CN109369667B - 2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound and preparation method and application thereof - Google Patents
2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 2, 3, 6-trideoxyglucosyl demethylepipodophyllotoxin compound or pharmaceutically-formable ester thereof, wherein the chemical structural formula is as follows:
wherein R represents C1‑C6Alkyl, -OH, -NH of2、NO2A halogen group. The cell toxicity activity of the compound of the invention on human lung cancer cells (A549), human liver cancer cells (HepG2), human cervical cancer cells (Hela), human neuroblastoma cells (SH-SY5Y) and oral cancer vincristine-resistant cells (KB/VCR) is obviously improved compared with that of etoposide which is a clinical drug, and the compound has the potential of being developed into an anti-tumor drug.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry and pharmacology. Specifically, the invention relates to a novel podophyllotoxin derivative 2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound, and a preparation method and application thereof.
Background
With the advance of medicine, infectious diseases in general are gradually controlled, and malignant tumor, cancer, becomes one of the major diseases that are common and seriously threaten human life and quality of life. The cytotoxic antitumor drugs used clinically at present have low selectivity, resulting in large side effects. Therefore, the search and discovery of novel antitumor drugs with high efficacy and low toxicity are the current research hotspots.
The podophyllotoxin is derived from rhizome extract of podophyllum peltate (podophyllum) and has antimitotic activity, and due to its serious toxic and side effects, the podophyllotoxin is used as an antitumor drug and is greatly limited in use. Researchers have carried out a great deal of structural modification work on podophyllotoxin so as to obtain a compound which has small toxic and side effects and can retain strong antitumor activity of the podophyllotoxin. At present, podophyllotoxin compounds have been well applied in the aspect of antitumor drugs, etoposide, teniposide and other drugs are sold in the market, and the two drugs are both glycosides of demethylepipodophyllotoxin. Etoposide and teniposide are podophyllotoxin derivatives developed by Sandoz corporation in the sixties and seventies of the 19 th century, and have limitations such as unsatisfactory therapeutic effect, poor water solubility, easy metabolic inactivation, multi-drug resistance and the like although having good therapeutic effect on various cancers. Until now, the structure of podophyllotoxin is still being deeply modified to obtain better antitumor drugs.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a novel podophyllotoxin derivative, namely a 2, 3, 6-trideoxyglycosyl demethylepipodophyllotoxin compound. Cell experiment results show that the compound has no toxic or side effects on five tumor cell strains: human lung cancer cells (A549), human liver cancer cells (HepG2), human cervical cancer cells (Hela), human neuroblastoma cells (SH-SY5Y) and oral cancer vincristine-resistant cells (KB/VCR) have certain activity of inhibiting the growth of tumor cells and can become potential antitumor drugs.
Specifically, the invention provides a compound with a structure shown in a formula (I).
R represents C1-C6Alkyl, -OH, -NH of2、NO2Halogen radical, preferably represents C1-C6Alkyl group of (1).
In the structure of the formula (I), R represents a group in an upright or flat bond, and a glycosidic bond is an upright or flat bond, namely the R group is R type or S type, and the glycosidic bond is alpha configuration or beta configuration.
Preferably, the 2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound of the invention has the following structure: wherein R is methyl with a solid wedge bond, and when the glycosidic bond is a virtual wedge bond, the compound is a compound Ia shown in the following formula (II).
R is an isopropyl group with a solid wedge bond, and when the glycosidic bond is the solid wedge bond, the compound is a compound Ib shown in the following formula (II).
R is a methyl group having a solid wedge bond, and when the glycosidic bond is a solid wedge bond, it is a compound Ic represented by the following formula (II).
R is a solid wedge bond n-propyl group, and when the glycosidic bond is a solid wedge bond, the compound Id is represented by the following formula (II).
R is ethyl of a virtual wedge bond, and when the glycosidic bond is a solid wedge bond, the compound is a compound Ie shown in the following formula (II).
R is an isopropyl group with a virtual wedge bond, and when the glycosidic bond is a solid wedge bond, the compound is a compound If shown in the following formula (II).
