CN113173857B - Cannabidiol derivative and preparation method and application thereof - Google Patents

Cannabidiol derivative and preparation method and application thereof Download PDF

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CN113173857B
CN113173857B CN202110248495.XA CN202110248495A CN113173857B CN 113173857 B CN113173857 B CN 113173857B CN 202110248495 A CN202110248495 A CN 202110248495A CN 113173857 B CN113173857 B CN 113173857B
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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, a preparation method and application thereof, which belong to the technical field of pharmaceutical chemistry, wherein the cannabidiol derivative is obtained by taking cannabidiol as a main body through a synthesis means, and an anti-tumor activity measurement result shows that the cannabidiol derivative prepared by the invention has an inhibition effect on lung cancer cell strains, human breast cancer cell strains, nasopharyngeal carcinoma and drug-resistant strains thereof.

Description

Cannabidiol derivative and preparation method and application thereof
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a cannabidiol derivative, a preparation method thereof and application thereof in tumor inhibition.
Background
Global cancer incidence and mortality have increased rapidly, and cancer is the leading cause of death in humans in the 21 st century and is the most important obstacle to extending life expectancy. Cannabidiol ((-) -cannabidiol, CBD) is one of the main components of the characteristic cannabinoid components in Cannabis (Cannabis sativa l.) plants. Research shows that cannabidiol has no mental activity, but has various pharmacological effects such as neuroprotection, antiepileptic, anxiolytic, antipsychotic, analgesic, anti-inflammatory, asthma treatment, etc.
Disclosure of Invention
The invention mainly provides cannabidiol derivatives with novel structures, a preparation method thereof and application thereof in tumor inhibition.
The cannabidiol derivative has the structure shown as I, II and III:
Figure BDA0002966980310000011
wherein R in I, II and III 1 ，R 2 ，R 3 ，R 4 ，R 5 ，R 6 ，R 7 And R is 8 Can be a substituent such as hydrogen, hydroxyl, methoxy, methyl or halogen.
The cannabidiol derivatives I, II and III are prepared by taking cannabidiol as a basic skeleton and carrying out benzoate substitution on phenolic hydroxyl groups and different groups, and the obtained cannabidiol derivatives are novel compounds.
The invention proves that the cannabidiol derivative has obvious inhibition activity on lung cancer cell strain (A549), human breast cancer cell strain (MDA-MB-231), nasopharyngeal carcinoma and drug-resistant strain (KB, KB-VIN) and human breast cancer cell strain (MCF-7) through in vitro anti-tumor activity, wherein the activity of the compound 5 is most obvious, and the IC is the most obvious 50 The 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 mother nucleus, reasonably modifies phenolic hydroxyl groups of the cannabidiol, and constructs a cannabidiol derivative with novel structure, and the chemical structure of the product is that 1 H NMR， 13 C NMR and MS confirmation.
(2) The cannabidiol derivative compounds 1-5 provided by the invention have stronger inhibition effect on 5 cancer cell lines (A549, MDA-MB-231, KB-VIN and MCF-7) than cannabidiol, and are expected to be developed into novel antitumor drugs.
Drawings
FIG. 1 shows the CD of Compound 1 of the present invention 3 Nuclear magnetic resonance hydrogen spectrogram in OD;
FIG. 2 shows the CD of Compound 1 of the present invention 3 Nuclear magnetic resonance carbon spectrum in OD;
FIG. 3 shows the CD of Compound 2 of the present invention 3 Nuclear magnetic resonance hydrogen spectrogram in OD;
FIG. 4 shows the CD of Compound 2 of the present invention 3 Nuclear magnetic resonance carbon spectrum in OD;
FIG. 5 shows the CD of Compound 3 of the present invention 3 Nuclear magnetic resonance hydrogen spectrogram in OD;
FIG. 6 shows the CD of Compound 3 of the present invention 3 Nuclear magnetic resonance carbon spectrum in OD;
FIG. 7 shows the CD of Compound 4 of the present invention 3 Nuclear magnetic resonance hydrogen spectrogram in OD;
FIG. 8 shows the CD of Compound 4 of the present invention 3 Nuclear magnetic resonance carbon spectrum in OD;
FIG. 9 shows the CD of Compound 5 of the present invention 3 Nuclear magnetic resonance hydrogen spectrogram in OD;
FIG. 10 shows the CD of Compound 5 of the present invention 3 Nuclear magnetic resonance carbon spectrum in OD.
