CN115073406A - Eucalyptus alkane type sesquiterpene lactone TBA derivative and application thereof - Google Patents
Eucalyptus alkane type sesquiterpene lactone TBA derivative and application thereof Download PDFInfo
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Abstract
The invention provides a eudesmane sesquiterpene lactone TBA derivative, which is prepared by chemical reaction of 5 TBA derivatives, wherein the synthesized eudesmane sesquiterpene lactone TBA derivative 1a-5a has better activity of inhibiting the proliferation of cancer cells against human breast cancer cells MCF-7, cervical cancer cells HeLa and lung cancer cells A549, the anti-proliferation activity of the eudesmane sesquiterpene lactone TBA is higher than that of eudesmane sesquiterpene lactone TBA, and the eudesmane sesquiterpene lactone TBA can be clinically applied to the preparation of medicaments for resisting breast cancer, cervical cancer and lung cancer.
Description
Technical Field
The invention relates to the field of medicinal chemistry, and particularly relates to a eudesmane type sesquiterpene lactone TBA derivative and application thereof.
Background
In recent 30 years, the number of cancer diseases is increased at a speed of 3% -5% per year on average, and the cancer disease becomes the second leading cause of death next to cardiovascular diseases, seriously threatens human life health and social development, has complicated etiology and complicated cause, and is diligent and far-off in developing related researches.
Sesquiterpene compounds are the most numerous terpenoids in terms of number and structural skeleton type, and are widely distributed in plants of various genera such as Compositae. As early as 2006, more than 11000 natural sesquiterpene compounds were discovered, of which nearly 5000 contain at least one lactone ring, mainly consisting of: germacrane lactone type, guaiane lactone type, eudesmane lactone type, etc. The sesquiterpene lactone compounds are effective components with good antitumor activity. According to the Lipinsky's' principle of five drugs, sesquiterpene lactone is a compound which can mostly accord with the principle of the drugs.
The eudesmane sesquiterpene lactone Trilobolide-6-O-isobutyrate A (TBA) is a high-oxygen eudesmane sesquiterpene lactone compound separated from Wedelia trilobata, and the absolute structure of the high-oxygen eudesmane sesquiterpene lactone compound is further determined by an X-ray single crystal diffraction experiment at the earlier stage of a research team. The invention further modifies the structure of the compound to obtain a series of analogues with novel structures, and researches the antitumor cell activity of the analogues, thereby laying a research foundation for preparing antitumor drugs in the next step.
Disclosure of Invention
Therefore, the invention aims to provide a eudesmane type sesquiterpene lactone TBA derivative and application thereof, and the prepared compounds 1a-5a are applied to inhibiting proliferation of human breast cancer cells MCF-7, cervical cancer cells HeLa and lung cancer cells A549. Compared with parent molecules, the 5 compounds have better effect of inhibiting cancer cell proliferation, and can be applied to clinically preparing medicines for resisting human breast cancer, cervical cancer and lung cancer.