Another object of the present invention is to provide a process for producing the above 2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound, which comprises the steps of:
(1) in a dry aprotic solvent, the demethylepipodophyllotoxin protected by benzyl and corresponding tert-butyl carbonate based pyrone are subjected to allyl glycosylation reaction in the presence of a palladium catalyst and an organophosphorus ligand to obtain the pyrone based demethylepipodophyllotoxin,
the palladium catalyst is one or more selected from tri (dibenzylidene indene acetone) dipalladium, tetra (triphenyl phosphorus) palladium and tri (dibenzylidene acetone) dipalladium chloroform adduct, the phosphorus ligand is one or more selected from triphenyl phosphorus, tributyl phosphorus and triphenoxy phosphorus, and the solvent is one or more selected from dichloromethane, dichloroethane, acetonitrile, tetrahydrofuran and benzene. One preferred reaction condition of the present invention is the reaction of benzyl protected demethylepipodophyllotoxin with the corresponding tert-butylcarbonate-based pyrone with tris (dibenzylideneacetone) dipalladium and triphenylphosphine in dichloromethane to yield the pyranone demethylepipodophyllotoxin.
(2) In the presence of cerous chloride, in a protic solvent, pyranosyl demethyl epipodophyllotoxin and a reducing agent are subjected to Luche reduction reaction to obtain hydroxypyranyl demethyl epipodophyllotoxin,
the reducing agent is selected from one or more of sodium borohydride, potassium borohydride and sodium cyanoborohydride, and the protic solvent is selected from one or more of methanol, ethanol and isopropanol. The reaction temperature is preferably from-80 to-40 ℃ and the reaction time is preferably from 1 to 4 hours. One preferred reaction condition of the invention is that pyranosyl demethylepipodophyllotoxin reacts with sodium borohydride in cerous chloride methanol solution to obtain hydroxypyranyl demethylepipodophyllotoxin.
(3) Reducing the hydroxypyranyl demethylepipodophyllotoxin to obtain 2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin,
preferably, the reduction reaction is carried out in methanol under the conditions of hydrogen and palladium on carbon catalyst. The reaction temperature is preferably 0 to 25 ℃ and the reaction time is preferably 6 to 24 hours.
The invention also aims to provide the application of the 2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound or the pharmaceutically-formable ester thereof in preparing the antitumor drugs. Preferably, the anti-tumor drug is a drug for preventing and treating oral cancer, liver cancer, cervical cancer, lung cancer and neuroblastoma.
In the pharmacological activity research of the invention, according to the sensitivity of the Chinese frequently-occurring tumor diseases and tumor cells, human lung cancer cells (A549), human liver cancer cells (HepG2), human cervical cancer cells (Hela), human neuroblastoma cells (SH-SY5Y) and oral cancer vincristine-resistant cells (KB/VCR) are selected as indexes for pharmacological evaluation of in vitro cytotoxic activity, and the synthesized compounds are screened for cytotoxicity. The result shows that the compound has good anti-tumor activity.
The 2, 3, 6-trideoxyglucosyl demethylepipodophyllotoxin or the medicinal ester and the solvate thereof can be combined with auxiliary materials or carriers commonly used in pharmacy to prepare the medicinal composition which has the tumor cell growth inhibition activity and can be used for preventing and treating tumors. The pharmaceutical composition can be made into tablet, capsule, injection, aerosol, suppository, pellicle, dripping pill, patch, subcutaneous implant, topical liniment, oral liquid or ointment, or controlled release or sustained release preparation or nanometer preparation known in modern pharmaceutical industry.
The 2, 3, 6-trideoxyglycosyl demethylepipodophyllotoxin or the medicinal ester and the solvate thereof can be combined with the anti-tumor medicaments on the market such as platinum medicament cisplatin (DDP), camptothecin medicament irinotecan (CPT-11), vinca alkaloid medicament nor-carbon vinblastine (NVB navelbine), etoposide (VP-16), paclitaxel (paclitaxel) and the like to prepare the cytotoxic composition with the tumor growth inhibition activity, and can be used for treating tumor diseases. The pharmaceutical composition can be tablets, capsules, injections, aerosols, suppositories, membranes, dropping pills, patches, subcutaneous implants, external liniments, oral liquids or ointments, and can also be controlled-release or sustained-release formulations or nano preparations known in the modern pharmaceutical industry.
Detailed Description
The invention is further illustrated by the following examples. The examples present synthesis of representative novel compounds and associated structural identification data as well as partial activity data. It must be noted that the following examples are intended to illustrate the invention and are not intended to limit the invention. Simple modifications of the invention in accordance with its spirit fall within the scope of the claimed invention.
Example 1(2R,3R,6R) -3, 6-dihydro-2-methyl-6-norepipodophyllotoxin-2H-pyran-3-ol (Ia)
In a 50mL round bottom flask was added n-butyl ((2S,6R) -6-methyl-5-oxo-5, 6-dihydro-2H-pyran-2-yl) carbonate (912mg,4mmol) and norepipodophyllotoxin (2.2g,4.4mmol) dissolved in 20mL of dichloromethane followed by addition of Pd2(dba)3(91.6mg,0.1mmol) and PPh3(105.0mg,0.4mmol), and reacted under nitrogen in an ice bath for 12 h. TLC, concentrated and chromatographed (prtroleum ether: EtOAc 1:1) to give IIIa (1.4g) as a yellowish solid in 60% yield.