Detailed Description
The present invention will be described in further detail with reference to specific examples and drawings, and the protection of the present invention includes, but is not limited to, the following examples. All other embodiments obtained by those skilled in the art based on the embodiments of the invention without making any inventive result fall within the scope of protection of the invention. The procedures, conditions, reagents, experimental methods, etc. in the following examples are common general knowledge in the art except for the following specific references. The reagents used in the invention are all commercially available chemical pure or analytically pure products.
The cannabidiol derivatives have the structures shown as I, II and III:
Figure BDA0002966980310000021
the synthesis of the cannabidiol derivatives comprises the following 3 routes:
route 1:
Figure BDA0002966980310000031
taking 1a and 2a as raw materials, carrying out methylation reaction, benzyl protection, demethylation reaction, esterification with cannabidiol, debenzylation protection to obtain a compound 1 and a compound 2, taking 3a as raw materials, carrying out benzyl protection, demethylation reaction, esterification with cannabidiol, debenzylation protection to obtain a compound 3.
Route 2:
Figure BDA0002966980310000041
compounds 4a and 5a were protected for hydroxy groups by reaction with 3, 4-Dihydropyran (DHP), respectively, and were reacted with cannabidiol to give intermediate products 4c and 5c, respectively, and finally deprotected by 2-Tetrahydropyran (THP) to give compound 4 and compound 5, respectively.
Route 3:
Figure BDA0002966980310000042
under the action of CMPI and DMAP, cannabidiol reacts with 6a and 7a, respectively, to give compound 6 and compound 7, respectively.
Example 1
A process for the preparation of cannabidiol derivative compound 1 comprising the steps of:
step 1. Compound 1a (18 mmol) was added to 19mL of methanol MeOH solution, stirred, and then 0.45mL of 98.3% H was added 2 SO 4 The reaction mixture was refluxed at 100deg.C for 2 hours, distilled under reduced pressure, the residue was dissolved in water and extracted with Dichloromethane (DCM), the organic layer was washed with saturated brine, anhydrous Na 2 SO 4 Drying, filtering, concentrating the filtrate under reduced pressure to obtain compound 1b (2.68 g);
step 2. Compounds 1b (17.11 mmol) and K 2 CO 3 (17.11 mmol) was added to 25mL of Dimethylformamide (DMF), stirred, benzyl chloride (BnCl, 17.11 mmol) was further added, the reaction mixture was stirred under nitrogen at 80℃for 10 hours, water was added, extracted with dichloromethane, and the organic layer was washed with saturated brine, and dried over anhydrous Na 2 SO 4 Drying, vacuum concentrating, and subjecting to silica gel column chromatography (n-hexane: two)Methyl chloride, volume ratio 1:1) to give compound 1c (3.04 g);
step 3. Compound 1c (14.88 mmol) was added to methanol (MeOH, 20 mL), dioxane (40 mL) and H 2 To the mixed solution of O (15 mL), naOH (0.50 mol) was added again, 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, and the organic layer was washed with saturated brine, anhydrous Na 2 SO 4 Drying, filtering and vacuum concentrating to obtain compound 1d (2.69 g);
step 4. Under nitrogen protection at 0deg.C, compound 1d (0.96 mmol) and cannabidiol (0.48 mmol) are added to a solution of DCM (15 mL) and stirred, CMPI (0.96 mmol) and DMAP (0.96 mmol) are added to the reaction mixture and the reaction mixture is stirred for 1 hour, the reaction precipitate is filtered off and the filtrate is successively treated with saturated NaHCO 3 Washing with aqueous solution and saturated saline, and passing through Na 2 SO 4 Drying, concentrating in vacuum, and purifying by silica gel column chromatography (n-hexane: acetone, volume ratio 95:5) to obtain compound 1e (110.4 mg);
step 5, at H 2 10% w/w palladium on charcoal (184 mg) and compound 1e (0.29 mmol) were added to methanol in the presence of the above solution, reacted at room temperature for 2 hours, filtered, and the filtrate was concentrated to give 57.8mg of a white oil as compound 1 in a yield of 72.22%.
The nuclear magnetic resonance spectra of the compound 1 are shown in fig. 1 and 2, and the data are as follows: 1 H NMR(400MHz,CD 3 OD)δ H 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). 13 C NMR(100MHz,CH 3 OD):δ C 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 structural formula of the compound obtained in this example was found to be as follows:
Figure BDA0002966980310000051
example 2
A process for the preparation of cannabidiol derivative compound 2 comprising the steps of:
the procedure of example 1 was followed except that compound 1a was replaced with compound 2a and the other reagents were unchanged, to give 34.2mg of compound 2 as a colorless oil in 96.89% yield in the final step.