The technical scheme of the invention is realized as follows:
a eudesmane type sesquiterpene lactone TBA derivative has a structural formula as follows:
wherein: the compound 1a is (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4-hydroxy-13-methoxy-1, 9-diacetoxy-6-isobutyryloxyhalodendrilactone;
the compound 2a is (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4-hydroxy-13-acetonyl-1, 9-diacetoxy-6-isobutyryloxyhalodendrilactone;
the compound 3a is (1S,4S,5S,6S,7S,8S,9R,10S,11R) -1,4, 9-trihydroxy-13-methoxy-6-isobutyryloxyhalodendrilactone;
the compound 4a is (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4, 6-dihydroxy-13-methoxy-1, 9-diacetoxy halodendrin lactone;
compound 5a is (1S,4S,5S,6S,7S,8S,9R,10S,11R) -1,4,6, 9-tetrahydroxy-13-methoxyhalojerusalem artichoke lactone;
further, the eudesmane type sesquiterpene lactone TBA derivative is prepared by using sesquiterpene lactone TBA as a starting material, performing addition reaction on the sesquiterpene lactone TBA and a methanol solution under the action of calcium hydride to obtain a mixture, adjusting the pH of the mixture by using a hydrochloric acid solution with the mass concentration of 10%, extracting the mixture by using an ethyl acetate solution, drying the mixture by using anhydrous sodium sulfate, performing reduced pressure concentration and column chromatography purification to obtain (1S,4S,5S,6S,7S,8S,9R,10S,11R) -1, 9-diacetoxy-4-hydroxy-6-isobutyryloxy-13-methoxy halojerusalem lactone (1 a);
further, under the action of potassium hydroxide, sesquiterpene lactone TBA and acetone are subjected to addition reaction, and the (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4-hydroxy-13-acetonyl-1, 9-diacetoxy-6-isobutyryloxy halodendric lactone (2a) is obtained through column chromatography purification;
further, under the action of potassium hydroxide and methanol solution, the sesquiterpene lactone TBA undergoes hydrolysis reaction, and is separated and purified by column chromatography to obtain the compound (3a-5 a).
Further illustrates the proliferation inhibition effect of 5 eudesmane type sesquiterpene lactone TBA derivatives on human breast cancer cells MCF-7, cervical cancer cells HeLa and lung cancer cells A549, and the result shows that: compared with parent molecules, the eudesmane type sesquiterpene lactone TBA derivative can show equivalent or better cancer cell proliferation inhibition activity on human breast cancer cells MCF-7, cervical cancer cells HeLa and lung cancer cells A549, and can be clinically used for preparing medicines for treating breast cancer, cervical cancer and lung cancer.
Further, the chemical reaction formula for preparing the eudesmane type sesquiterpene lactone TBA derivative is as follows:
wherein (A) CaH 2 ,MeOH,rt,5h；(B):KOH,acetone,rt,8.5h；(C):KOH,MeOH,rt,3.5h。
Compared with the prior art, the invention has the beneficial effects that: the eudesmane type sesquiterpene lactone TBA derivative provided by the invention shows good proliferation activity for inhibiting human breast cancer cells MCF-7, cervical cancer cells HeLa and lung cancer cells A549, has a better proliferation effect for inhibiting three kinds of cancer cells than eudesmane type sesquiterpene lactone TBA, and can be applied to clinically preparing medicines for resisting human breast cancer cells MCF-7, cervical cancer cells HeLa and lung cancer cells A549.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
The experimental methods used in the examples of the present invention are all conventional methods unless otherwise specified.
The materials, reagents and the like used in the examples of the present invention can be obtained commercially without specific description. The invention provides a eudesmane type sesquiterpene lactone TBA derivative, which has a structural general formula (I) as follows:
wherein: 1a:
2a:
3a:R 1 ＝R 2 ＝-OH 
4a:
R 3 ＝-OH 
5a:R 1 ＝R 2 ＝R 3 ＝-OH 
the invention is further described below with reference to specific assays.
Example 1
Compound 1a, (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4-hydroxy-13-methoxy-1, 9-diacetoxy-6-isobutyryloxyhalodendrilactone, prepared as follows:
a50 mL round bottom flask was charged with 70mg (0.155mmol) TBA, 35mg CaH 2 And 5mL of a methanol solution, stirring the mixture at room temperature for 5 hours, detecting the reaction completion by TLC (trichloromethane: ethyl acetate ═ 2:1) to obtain a mixture, adjusting the pH of the mixture to 6 to 7 with a hydrochloric acid solution having a mass concentration of 10%, extracting the mixture three times with ethyl acetate and water (3:1), drying the mixture with anhydrous sodium sulfate, filtering the mixture, concentrating the filtrate under reduced pressure by a rotary evaporator, and purifying the obtained crude product by column chromatography (trichloromethane: ethyl acetate ═ 4:1) to obtain 17.6mg of the compound 1a with a yield of 23.23%.
