CN113173857A - Cannabidiol derivative and preparation method and application thereof - Google Patents

Cannabidiol derivative and preparation method and application thereof Download PDF

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CN113173857A
CN113173857A CN202110248495.XA CN202110248495A CN113173857A CN 113173857 A CN113173857 A CN 113173857A CN 202110248495 A CN202110248495 A CN 202110248495A CN 113173857 A CN113173857 A CN 113173857A
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李蓉涛
全丽秋
李洪梅
刘丹
叶瑞绒
陈宣钦
张治军
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Kunming University of Science and Technology
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Abstract

The invention discloses a cannabidiol derivative and a preparation method and application thereof, belonging to the technical field of pharmaceutical chemistry.

Description

Cannabidiol derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a cannabidiol derivative, a preparation method thereof and application thereof in tumor inhibition.
Background
The incidence of cancer and the mortality rate are rapidly increasing globally, and cancer is the leading cause of human death in the 21 st century and is one of the most important obstacles for extending the life expectancy of people. Cannabidiol ((-) -cannabidiol, CBD) is one of the major components of the unique cannabinoid component in Cannabis sativa L plants. The research shows that the cannabidiol has no mental activity, but has various pharmacological effects, such as neuroprotection, epilepsy resistance, anxiety resistance, antipsychotic, analgesia, anti-inflammation, asthma treatment and the like.
Disclosure of Invention
The invention mainly provides cannabidiol derivatives with novel structures, a preparation method thereof and application thereof in tumor inhibition.
The structure of the cannabidiol derivative is shown as I, II and III:
Figure BDA0002966980310000011
wherein R in I, II and III1，R2，R3，R4，R5，R6，R7And R8Can be a substituent such as hydrogen, hydroxyl, methoxy, methyl or halogen.
The cannabidiol derivatives I, II and III are obtained by using cannabidiol as a basic skeleton and esterifying phenolic hydroxyl groups of the cannabidiol derivatives with benzoic acid substituted by different groups, and the obtained cannabidiol derivatives are new compounds.
The in vitro anti-tumor activity proves that the cannabidiol derivative has obvious inhibitory activity on lung cancer cell strains (A549), human breast cancer cell strains (MDA-MB-231), nasopharyngeal carcinoma and drug-resistant strains (KB, KB-VIN) thereof and human breast cancer cell strains (MCF-7), wherein the activity of the compound 5 is most obvious, and IC (integrated Circuit) is shown in the specification50The value is between 2.96 and 4.93. mu.M.
The invention has the advantages and positive effects that:
(1) the cannabidiol derivative provided by the invention takes cannabidiol as a parent nucleus and carries out the treatment on phenolic hydroxyl group of the cannabidiol derivativeReasonably modifying to construct a cannabidiol derivative with novel structure, and obtaining the product with chemical structure1H NMR，13C NMR and MS confirmation.
(2) The cannabidiol derivative compound 1-5 provided by the invention has stronger inhibiting effect on 5 cancer cell lines (A549, MDA-MB-231, KB, KB-VIN and MCF-7) than cannabidiol, and is expected to be developed into a new anti-tumor drug.
Drawings
FIG. 1 shows CD of Compound 1 of the present invention3Nuclear magnetic resonance hydrogen spectrum in OD;
FIG. 2 shows CD of Compound 1 of the present invention3Nuclear magnetic resonance carbon spectrum in OD;
FIG. 3 shows CD of Compound 2 of the present invention3Nuclear magnetic resonance hydrogen spectrum in OD;
FIG. 4 shows CD of Compound 2 of the present invention3Nuclear magnetic resonance carbon spectrum in OD;
FIG. 5 shows CD of Compound 3 of the present invention3Nuclear magnetic resonance hydrogen spectrum in OD;
FIG. 6 shows CD of Compound 3 of the present invention3Nuclear magnetic resonance carbon spectrum in OD;
FIG. 7 shows CD of Compound 4 of the present invention3Nuclear magnetic resonance hydrogen spectrum in OD;
FIG. 8 shows CD of Compound 4 of the present invention3Nuclear magnetic resonance carbon spectrum in OD;
FIG. 9 shows CD of Compound 5 of the present invention3Nuclear magnetic resonance hydrogen spectrum in OD;
FIG. 10 shows CD of Compound 5 of the present invention3Nuclear magnetic resonance carbon spectrum in OD.
Detailed Description
The present invention will be described in further detail below with reference to specific embodiments and drawings, and the protected contents of the present invention include, but are not limited to, the following embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any inventive effort, are within the scope of the present invention. The procedures, conditions, reagents, experimental methods, etc. in the following examples are all common general knowledge in the art, except for those specifically mentioned below. The reagents used in the invention are all commercially available chemically pure or analytically pure products.