A50 mL round bottom flask was charged with IIIa (600mg,1mmol), CeCl3MeOH (5mL,0.4eq), sodium borohydride (42mg,1.1mmol) and 5mL dichloromethane were mixed and stirred for 2.5h at-78 ℃. The reaction was stopped by TLC, quenched with deionized water, extracted with dichloromethane (50mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated, and column chromatographed (prtroleum ether: EtOAc ═ 1:1) to give IIa (542mg) as a white solid in 90% yield.
A50 mL round-bottomed flask was charged with IIa (257mg,0.5mmol) dissolved in 10mL of tetrahydrofuran, the gas was replaced with nitrogen, an appropriate amount of palladium on carbon as a hydrogenation catalyst was added, the gas was replaced with nitrogen, hydrogen was introduced, the gas was replaced again, and the reaction was carried out at room temperature for 24 hours. TLC detection was complete, filtration, concentration and column chromatography (prtraleum ether: EtOAc 1:1) gave Ia (197mg) as a white solid in 90% yield.1H NMR(400MHz,DMSO-d6):δ8.24(s,1H,Ar-OH), 7.01(s,1H,ArH),6.51(s,1H,ArH),6.20(s,2H,ArH),6.02(d,2H,J＝11.6Hz,CH2),4.92 (m,1H,H2),4.81(m,1H,CH),4.37(m,4H,CH2,CH,OH),3.59(m,7H,OCH3,H6),3.25 (m,1H,H5),3.13(m,1H,CH),2.99(m,1H,CH),1.87(m,1H,H3),1.68(m,3H,H3,H4), 1.17(d,3H,J＝6.4Hz,CH3).13C NMR(100MHz,DMSO-d6):δ175.1,148.1,147.6,146.8, 135.2,132.8,130.7,110.2,109.7,108.9,101.7,101.1,76.0,73.8,70.6,65.1,56.5,43.4,41.1, 37.8,30.1,25.8,17.7；HRMS(ESI):m/z calcd for C27H34O10N:532.2178；found:532.2177 [M+NH4]+。
Example 2
The compounds Ib to If were prepared according to the method of reference example 1, the physicochemical data for the individual compounds Ib to If were as follows:
(2R,3R,6R) -3, 6-dihydro-2-isopropyl-6-norepipodophyllotoxin-2H-pyran-3-ol (Ib)
1H NMR(400MHz,DMSO-d6):δ8.24(s,1H,Ar-OH),6.93(s,1H,ArH),6.52(s,1H,ArH), 6.21(s,2H,ArH),6.02(d,2H,J＝4.8Hz,CH2),4.85(m,2H,H2,CH),4.64(d,1H,J＝5.6 Hz,CH2),4.52(d,1H,J＝5.2Hz,CH2),4.46(m,1H,CH),4.03(m,1H,H6),3.95(m,1H, OH),3.63(s,6H,OCH3),3.33(m,1H,H5),3.20(dd,1H,J1＝14Hz,J2＝4.8Hz,CH),2.85 (m,1H,CH),2.14(m,1H,CH),1.85(d,1H,J＝12.4Hz,H3),1.89(m,3H,H3,H4),1.08(d, 3H,J＝6.8Hz,CH3),0.92(d,3H,J＝6.4Hz,CH3).13C NMR(100MHz,DMSO-d6):δ 175.0,147.9,147.6,146.8,135.2,132.9,130.6,130.6,110.6,109.9,109.0,101.8,97.3,77.6, 73.1,68.2,66.4,56.5,49.1,43.2,41.1,38.6,29.4,28.3,27.7,20.4,16.6.HRMS(ESI):m/z calcd for C29H34O10:542.2140；found:542.2146[M]。
(2R,3R,6R) -3, 6-dihydro-2-methyl-6-demethylepipodophyllotoxin-2H-pyran-3-ol (Ic)
1H NMR(400MHz,DMSO-d6):δ8.23(s,1H,Ar-OH),6.82(s,1H,ArH),6.52(s,1H,ArH), 6.21(s,2H,ArH),6.02(m,2H,CH2),4.82(m,2H,H2,CH2),4.70(d,1H,J＝6Hz,CH2), 4.53(d,1H,J＝5.2Hz,CH2),4.42(d,1H,J＝7.6Hz,CH),4.01(m,1H,H6),3.63(s,6H, OCH3),3.38(m,1H,H5),3.21(dd,1H,J1＝14Hz,J2＝5.2Hz,CH),3.04(m,1H,OH),2.85 (m,1H,CH),1.96(m,1H,H3),1.66(m,2H,H3,H4),1.47(m,1H,H4),1.19(d,3H,J＝6 Hz,CH3).13C NMR(100MHz,DMSO-d6):δ175.0,147.9,147.8,146.7,135.2,133.0,130.6, 130.6,110.2,110.0,108.9,101.8,97.6,73.6,70.9,70.6,68.1,56.5,43.3,40.9,38.4,29.6, 27.7,18.2.HRMS(ESI):m/z calcd for C27H34O10N:532.2170；found:532.2177[M+NH4]+. (2R,3R,6R) -3, 6-dihydro-2-propyl-6-norepipodophyllotoxin-2H-pyran-3-ol (Id)