Spectral data of (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4-hydroxy-13-methoxy-1, 9-diacetoxy-6-isobutyryloxyhalojerusalem lactone (1 a):
1 H NMR(400MHz,CDCl 3 )δ:5.78(1H,dd,J＝8.8,10.8Hz,H-6),5.46(1H,dt,J＝8.8Hz,H-1),5.27(1H,d,J＝3.2Hz,H-9),4.83(1H,dd,J＝2.8,10.4Hz,H-8),3.33-3.73(2H,m,H-13),3.31(3H,s,H-OCH 3 ),2.97(1H,m,H-7),2.85(1H,m,H-11),2.56(1H,m,H-6-OCOPr i ),2.22,1.43(2H,m,H-2),2.01(3H,s,H-9-OAc),1.96(3H,s,H-1-OAc),1.88,1.84(2H,m,H-3),1.67(1H,d,J＝2.8Hz,H-5),1.34(3H,s,H-14),1.27(3H,s,H-15),1.22(3H,d,H-6-OCOPr i ),1.19(3H,d,H-6-OCOPr i )； 13 C NMR(100MHz,CDCl 3 )δ；177.2(C-6-OCOPr i ),176.5(C-12),170.7(C-1-OAc),169.1(C-9-OAc),74.2(C-8),72.8(C-6),72.8(C-9),71(C-13),70.5(C-4),68.5(C-1),59.3(C-OCH 3 ),53.6(C-5),46.3(C-11),41.4(C-7),40.6(C-10),35.3(C-3),34.6(C-6-OCOPr i ),32.5(C-14),29.8,22.4(C-2),22.1(C-15),21.4(C-1-OAc),20.9(C-9-OAc),19.3(C-6-OCOPr i ),18.6(C-6-OCOPr i ).HRESIMS m/z:483.2217[M-H] - (calcd for C 24 H 35 O 10 ,483.2234)。
TABLE 1 Single Crystal data for Compound 1a
Example 2
Compound 2a, (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4-hydroxy-13-acetonyl-1, 9-diacetoxy-6-isobutyryloxyhalodendrilactone, prepared as follows:
40mg (0.088mmol) of TBA, 20mg of potassium hydroxide and 2mL of acetone solution are added into a 50mL round bottom flask, the mixture is stirred at room temperature for 8.5h, after the reaction is detected to be complete by TLC (trichloromethane: acetone ═ 3:1), the mixture is adjusted to pH 6-7 by using a hydrochloric acid solution with the mass concentration of 10%, the adjusted mixture is extracted three times by using ethyl acetate and water (3:1), anhydrous sodium sulfate is dried, the mixture is filtered and then concentrated by a rotary evaporator under reduced pressure, and the crude product is purified by column chromatography (trichloromethane: acetone ═ 4:1), so that 5.6mg of compound 2a is obtained, and the yield is 7.45%.
Spectral data of (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4-hydroxy-13-acetonyl-1, 9-diacetoxy-6-isobutyryloxyhalodendrilactone (2 a):
