CN115073406B - Eucalyptus type sesquiterpene lactone TBA derivative and application thereof - Google Patents

Eucalyptus type sesquiterpene lactone TBA derivative and application thereof Download PDF

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CN115073406B
CN115073406B CN202110943503.2A CN202110943503A CN115073406B CN 115073406 B CN115073406 B CN 115073406B CN 202110943503 A CN202110943503 A CN 202110943503A CN 115073406 B CN115073406 B CN 115073406B
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tba
sesquiterpene lactone
type sesquiterpene
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CN115073406A (en
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陈文豪
周秀悄
惠阳
刘亚军
陈光英
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Hainan Normal University
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Abstract

The invention provides a eucalyptus type sesquiterpene lactone TBA derivative, which is prepared by chemical reaction, wherein the synthesized eucalyptus type sesquiterpene lactone TBA derivative 1a-5a has better activity of inhibiting cancer cell proliferation against human breast cancer cells MCF-7, cervical cancer cells HeLa and lung cancer cells A549, has higher antiproliferative activity than the eucalyptus type sesquiterpene lactone TBA, and can be used for clinically preparing medicaments for resisting breast cancer, cervical cancer and lung cancer.

Description

Eucalyptus type sesquiterpene lactone TBA derivative and application thereof
Technical Field
The invention relates to the field of pharmaceutical chemistry, in particular to a eudesmane type sesquiterpene lactone TBA derivative and application thereof.
Background
In recent 30 years, the number of cancer attacks increases at a rate of 3% -5% of the average year, and the cancer attacks become the second highest cause of death next to cardiovascular diseases, seriously threaten human life health and social development, have complicated etiology, and are serious and far away in developing related researches.
Sesquiterpenoids are the most abundant ones of the terpenoids, both in terms of number and type of structural skeleton, and are widely distributed in plants of various genera such as the Compositae. As early as 2006, more than 11000 natural sesquiterpenoids have been found, of which nearly 5000 compounds contain at least one lactone ring, consisting essentially of: a germacrane lactone type, a guaianolide type, a eucalyptol type, and the like. The sesquiterpene lactone compounds are active ingredients with better anti-tumor activity of Chinese herbal medicines. According to Lipinsky's ' class five principles of medicine ', sesquiterpene lactones are a class of compounds most of which can accord with the class five principles of medicine.
Eucalyptus type sesquiterpene lactone Trilobolide-6-O-isobutyl A (TBA) is a high-oxygen-content eucalyptol type sesquiterpene lactone compound separated from trilobate wedelia only, and the absolute structure of the compound is further determined by X-ray single crystal diffraction experiments in the early stage of research teams. The invention obtains a series of analogues with novel structures by further structural modification of the compound, and researches on the activity of the analogues against tumor cells, thereby laying a research foundation for preparing antitumor drugs in the next step.
Disclosure of Invention
Accordingly, 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 show better effect of inhibiting cancer cell proliferation, and can be applied to preparing medicaments for resisting human breast cancer, cervical cancer and lung cancer clinically.
The technical scheme of the invention is realized as follows:
a eudesmane type sesquiterpene lactone TBA derivative has a structural formula:
wherein: compound 1a is (1S, 4S,5S,6S,7S,8S,9R,10S, 11R) -4-hydroxy-13-methoxy-1, 9-diacetoxy-6-isobutyryloxy geothrin;
compound 2a is (1S, 4S,5S,6S,7S,8S,9R,10S, 11R) -4-hydroxy-13-propanoyl-1, 9-diacetoxy-6-isobutyryloxy geothrin;
compound 3a is (1S, 4S,5S,6S,7S,8S,9R,10S, 11R) -1,4, 9-trihydroxy-13-methoxy-6-isobutyryloxy geothrin;
compound 4a is (1S, 4S,5S,6S,7S,8S,9R,10S, 11R) -4, 6-dihydroxy-13-methoxy-1, 9-diacetoxy-geothrin;
compound 5a is (1S, 4S,5S,6S,7S,8S,9R,10S, 11R) -1,4,6, 9-tetrahydroxy-13-methoxyl geothrin;