1H NMR(400MHz,DMSO-d6):δ8.23(s,1H,Ar-OH),6.87(s,1H,ArH),6.51(s,1H,ArH), 6.20(s,2H,ArH),6.02(d,2H,J＝5.6Hz,CH2),4.86(d,1H,J＝3.2Hz,H2),4.80(s,1H, CH),4.68(d,1H,J＝6Hz,CH2),4.52(d,1H,J＝5.2Hz,CH2),4.44(t,1H,J＝7.6Hz,CH), 3.97(m,1H,H6),3.63(s,6H,OCH3),3.36(m,1H,H5),3.21(dd,1H,J1＝14Hz,J2＝5.2 Hz,CH),3.11(m,1H,OH),2.85(m,1H,CH),1.81(m,2H,H3,H4),1.53(m,6H,H3,H4, CH2),0.93(t,3H,J＝6.8Hz,CH3).13C NMR(100MHz,DMSO-d6):δ175.0,147.9,147.6, 146.7,135.2,133.0,130.6,110.5,109.9,108.9,101.8,97.3,74.1,73.4,69.2,68.1,56.5,49.1, 43.2,41.0,38.6,34.9,29.5,27.6,18.7,15.1.HRMS(ESI):m/z calcd for C29H34O10: 542.2140；found:542.2146[M]。
(2S,3R,6R) -3, 6-dihydro-2-ethyl-6-norepipodophyllotoxin-2H-pyran-3-ol (Ie)
1H NMR(400MHz,DMSO-d6):δ8.25(s,1H,Ar-OH),6.90(s,1H,ArH),6.56(s,1H,ArH), 6.19(s,2H,ArH),6.03(m,2H,CH2),4.90(s,1H,H2),4.79(m,1H,CH),4.54(d,1H,J＝ 5.6Hz,CH2),4.41(t,1H,J＝7.6Hz,CH),4.34(m,1H,CH2),4.04(q,1H,J＝7.2Hz,H6), 3.63(s,6H,OCH3),3.36(m,1H,OH),3.16(m,2H,CH,H5),2.99(m,1H,CH),1.92(m,1H, H3),1.69(m,2H,H3,H4),1.33(m,3H,H4,CH2,),1.02(t,3H,J＝7.2Hz,CH3).13C NMR (100MHz,DMSO-d6):δ175.1,148.1,147.6,146.2,135.2,133.7,131.2,128.3,110.3,109.0, 101.8,91.4,75.7,68.9,67.4,60.2,56.6,43.5,38.0,29.4,24.8,21.2,14.6,10.6.HRMS(ESI): m/z calcd for C28H32O10:528.1986；found:528.1990[M]。
(2S,3R,6R) -3, 6-dihydro-2-isopropyl-6-norepipodophyllotoxin-2H-pyran-3-ol (If)
1H NMR(400MHz,DMSO-d6):δ8.24(s,1H,Ar-OH),6.89(s,1H,ArH),6.56(s,1H,ArH), 6.20(s,2H,ArH),6.03(d,2H,J＝12Hz,CH2),4.91(s,1H,H2),4.74(m,2H,CH,CH2), 4.53(d,1H,J＝6Hz,CH),4.39(m,2H,CH2,H6),3.61(s,6H,OCH3),3.19(m,2H,OH, H5),3.00(m,1H,CH),2.18(m,1H,CH),1.76(m,2H,H3,H4),1.60(m,2H,H3,H4),1.07 (d,3H,J＝7.2Hz,CH3),0.91(d,3H,J＝6.8Hz,CH3).13C NMR(100MHz,DMSO-d6):δ 175.1,148.1,147.6,146.2,135.3,133.7,131.2,128.2,111.2,110.3,109.0,101.8,91.4,77.8, 67.5,67.2,66.2,56.6,49.1,43.5,38.0,29.3,27.2,25.6,21.0,15.5.HRMS(ESI):m/z calcd for C29H34O10:542.2140；found:542.2146[M]。
Example 3
In order to better understand the essence of the invention, the pharmacological experiment results of the inhibition effect of the 2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound on the growth of five tumor cell strains show the new application of the compound in the research field of antitumor drugs. The pharmacological examples give partial activity data for representative compounds. It must be noted that the pharmacological examples of the invention are intended to illustrate the invention and not to limit it. Simple modifications of the invention in accordance with its spirit fall within the scope of the claimed invention.