1 H NMR(400MHz,CDCl 3 )δ:5.66(1H,H-6),5.09(1H,dd,J＝3.2,3.6Hz,H-1),4.77(1H,dd,J＝4.0,9.0Hz,C-8),3.80(1H,d,J＝4.0Hz,H-9),3.10(1H,m,H-11),2.82(2H,m,H-1′),2.53(1H,m,H-6-OCOPr i ),2.39(1H,m,H-7),2.34,1.68(2H,m,H-2),2.16(3H,s,H-3′),2.09(3H,s,H-9-OAc),2.04,1.80(2H,m,H-13),1.82,1.6(2H,m,H-3),1.79(1H,d,H-5),1.44(3H,s,H-14),1.17(6H,dd,J＝7.0,1.9Hz,H-6-OCOPr i ),1.07(3H,s,H-15)； 13 C NMR(100MHz,CDCl 3 )δ:209.51(C-2′),179.0(C-12),175.6(C-6-OCOPr i ),170.3(C-9-OAc),75.7(C-1),74.4(C-8),71.8(C-9),69.9(C-6),69.5(C-4),51.6(C-5),45.6(C-7),41.3(C-10),40.2(C-1′),40.2(C-11),34.6(C-3),34.3(C-6-OCOPr i ),30.2(C-3′),29.7(C-14),25.0(C-2),24.4(C-13),22.5(C-15),21.4(C-9-OAc),19(C-6-OCOPr i ),18.9(C-6-OCOPr i ).HRESIMS m/z:509.2369[M-H] - (calcd for C 26 H 37 O 10 ,509.2390)。
example 3
Compound 3a, (1S,4S,5S,6S,7S,8S,9R,10S,11R) -1,4, 9-trihydroxy-13-methoxy-6-isobutyryloxyhalodendrilactone, compound 4a, (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4, 6-dihydroxy-13-methoxy-1, 9-diacetoxyhalodendrilactone and compound 5a, (1S,4S,5S,6S,7S,8S,9R,10S,11R) -1,4,6, 9-tetrahydroxy-13-methoxyhalodendrilactone, prepared as follows:
64.4mg (0.142mmol) of TBA, 31.7mg of potassium hydroxide and 10mL of methanol solution are added into a 50mL round bottom flask, the mixture is stirred for 3.5 hours at room temperature, TLC is used for detecting that the reaction is completed (trichloromethane: acetone ═ 3:1), a mixture is obtained, the mixture is transferred into a 50mL beaker, the pH value of the mixture is adjusted to 6-7 by using a hydrochloric acid solution with the mass concentration of 10%, the mixture after the pH value adjustment is transferred into a 60mL separating funnel, the mixture is extracted three times by using ethyl acetate and water (3:1), anhydrous sodium sulfate is dried, the mixture is filtered and evaporated to dryness under reduced pressure by using a rotary evaporator, and the crude product is separated by column chromatography (trichloromethane: acetone ═ 3:1) to obtain three main products, namely 3.9mg of compound 3a, 5.7mg of compound 4a and 29.9mg of compound 5a, so as to obtain 80.98% of total yield.
Spectral data of (1S,4S,5S,6S,7S,8S,9R,10S,11R) -1,4, 9-trihydroxy-13-methoxy-6-isobutyryloxyhalodendrilactone (3 a):