The cannabidiol derivatives have the structures shown as I, II and III:
Figure BDA0002966980310000021
the synthesis of the cannabidiol derivative comprises the following 3 routes:
route 1:
Figure BDA0002966980310000031
taking 1a and 2a as raw materials, performing methylation reaction, benzyl protection and demethylation reaction on the raw materials, esterifying the raw materials with cannabidiol, removing benzyl protection to obtain a compound 1 and a compound 2, taking 3a as a raw material, performing benzyl protection and demethylation reaction on the raw materials, esterifying the raw materials with cannabidiol, and removing benzyl protection to obtain a compound 3.
Route 2:
Figure BDA0002966980310000041
the compound 4a and 5a are respectively reacted with 3, 4-Dihydropyran (DHP) to protect the hydroxyl group, then respectively reacted with cannabidiol to obtain intermediate products 4c and 5c, and finally deprotected by 2-Tetrahydropyran (THP) to obtain compound 4 and compound 5.
Route 3:
Figure BDA0002966980310000042
cannabidiol reacts with 6a and 7a under the action of CMPI and DMAP to give compound 6 and compound 7, respectively.
Example 1
A process for preparing cannabidiol derivative compound 1, comprising the steps of:
step 1. Compound 1a (18mmol) was added to 19mL of methanol MeOH solution, stirred, and 0.45mL of 98.3% by mass H was added2SO4The reaction mixture was refluxed at 100 ℃ for 2 hours, distilled under reduced pressure, the residue was dissolved in water and extracted with Dichloromethane (DCM), and the organic layer was washed with saturated brine, anhydrous Na2SO4Drying, filtering, and concentrating the filtrate under reduced pressure to obtain compound 1b (2.68 g);
step 2. Compound 1b (17.11mmol) and K2CO3(17.11mmol) was added to 25mL of Dimethylformamide (DMF), stirred, then benzyl chloride (BnCl, 17.11mmol) was added, the reaction mixture was stirred at 80 ℃ under nitrogen for 10 hours, water was added, extraction was performed with dichloromethane, the organic layer was washed with saturated brine, and the residue was washed with anhydrous Na2SO4Drying, vacuum concentrating, and purifying by silica gel column chromatography (n-hexane: dichloromethane, volume ratio 1:1) to obtain compound 1c (3.04 g);
step 3. Compound 1c (14.88mmol) is added to methanol (MeOH, 20mL), dioxane (40mL) and H2To a mixed solution of O (15mL), NaOH (0.50mol) was added, the reaction was stirred overnight, the reaction mixture was refluxed at 120 ℃ overnight, the solvent was removed by concentration under reduced pressure, the residue was extracted with DCM, the organic layer was washed with saturated brine, and anhydrous Na2SO4Drying, filtering and concentrating in vacuo to give compound 1d (2.69 g);
step 4, adding the compound 1d (0.96mmol) and cannabidiol (0.48mmol) into DCM (15mL) solution at 0 ℃ under the protection of nitrogen, stirring, adding CMPI (0.96mmol) and DMAP (0.96mmol) into the reaction solution, stirring the reaction mixture for reaction for 1 hour, filtering the reaction precipitate, and sequentially using saturated NaHCO for the filtrate3Washing with saturated brine, and purifying with Na2SO4Drying, vacuum concentrating, and purifying by silica gel column chromatography (n-hexane: acetone, volume ratio 95:5) to obtain compound 1e (110.4 mg);
step 5. in H 210% w/w palladium on charcoal (184mg) and Compound 1e (0.29mmol) were added to methanol in the presence ofThe reaction was carried out at room temperature for 2 hours, filtered, and the filtrate was concentrated to give 57.8mg of a white oil, i.e., compound 1, in 72.22% yield.