The nuclear magnetic resonance spectra of compound 2 are shown in fig. 3 and 4, and the data are as follows: 1 H NMR(400MHz,CD 3 OD)δ H 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). 13 C NMR(100MHz,CH 3 OD):δ C 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 structural formula of the compound obtained in this example was found to be as follows:
Figure BDA0002966980310000061
example 3
A process for the preparation of cannabidiol derivative compound 3 comprising the steps of:
the procedure was as in steps 2-5 of example 1, substituting compound 1b for compound 3a, leaving the other reagents unchanged, to give 98.1mg of pale violet powder, compound 3, in 93.07% yield in the final step.
The nuclear magnetic resonance spectrum of the compound 3 is shown in the figure5. 6, the data are as follows: 1 H NMR(400MHz,CD 3 OD)δ H 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). 13 C NMR(100MHz,CH 3 OD):δ C 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 structural formula of the compound obtained in this example was found to be as follows:
Figure BDA0002966980310000071
example 4
A process for the preparation of cannabidiol derivative compound 4 comprising the steps of:
step 1. Compounds 4a (8.00 mmol) and pyridine p-toluenesulfonate (PPTS, 2.00 mmol) were added to DCM (25 mL) at room temperature with stirring, then DHP (32.00 mmol) was added and the reaction mixture stirred overnight with saturated NaHCO 3 The solution, water and saturated brine were washed successively, 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. Compounds 4b (1.34 mmol) and cannabidiol (0.67 mmol) were added to a solution of DCM (15 mL) at 0deg.C under nitrogen, stirred, CMPI (1.34 mmol) and DMAP (1.34 mmol) were added to the reaction mixture, stirred for 1 hour, the reaction mixture was filtered, and the filtrate was sequentially washed with saturated NaHCO 3 Aqueous solution, saturated brine, and anhydrous Na 2 SO 4 Drying, 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 4c;
step 3. Compound 4c (0.36 mmol) and p-toluenesulfonic acid (PTSA, 0.01 mmol) were added to 25mL of methanol at room temperature, and the mixture was stirred for 4 hours, concentrated under reduced pressure, and then taken up in 5% by mass of NaHCO 3 The solution was neutralized and extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, respectively, and then with anhydrous Na 2 SO 4 Drying and distillation under reduced pressure gave compound 4 (204.0 mg, yield: 92.25%) as a pale brown solid.
The nmr spectra of compound 4 are shown in fig. 7 and 8, and the data are as follows: 1 H NMR(400MHz,CD 3 OD)δ H 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). 13 C NMR(100MHz,CH 3 OD):δ C 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 structural formula of the compound obtained in this example was found to be as follows:
Figure BDA0002966980310000081
example 5
A process for the preparation of cannabidiol derivative compound 5 comprising the steps of:
the procedure of steps 1-3 in example 4 was followed, except that compound 4a of example 4 was replaced with compound 5a and the other reagents were unchanged, to give 7.1mg of colorless oil as compound 5 in 28.87% yield in the final step.
The nmr spectra of compound 5 are shown in fig. 9 and 10, and the data are as follows: 1 H NMR(400MHz,CD 3 OD)δ H 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). 13 C NMR(100MHz,CH 3 OD):δ C 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 structural formula of the compound obtained in this example was found to be as follows:
Figure BDA0002966980310000082
example 6
A process for the preparation of cannabidiol derivative compound 6 comprising the steps of:
compound 6a (0.38 mmol) and cannabidiol (0.19 mmol) were added to a solution of DCM (5 mL) under nitrogen at 0deg.C, stirred, CMPI (0.38 mmol) and DMAP (0.38 mmol) were added to the reaction mixture and stirred for 1 hour, the reaction precipitate was filtered off and the filtrate was successively washed with saturated NaHCO 3 Washing with aqueous solution and saturated saline solution, na 2 SO 4 Drying, concentrating, and purifying with silica gel column chromatography (n-hexane: acetone, volume ratio of 95:5) to obtain 10.6mg of white oily substance, namely compound 6, with yield of 10.89%.