1 H NMR(400MHz,CDCl 3 )δ:5.59(1H,dd,J＝5.2,4.8Hz,H-6),4.8(1H,dd,J＝4,10Hz,H-8),4.14(1H,H-1),3.96(1H,d,J＝3.9Hz,H-9),3.52-3.74(2H,H-13),3.33(3H,s,H-OCH 3 ),3.16(1H,m,H-11),2.86(1H,m,H-7),2.51(1H,m,H-6-OCOPr i ),2.11-1.66(2H,m,H-2),1.62,1.82(2H,m,H-3),1.20(3H,s,H-14),1.16(3H,s,H-15),1.16(6H,H-6-OCOPr i ). 13 C NMR(100MHz,CDCl 3 )δ:178.2(C-6-OCOPr i ),176.4(C-12),76.3(C-8),72(C-6),70.8(C-4),70.4(C-9),70.1(C-13),69.6(C-1),59.3(C-OCH3),51.7(C-5),45.8(C-11),42.3(C-10),40.7(C-7),35(C-3),34.4(C-6-OCOPr i ),30(C-14),26.0(C-2),21.1(C-15),19.1(C-6-OCOPr i ),18.8(C-6-OCOPr i ).HRESIMS m/z:423.1989[M+Na] + (calcd for C 20 H 32 O 8 Na,423.1989)。
spectroscopic data of (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4, 6-dihydroxy-13-methoxy-1, 9-diacetoxy halodendrilactone (4 a):
1 H-NMR(400MHz,CDCl 3 )δ:5.37(1H,t,J＝8.8Hz),5.23(1H,d,J＝2.4Hz),4.80(1H,dd,J＝2.8,10.4Hz),4.26(1H,dd,J＝8.8,11.6Hz),3.92(1H,dd,J＝4.4,8.8Hz),3.49(3H,s,OMe),3.38(1H,dd,J＝8.8,10.8Hz),2.89(1H,m),2.55(1H,m,H-11),2.35(1H,m,H-7),1.95(3H,s,H-1-OAc),1.93(3H,s,H-1-OAc),1.83(2H,s,H-2),1.67(2H,s,H-3),1.46(3H,s,H-14),1.28(3H,s,H-15). 13 C NMR(100MHz,CDCl 3 )δ:174.5(C-12),170.6(C-1-OAc),169.0(C-9-OAc),74.8(C-6),73.9(C-8),72.5(C-9),71.2(C-13),71.1(C-4),68.3(C-1),59.4(C-OMe),53.8(C-5),48.8(C-7),47.5(C-11),40.3(C-10),33.8(C-3),33.6(C-14),22.5(C-2),22.1(C-15),21.2(C-9-OAc),20.9(C-1-OAc).HRESIMS m/z:437.1788[M+Na] + (calcd for C 20 H 30 O 9 Na,437.1782)。
(1S,4S,5S,6S,7S,8S,9R,10S,11R) -1,4,6, 9-tetrahydroxy-13-methoxyhalodilactone (5 a):
1 H NMR(400MHz,Methanol-d 4 )δ:4.77(1H,d,J＝3.2,9.6Hz,H-8),4.37(1H,dd,J＝6,10.4Hz,H-1),4.26(1H,dd,J＝8.4Hz,H-6),3.82(1H,d,J＝3.6Hz,H-9),3.7(2H,m,H-13),3.37(3H,s,H-OMe),2.86(1H,m,H-11),2.74(1H,m,H-7),1.97,1.6(2H,m,H-2),1.81,1.71(2H,m,H-3),1.50(1H,d,J＝8.8Hz,H-5),1.34(3H,s,H-14),1.07(3H,s,H-15)； 13 C NMR(100MHz,Methanol-d 4 )δ:180.27(C-12),78.92(C-8),73.09(C-13),72.69(C-9),72.19(C-6),72.08(C-4),68.04(C-1),59.42(C-OMe),56.00(C-5),49.85(C-11),45.43(C-7),43.44(C-10),36.39(C-3),32.34(C-14),26.16(C-2),20.65(C-15).HRESIMS m/z:353.1574[M+Na] + (calcd for C 16 H 26 O 7 Na,353.1571)。
example 4
An activity experiment of the eudesmane type hemiterpene lactone TBA and the derivatives thereof in preparing anti-cervical cancer cells HeLa, lung cancer cells A549 and anti-human breast cancer cells MCF-7.
(1) Tumor cell lines: the cervical cancer cell HeLa, the human breast cancer cell MCF-7 and the lung cancer cell A549, the positive control: and (3) adriamycin.