The nuclear magnetic resonance spectrum of the compound 1 is shown in figures 1 and 2, and the data are as follows:1H NMR(400MHz,CD3OD)δH 7.99(d,J＝8.7Hz,4H),6.88(d,J＝8.8Hz,4H),6.83(s,2H),5.11(s,1H),3.45(d,J＝10.5Hz,1H),2.63-2.59(m,2H),1.97-1.91(m,1H),1.71-1.59(overlap,5H),1.55-1.50(m,1H),1.36-1.35(m,4H),1.23(s,3H),1.17-1.06(m,1H),0.90(t,J＝6.7Hz,3H),0.82(d,J＝6.8Hz,3H),0.65(d,J＝6.8Hz,3H).13C NMR(100MHz,CH3OD):δC 166.7,166.7,164.3,164.3,151.7,151.7,143.5,134.7,133.6,133.6,133.6,133.6,128.7,128.7,125.5,125.5,121.2,121.2,116.4,116.4,116.4,116.4,44.4,39.1,36.1,32.6,31.8,31.4,29.1,23.5,23.5,23.4,22.0,16.8,14.4.ESI-MS:m/z 555.80[M-H]-。
the formula of the compound obtained in this example was derived as follows:
Figure BDA0002966980310000051
example 2
A process for preparing cannabidiol derivative compound 2, comprising the steps of:
by substituting compound 1a in example 1 with compound 2a and keeping the other reagents unchanged, 34.2mg of a colorless oil, compound 2, was prepared according to the method of example 1, with a final yield of 96.89%.
The nuclear magnetic resonance spectrum of the compound 2 is shown in figures 3 and 4, and the data are as follows:1H NMR(400MHz,CD3OD)δH 7.57-7.55(overlap,4H),6.87(d,J＝8.8Hz,2H),6.83(s,2H),5.09(s,1H),3.46(d,J＝10.6Hz,1H),2.64-2.60(m,2H),2.01-1.95(m,1H),1.70-1.63(overlap,5H),1.57-1.50(m,1H),1.39-1.34(m,4H),1.24(s,3H),1.19-1.09(m,1H),0.91(t,J＝6.8Hz,3H),0.85(d,J＝6.8Hz,3H),0.67(d,J＝6.8Hz,3H).13C NMR(100MHz,CH3OD):δC 166.9,166.9,152.4,152.4,151.8,151.8,146.4,146.4,143.5,134.9,128.8,128.8,125.4,125.4,124.5,124.5,121.7,121.7,118.0,118.0,115.9,115.9,44.3,39.0,36.1,32.6,31.8,31.3,29.1,23.5,23.5,23.5,22.0,16.8,14.4.ESI-MS:m/z 587.75[M-H]-。
the formula of the compound obtained in this example was derived as follows:
Figure BDA0002966980310000061
example 3
A process for preparing cannabidiol derivative compound 3, comprising the steps of:
the preparation was carried out by following the steps 2 to 5 in example 1 except for replacing the compound 1b in example 1 with the compound 3a and leaving the other reagents unchanged, to obtain 98.1mg of a pale purple powder, i.e., the compound 3, in 93.07% yield as the final step.
The nuclear magnetic resonance spectrum of the compound 3 is shown in fig. 5 and 6, and the data is as follows:1H NMR(400MHz,CD3OD)δH 7.19(s,4H),6.81(s,2H),5.07(s,1H),3.47(d,J＝10.5Hz,1H),2.65-2.61(m,2H),2.04-1.99(m,1H),1.83-1.71(m,2H),1.68-1.64(m,3H),1.58-1.49(s,1H),1.40-1.34(m,4H),1.24(s,3H),1.21-1.10(m,1H),0.92(t,J＝6.6Hz,3H),0.86(d,J＝6.8Hz,3H),0.68(d,J＝6.8Hz,3H).13C NMR(100MHz,CH3OD):δC 167.1,167.1,151.8,151.8,146.6,146.6,146.6,146.6,143.4,140.7,140.7,135.1,128.9,128.9,125.2,125.2,120.4,120.4,110.8,110.8,110.8,110.8,44.3,39.0,36.2,32.6,31.8,31.3,29.2,23.6,23.6,23.5,22.0,16.9,14.4.ESI-MS:m/z 619.65[M-H]-。
the formula of the compound obtained in this example was derived as follows:
Figure BDA0002966980310000071
example 4
A process for preparing cannabidiol derivative compound 4 comprising the steps of:
step 1. Compound 4a (8.00mmol) and pyridine couple at room temperatureTosylate (PPTS, 2.00mmol) was added to DCM (25mL) and stirred, followed by DHP (32.00mmol), the reaction mixture was stirred overnight and then saturated NaHCO was used3The solution, water and saturated brine were washed in this order, each time, the organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (n-hexane: acetone, volume ratio 80:20) to give compound 4b (1.22 g);
step 2. Compound 4b (1.34mmol) and cannabidiol (0.67mmol) were added to a solution of DCM (15mL) at 0 deg.C under nitrogen, stirred, and CMPI (1.34mmol) and DMAP (1.34mmol) were added to the reaction mixture, stirred for 1 hour, the reaction mixture was filtered, and the filtrate was sequentially washed with saturated NaHCO3The aqueous solution was washed with saturated brine and then with anhydrous Na2SO4Drying, concentrating under reduced pressure, and purifying the crude product by silica gel column chromatography (n-hexane: acetone, volume ratio 75:25) to obtain 472mg of compound 4 c;
step 3. adding the compound 4c (0.36mmol) and p-toluenesulfonic acid (PTSA, 0.01mmol) into 25mL of methanol at room temperature, stirring for reaction for 4 hours, concentrating under reduced pressure, and then adding NaHCO with the mass fraction of 5%3Neutralizing the solution, extracting with ethyl acetate, washing the organic layer with water and saturated brine, and passing through anhydrous Na2SO4Drying and distillation under the reduced pressure gave compound 4(204.0mg, yield: 92.25%) as a pale brown solid.
