | 2022-08-04 | 2022-10-14 | 中国药科大学 | Optimization of synthesis process and pharmacological activity research of daphnetin derivatives |
| CN115368333A (en) * | 2022-09-26 | 2022-11-22 | 湖北医药学院 | Compound containing ibuprofen-coumarin skeleton and application thereof |
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