(2) The experimental method comprises the following steps: cell proliferation inhibition assay using MTT colorimetric method:
inoculating: taking a 96-well plate, operating in a super clean bench, adding 100 mu LPBS around edge holes on the periphery of the 96-well plate in a circle, inoculating 100 mu L of cell culture solution into each of the rest holes, and culturing for 24 hours to ensure that cells grow adherent;
② culturing: sequentially loading eudesmane type sesquiterpene lactone TBA and derivatives 1a-5a thereof from low concentration to high concentration, wherein each well is loaded with 10 mu L, the final concentration of each well is 1 mu mol/L, 10 mu mol/L and 100 mu mol/L respectively, each concentration is 6 in parallel, 10 mu L PBS is added into each well of a blank group, and the blank group is cultured for 48h at 37 ℃;
③ developing color: after culturing for 48h, adding 10 mu L of 5mg/mL MTT solution into each hole, continuously incubating for 4h, discarding the culture supernatant, and adding 150 mu L DMSO into each hole to fully melt the crystal;
and fourthly, color comparison: measuring the photometric value of each well with enzyme-labeling instrument (BioTek ELx800), selecting 570nm wavelength, recording photometric value, repeatedly measuring photometric value three times, using tumor cells treated with solvent control as control group, and calculating the relative tumor by the following formulaTumor cell inhibition rate,% inhibition (control group mean OD value-administration group mean OD value)/(control group mean OD value) × 100%, and IC was calculated by SPSS 13.0 software 50 Values, experimental results are given in table 1:
experimental results show that the eudesmane type sesquiterpene lactone TBA derivatives 1a-5a have different degrees of inhibition effects on the proliferation activities of cervical cancer cells HeLa, human breast cancer cells MCF-7 and lung cancer cells A549, and show that the eudesmane type sesquiterpene lactone TBA derivatives have the same or better inhibition activities on the proliferation activities of 3 cancer cells compared with the parent TBA, and the TBA has weaker activities on MCF-7, Hela and A549, so that the eudesmane type sesquiterpene lactone TBA derivatives provided by the invention have better activities on the anti-cervical cancer cells HeLa, the human breast cancer cells MCF-7 and the lung cancer cells A549, and can be used for clinically preparing medicines for treating the anti-cervical cancer cells HeLa, the human breast cancer cells MCF-7 and the lung cancer cells A549.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (7)
1. A eudesmane type sesquiterpene lactone TBA derivative is characterized in that: the structural general formula (I) of the derivative is as follows:
wherein R is 1 Is acetoxy or hydroxy, R 2 Is acetoxy or hydroxy, R 3 Is isobutyryloxy or hydroxy, R 4 Is methoxy or acetonyl.
2. The eudesmane type sesquiterpene lactone TBA derivative of claim 1 characterized by: the compound of the structural general formula (I) of the derivative is:
wherein: the compound 1a is (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4-hydroxy-13-methoxy-1, 9-diacetoxy-6-isobutyryloxyhalodendrilactone;
the compound 2a is (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4-hydroxy-13-acetonyl-1, 9-diacetoxy-6-isobutyroyloxy halodendric lactone;
the compound 3a is (1S,4S,5S,6S,7S,8S,9R,10S,11R) -1,4, 9-trihydroxy-13-methoxy-6-isobutyryloxyhalodendrilactone;
the compound 4a is (1S,4S,5S,6S,7S,8S,9R,10S,11R) -4, 6-dihydroxy-13-methoxy-1, 9-diacetoxy halodendrin lactone;
the compound 5a is (1S,4S,5S,6S,7S,8S,9R,10S,11R) -1,4,6, 9-tetrahydroxy-13-methoxy halodendrilactone.
3. A process for the preparation of the eudesmane type sesquiterpene lactone TBA derivatives of claim 2, characterized in that: the compound 1a is eudesmane type sesquiterpene lactone TBA, calcium hydride and a methanol solution are added for reaction to obtain a mixture, the pH of the mixture is adjusted by a hydrochloric acid solution with the mass concentration of 10%, the mixture is extracted by an ethyl acetate solution, dried by anhydrous sodium sulfate, decompressed and concentrated, and purified by column chromatography.
4. A process for the preparation of the eudesmane type sesquiterpene lactone TBA derivatives of claim 2, characterized in that: the compound 2a is obtained by adding potassium hydroxide and acetone solution into eudesmane type sesquiterpene lactone TBA for reaction and purifying by column chromatography.
5. A process for the preparation of the eudesmane type sesquiterpene lactone TBA derivatives of claim 2, characterized in that: the compound 3a-5a is obtained by adding potassium hydroxide and methanol solution into alkane sesquiterpene lactone TBA for reaction and performing column chromatography separation and purification.
6. The use of the eudesmane type sesquiterpene lactone TBA derivative according to any one of claims 1-5 in the preparation of an antitumor medicament.
7. The use of the eudesmane type sesquiterpene lactone TBA derivatives of claim 6 in the preparation of anti-tumor drugs, characterized in that: application of eudesmane type sesquiterpene lactone TBA derivatives in preparing medicines for resisting breast cancer, cervical cancer and lung cancer is provided.
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