The nuclear magnetic resonance spectrum of the compound 4 is shown in fig. 7 and 8, and the data are as follows:1H NMR(400MHz,CD3OD)δH 7.70(d,J＝8.3Hz,2H),7.66(s,2H),6.92(d,J＝8.3Hz,2H),6.84(s,2H),5.14(s,1H),4.58(s,1H),4.53(s,1H),3.92(s,6H),3.53(d,J＝10.4,1H),2.85-2.79(m,1H),2.65-2.61(m,2H),1.73-1.62(m,6H),1.59(s,3H),1.38-1.34(m,4H),1.22(s,3H),0.92(t,J＝6.9Hz,3H).13C NMR(100MHz,CH3OD):δC 166.6,166.6,153.6,153.6,151.5,151.5,149.1,148.9,148.9,143.5,134.5,128.4,128.4,125.9,125.9,125.0,125.0,121.7,121.7,116.1,116.1,114.1,114.1,111.7,56.5,47.3,40.0,36.1,32.5,31.8,31.1,30.0,23.6,23.5,20.2,14.4,14.4.ESI-MS:m/z 613.70[M-H]-。
the formula of the compound obtained in this example was derived as follows:
Figure BDA0002966980310000081
example 5
A process for preparing cannabidiol derivative compound 5, comprising the steps of:
the compound 4a in example 4 was replaced with the compound 5a, and the other reagents were not changed, according to the procedures of steps 1 to 3 in example 4, to give 7.1mg of a colorless oil, i.e., compound 5, in a final step at a yield of 28.87%.
The nuclear magnetic resonance spectrum of the compound 5 is shown in fig. 9 and 10, and the data is as follows:1H NMR(400MHz,CD3OD)δH 7.12(s,4H),6.81(s,2H),5.08(s,1H),4.54(s,1H),4.50(s,1H),3.54(dd,J＝10.4,1.5Hz,1H),2.91-2.84(m,1H),2.64-2.60(m,2H),2.13(s,6H),1.72-1.56(m,6H),1.55(s,3H),1.37-1.33(m,4H),1.18(s,3H),0.91(t,J＝6.9Hz,3H).13C NMR(100MHz,CH3OD):δC 166.9,166.9,157.6,157.6,157.6,157.6,151.5,151.5,149.1,143.4,135.0,128.4,128.4,128.2,124.7,119.2,119.2,119.2,119.2,111.8,109.0,109.0,109.0,109.0,47.2,40.0,36.1,32.5,31.8,30.9,29.9,23.5,23.5,20.0,14.4,9.0,9.0.ESI-MS:m/z 613.50[M-H]-。
the formula of the compound obtained in this example was derived as follows:
Figure BDA0002966980310000082
example 6
A process for preparing cannabidiol derivative compound 6, comprising the steps of:
adding compound 6a (0.38mmol) and cannabidiol (0.19mmol) to a solution of DCM (5mL) at 0 deg.C under nitrogen, stirring, adding CMPI (0.38mmol) and DMAP (0.38mmol) to the reaction mixture, stirring for 1 hr, filtering off the reaction precipitate, sequentially adding saturated NaHCO to the filtrate3Washing with saturated brine and Na2SO4Drying, concentrating, and purifying with silica gel column chromatography (n-hexane: acetone, volume ratio, 95:5) to obtain 10.6mg of white oil, i.e., compound 6, with a yield of 10.89%.