The data for the nuclear magnetic resonance spectrum of compound 6 are as follows: 1 H NMR(400MHz,CDCl 3 )δ H 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 structural formula of the compound obtained in this example was found to be as follows:
Figure BDA0002966980310000091
example 7
A process for the preparation of cannabidiol derivative compound 7 comprising the steps of:
the procedure of example 6 was followed except that compound 6a of example 6 was replaced with compound 7a and the other reagents were changed to give 20.0mg of compound 7 as a white oil in 20.16% yield.
The data for the nuclear magnetic resonance spectrum of compound 7 are as follows: 1 H NMR(400MHz,CDCl 3 )δ H 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 structural formula of the compound obtained in this example was found to be as follows:
Figure BDA0002966980310000092
example 8
The method adopts a sulfonyl rhodamine B protein staining method (Sulforhodamine B, SRB) to determine the drug concentration (half maximal inhibitory concentration, IC) when the inhibition rate of cannabidiol derivatives to lung cancer cell lines (A549), human breast cancer cell lines (MDA-MB-231), nasopharyngeal cancer and drug-resistant lines (KB, KB-VIN) and human breast cancer cell lines (MCF-7) reaches 50 percent 50 ) Paclitaxel is a positive drug.
The method comprises the following specific steps:
(1) To RPMI 1640 medium was added 25mM HEPES (4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid), 2mM l-glutamine, 10% heat-inactivated fetal bovine serum, 100IU penicillin, 100 μg/mL streptomycin and 0.25 μg/mL amphotericin B;
(2) Culturing cells: different tumor cell lines are cultured in the culture solution at 37 deg.c and 5% CO 2 Culturing in an incubator;
(3) Preparing the medicine: seven compounds prepared in examples 1 to 7 were prepared as 10mM stock solutions in DMSO;
(4) Seed plate: regulating cell suspension concentration to 8000-22000 cells per well, mixing, adding into 96-well plate, adding into each well (100 μl), and adding 5% CO at 37deg.C 2 Culturing in an incubator;
(5) Adding the medicine: adding the medicines in the step (3) into 96-well culture plates respectively, wherein the final concentration is 100 mu M,10 mu M,1 mu M and 0.1 mu M respectively, and culturing for 72h by setting 3 flat wells for each concentration gradient; the experiments were divided into drug groups, control groups (culture medium and cells only) and blank groups (culture medium only);
(6) And (3) detection: cells were fixed in 10% by mass trichloroacetic acid, then stained with 0.04%sulforhodamine B, protein-bound dye was dissolved with 10mM Tris base, and absorbance (OD) was measured at 515nm using a ELx800 microplate reader with Gen5 software.
Cell viability (%) = (experimental OD-blank OD)/(control OD-blank OD) ×100%
IC was determined based on a standard curve of drug concentration-cell growth inhibition ratio 50 。
The inhibition of tumor cells by cannabidiol derivatives is shown in table 1.
TABLE 1 test results of antitumor Activity
Figure BDA0002966980310000101
The results show that compounds 1-5 inhibited 5 cancer cell lines (A549, MDA-MB-231, KB-VIN and MCF-7) better than cannabidiol, especially compound 5 was most significantly active, IC 50 The values were between 2.96-4.93. Mu.M, and compounds 6 and 7 were comparable to the antitumor activity of cannabidiol.

Claims (3)

1. Cannabidiol derivatives have structural formulas shown as I, II and III:
Figure FDA0004158454900000011
2. the method for preparing cannabidiol derivative as claimed in claim 1, comprising the specific steps of:
route 1:
Figure FDA0004158454900000012
taking 1a and 2a as raw materials, carrying out methylation reaction, benzyl protection, demethylation reaction, esterifying with cannabidiol, and carrying out debenzylation protection to obtain a compound 1 and a compound 2; or 3a is used as a raw material, benzyl protection and demethylation reaction are carried out on the raw material, and then the raw material is esterified with cannabidiol, and the compound 3 is obtained after the benzyl protection is carried out;
route 2:
Figure FDA0004158454900000021
compounds 4a and 5a are respectively reacted with 3, 4-dihydropyran to protect hydroxyl groups, respectively reacted with cannabidiol to obtain intermediate products 4c and 5c, and finally deprotected by 2-tetrahydropyran to obtain compound 4 and compound 5;
route 3:
Figure FDA0004158454900000022
under the action of CMPI and DMAP, cannabidiol reacts with 6a and 7a, respectively, to give compound 6 and compound 7, respectively.
3. Use of cannabidiol derivatives as claimed in claim 1 for the manufacture of a medicament for the treatment of lung cancer, human breast cancer and nasopharyngeal cancer.
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