The cytotoxic activity of the compounds Ia-If on five tumor cells including human lung cancer cell (A549), human liver cancer cell (HepG2), human cervical cancer cell (Hela), human neuroblastoma cell (SH-SY5Y) and oral cancer vincristine-resistant cell (KB/VCR) was controlled by etoposide (VP-16).
Tumor cells were cultured in RPMI1640 medium containing 10% fetal bovine serum, 100U/mL penicillin and 100U/mL streptomycin. Cells were plated at 5X 10 per well3Is added to a 96-well plate containing 5% CO at 37 deg.C2For 24 hours in a humidified air incubator.
Inoculating cells in logarithmic growth phase in 96-well plate, adding medicines with different concentrations after 24 hr adherence, setting 4 parallel holes for each concentration, culturingCulturing for 68h, adding MTT solution, culturing for 4h, discarding culture solution, adding DMSO 150 μ L, shaking for 10min, measuring absorbance (A) at 570nm with microplate reader, and calculating half Inhibitory Concentration (IC)50) The results are shown in Table 1.
TABLE 1 Demethyl Podophyllotoxin 2, 3, 6-Trideoxyglycoside Ia-If inhibition on five tumor cells (IC)50)
From the pharmacological examples, the cell toxicity activities of the compounds Ia-If on five tumor cells including human lung cancer cells (A549), human liver cancer cells (HepG2), human cervical cancer cells (Hela), human neuroblastoma cells (SH-SY5Y) and oral cancer vincristine-resistant cells (KB/VCR) are obviously improved compared with that of etoposide which is a clinical drug, and the compounds Ia-If have the potential of being developed into antitumor drugs.
Claims (9)
1. A2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound characterized by having the chemical structural formula:
r represents C1-C6Alkyl group of (1).
2. The 2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound of claim 1, wherein the R group is R-type or S-type and the glycosidic bond is in the alpha or beta configuration.
3. The 2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound of claim 1, characterized by the following structure:
4. a process for the preparation of a 2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound according to any of claims 1-3, characterized by comprising the steps of:
(1) in a dry aprotic solvent, the demethylepipodophyllotoxin protected by benzyl and corresponding tert-butyl carbonate based pyrone are subjected to allyl glycosylation reaction in the presence of a palladium catalyst and an organophosphorus ligand to obtain the pyrone based demethylepipodophyllotoxin,
(2) in the presence of cerous chloride, in a protic solvent, pyranosyl demethyl epipodophyllotoxin and a reducing agent are subjected to Luche reduction reaction to obtain hydroxypyranyl demethyl epipodophyllotoxin,
(3) the hydroxy pyranyl demethyl epipodophyllotoxin is subjected to hydrogen reduction reaction to obtain 2, 3, 6-trideoxyglycosyl demethyl epipodophyllotoxin,
5. the preparation method according to claim 4, wherein the palladium catalyst in step (1) is selected from one or more of tris (dibenzylideneacetone) dipalladium, tetrakis (triphenylphosphine) palladium and tris (dibenzylideneacetone) dipalladium chloroform adduct, the organophosphorus ligand is selected from one or more of triphenylphosphine, tributylphosphorus and triphenoxyphos, and the solvent is selected from one or more of dichloromethane, acetonitrile and benzene.
6. The preparation method according to claim 4, wherein the reducing agent in step (2) is selected from one or more of sodium borohydride, potassium borohydride and sodium cyanoborohydride, and the solvent is selected from one or more of methanol, ethanol and isopropanol.
7. The method according to claim 4, wherein the reduction reaction conditions in step (3) are hydrogen gas, palladium on carbon catalyst, and the reaction is carried out in methanol.
8. Use of a 2, 3, 6-trideoxyglycosyldemethylepipodophyllotoxin compound according to any one of claims 1-3 for the preparation of an anti-tumor medicament.
9. The use according to claim 8, wherein the antitumor agent is an agent for preventing and treating oral cancer, liver cancer, cervical cancer, lung cancer and neuroblastoma.
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