Data for the nmr spectrum of compound 6 are as follows:1H NMR(400MHz,CDCl3)δH 7.71(d,J＝16.0Hz,1H),7.64(s,1H),7.50(d,J＝8.3Hz,1H),7.39(d,J＝8.3Hz,1H),6.58(s,1H),6.54(d,J＝16.0Hz,1H),6.47(s,1H),5.56(br s,1H),4.63(s,1H),4.45(s,1H),3.54(br s,1H),2.54-2.50(overlap,3H),2.23-2.17(m,1H),2.08-2.03(m,1H),1.81-1.70(overlap,4H),1.61(s,3H),1.59(s,3H),1.33-1.29(m,4H),0.88(t,J＝6.9Hz,3H).ESI-MS:m/z 511.25[M-H]-。
the formula of the compound obtained in this example was derived as follows:
Figure BDA0002966980310000091
example 7
A process for preparing cannabidiol derivative compound 7 comprising the steps of:
by substituting compound 6a in example 6 with compound 7a and leaving the other reagents unchanged, the procedure of example 6 was followed to give 20.0mg of a white oil, i.e., compound 7, in 20.16% yield.
Data for the nmr spectrum of compound 7 are as follows:1H NMR(400MHz,CDCl3)δH 7.76(d,J＝16.0Hz,1H),7.56(d,J＝8.4Hz,2H),7.42(d,J＝8.4Hz,2H),6.58(s,1H),6.55(d,J＝16.0Hz,1H),6.47(s,1H),5.56(br s,1H),4.62(s,1H),4.45(s,1H),3.55(br s,1H),2.53-2.49(overlap,3H),2.22-2.19(m,1H),2.08-2.03(m,1H),1.83-1.67(overlap,4H),1.61(s,3H),1.59(s,3H),1.33-1.28(m,4H),0.88(t,J＝6.9Hz,3H).ESI-MS:m/z 523.20[M+H]+。
the formula of the compound obtained in this example was derived as follows:
Figure BDA0002966980310000092
example 8
A Sulforhodamine B protein staining method (Sulforhodamine B, SRB) is adopted to determine the drug concentration (IC) of cannabidiol derivatives (half maximum inhibition) when the inhibition rate of the cannabidiol derivatives on lung cancer cell lines (A549), human breast cancer cell lines (MDA-MB-231), nasopharyngeal carcinoma and drug-resistant strains (KB, KB-VIN) thereof and human breast cancer cell lines (MCF-7) reaches 50 percent50) Paclitaxel is a positive drug.
The method comprises the following specific steps:
(1) RPMI 1640 medium was supplemented with 25mM HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid), 2mM l-glutamine, 10% heat-inactivated fetal bovine serum, 100IU penicillin, 100. mu.g/mL streptomycin and 0.25. mu.g/mL amphotericin B;
(2) and (3) culturing the cells: different tumor cell strains were cultured in the above culture medium at 37 deg.C and 5% CO2Culturing in an incubator;
(3) preparing the medicine: seven compounds prepared in examples 1-7 were prepared as 10mM stock solutions in DMSO;
(4) plate preparation: adjusting the cell suspension concentration to 8000-2Culturing in an incubator;
(5) adding medicine: adding the medicines in the step (3) into a 96-well culture plate respectively until the final concentrations are respectively 100 mu M, 10 mu M, 1 mu M and 0.1 mu M, setting 3 flat wells for each concentration gradient, and culturing for 72 h; the experiment was divided into drug group, control group (only culture medium and cells) and blank group (only culture medium);
(6) and (3) detection: cells were fixed in 10% by mass trichloroacetic acid and then stained with 0.04% sulforhodamine B, the protein-bound dye was solubilized with 10mM Tris base, and the absorbance (OD) was measured at 515nm using a ELx800 microplate reader with Gen5 software.
Cell viability (%) - (experimental OD-blank OD)/(control OD-blank OD). times.100%
According to the standard curve of the concentration of the drug and the cell growth inhibition rate, the IC of the drug is obtained50。
The inhibitory effect of cannabidiol derivatives on tumor cells is shown in table 1.
TABLE 1 test results of antitumor Activity
Figure BDA0002966980310000101
The results show that the compounds 1-5 have better inhibiting effect on 5 cancer cell lines (A549, MDA-MB-231, KB, KB-VIN and MCF-7) than cannabidiol, especially the compound 5 has the most remarkable activity and IC50Values between 2.96-4.93 μ M, compounds 6 and 7 are comparable to the antitumor activity of cannabidiol.

Claims (3)

1. A cannabidiol derivative has a structural formula shown as I, II and III:
Figure FDA0002966980300000011
2. the method of producing cannabidiol derivatives as claimed in claim 1, wherein cannabidiol is used as a nucleus, and the phenolic hydroxyl group of cannabidiol is esterified with benzoic acid substituted with different groups to obtain cannabidiol derivatives.
3. Use of the cannabidiol derivative as claimed in claim 1 in the manufacture of an anti-tumour medicament.
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