further, a eudesmane type sesquiterpene lactone TBA derivative is prepared by taking sesquiterpene lactone TBA as a starting material, carrying out addition reaction on the sesquiterpene lactone TBA and a methanol solution under the action of calcium hydride to obtain a mixture, regulating the pH of the mixture by adopting a hydrochloric acid solution with the mass concentration of 10%, extracting by using an ethyl acetate solution, drying by using anhydrous sodium sulfate, concentrating under reduced pressure and purifying by column chromatography to obtain (1S, 4S,5S,6S,7S,8S,9R,10S, 11R) -1, 9-diacetoxy-4-hydroxy-6-isobutyryloxy-13-methoxyl geothrin (1 a);
further, under the action of potassium hydroxide, the sesquiterpene lactone TBA and acetone undergo an addition reaction, and are purified by column chromatography to obtain (1S, 4S,5S,6S,7S,8S,9R,10S, 11R) -4-hydroxy-13-acetonyl-1, 9-diacetoxy-6-isobutyryloxy geothrin (2 a);
further, under the action of potassium hydroxide and methanol solution, sesquiterpene lactone TBA undergoes hydrolysis reaction, and is separated and purified by column chromatography to obtain the compound (3 a-5 a).
Further, 5 eudesmane sesquiterpene lactone TBA derivatives have value-added inhibition effect on human breast cancer cells MCF-7, cervical cancer cells HeLa and lung cancer cells A549, and the results show that: compared with a parent molecule, 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 used for clinically preparing medicaments for treating breast cancer, cervical cancer and lung cancer.
Further illustrated, the chemical reaction formula for preparing the eudesmane-type sesquiterpene lactone TBA derivative is as follows:
wherein (A) is 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 has the advantages that the proliferation activity of human breast cancer cells MCF-7, cervical cancer cells HeLa and lung cancer cells A549 is well inhibited, the proliferation effect of inhibiting three cancer cells is better than that of the eudesmane type sesquiterpene lactone TBA, and the eudesmane type sesquiterpene lactone TBA derivative can be applied to the preparation of medicaments for resisting human breast cancer cells MCF-7, cervical cancer cells HeLa and lung cancer cells A549 clinically.
Detailed Description
In order to better understand the technical content of the present invention, the following provides specific examples to further illustrate the present invention.
The experimental methods used in the embodiment of the invention are conventional methods unless otherwise specified.
Materials, reagents, and the like used in the examples of the present invention are commercially available unless otherwise specified. The invention provides a eudesmane sesquiterpene lactone TBA derivative, which has the following structural general formula (I):
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 in connection with specific analysis.
Example 1
Compound 1a, (1S, 4S,5S,6S,7S,8S,9R,10S, 11R) -4-hydroxy-13-methoxy-1, 9-diacetoxy-6-isobutyryloxy-halothrin, prepared as follows:
70mg (0.155 mmol) of TBA,35mg of CaH are introduced into a 50mL round-bottomed flask 2 And 5mL of methanol solution, stirring at room temperature for 5h, detecting the reaction completion by TLC (chloroform: ethyl acetate=2:1), obtaining a mixture, adjusting the pH value of the mixture to 6-7 by using 10% hydrochloric acid solution, extracting three times by using ethyl acetate and water (3:1), drying by using anhydrous sodium sulfate, filtering, concentrating under reduced pressure by using a rotary evaporator, and purifying the obtained crude product by column chromatography (chloroform: ethyl acetate=4:1), thereby obtaining 17.6mg of compound 1a with the yield of 23.23%.
Spectral data of (1 s,4s,5s,6s,7s,8s,9r,10s,11 r) -4-hydroxy-13-methoxy-1, 9-diacetoxy-6-isobutyryloxy geothrin (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, (1 s,4s,5s,6s,7s,8s,9r,10s,11 r) -4-hydroxy-13-propanoyl-1, 9-diacetoxy-6-isobutyryloxy-halothrin, prepared as follows:
40mg (0.088 mmol) of TBA,20mg of potassium hydroxide and 2mL of acetone solution are added into a 50mL round bottom flask, the mixture is stirred for 8.5h at room temperature, after the reaction is detected by TLC (chloroform: acetone=3:1), a mixture is obtained, the pH value of the mixture is regulated to 6-7 by using 10% by mass hydrochloric acid solution, the regulated mixture is extracted three times by ethyl acetate and water (3:1), anhydrous sodium sulfate is dried, the filtered mixture is concentrated under reduced pressure by a rotary evaporator, and the crude product is purified by column chromatography (chloroform: acetone=4:1), so that 5.6mg of compound 2a is obtained, and the yield is 7.45%.
Spectral data of (1 s,4s,5s,6s,7s,8s,9r,10s,11 r) -4-hydroxy-13-propanoyl-1, 9-diacetoxy-6-isobutyryloxy-halothrin (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, (1 s,4s,5s,6s,7s,8s,9r,10s,11 r) -1,4, 9-trihydroxy-13-methoxy-6-isobutyryloxy-halothrin, compound 4a, (1 s,4s,5s,6s,7s,8s,9r,10s,11 r) -4, 6-dihydroxy-13-methoxy-1, 9-diacetoxy-halothrin and compound 5a, (1 s,4s,5s,6s,7s,8s,9r,10s,11 r) -1,4,6, 9-tetrahydroxy-13-methoxy-halothrin were prepared as follows:
64.4mg (0.142 mmol) 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 3.5h at room temperature, after the reaction is detected to be complete by TLC (chloroform: acetone=3:1), the mixture is transferred into a 50mL beaker, the pH value of the mixture is regulated to 6-7 by using 10% hydrochloric acid solution with mass concentration, the mixture after the pH value regulation 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 a rotary evaporator, and the crude product is separated by column chromatography (chloroform: 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, and the total yield is 80.98%.
Spectral data of (1 s,4s,5s,6s,7s,8s,9r,10s,11 r) -1,4, 9-trihydroxy-13-methoxy-6-isobutyryloxy-halothrin (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)。
spectral data of (1 s,4s,5s,6s,7s,8s,9r,10s,11 r) -4, 6-dihydroxy-13-methoxy-1, 9-diacetoxy-halothrin (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)。
spectroscopic data of (1 s,4s,5s,6s,7s,8s,9r,10s,11 r) -1,4,6, 9-tetrahydroxy-13-methoxygeothrin (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
The eucalyptus type diterpene lactone TBA and the derivatives thereof are used for preparing the activity experiments of anti-cervical cancer cells HeLa, lung cancer cells A549 and anti-human breast cancer cells MCF-7.
(1) Tumor cell lines: cervical cancer cell HeLa, human breast cancer cell MCF-7 and lung cancer cell A549, positive control: doxorubicin.
(2) The experimental method comprises the following steps: cell proliferation inhibition assay using MTT colorimetric assay:
(1) inoculating: taking a 96-well plate, operating in an ultra-clean bench, adding 100 mu LPBS around the peripheral edge holes of the 96-well plate, inoculating 100 mu L of cell culture solution to each other, and culturing for 24 hours to enable cells to grow on the wall;
(2) culturing: sequentially adding a sample of eudesmane sesquiterpene lactone TBA and its derivatives 1a-5a from low concentration to high concentration, adding 10 mu L of each hole, and culturing at 37 ℃ for 48h in a culture box, wherein the final concentration of each hole is respectively 1 mu mol/L, 10 mu mol/L and 100 mu mol/L, each concentration is 6 parallel, and 10 mu L of PBS is added to each hole of a blank group;
(3) color development: after 48h of culture, 10 mu L of MTT solution of 5mg/mL is added into each hole, incubation is continued for 4h, culture supernatant is removed, 150 mu L of DMSO is added into each hole, and crystals are fully dissolved;
(4) colorimetric: the enzyme-labeled instrument (BioTek ELx 800) measured the luminosity of each well, selected 570nm wavelength, recorded the luminosity, repeatedly measured the luminosity three times, treated tumor cells with solvent control as control group, calculated the inhibition rate of tumor cells with the following formula = (control group mean OD value-administration group mean OD value)/(control group mean OD value) ×100%, and calculated IC with SPSS 13.0 software 50 Values, experimental results are shown in table 1:
experimental results show that the eudesmane type sesquiterpene lactone TBA derivative 1a-5a has different degrees of inhibition effects on proliferation activities of cervical cancer cells HeLa, human breast cancer cells MCF-7 and lung cancer cells A549, the proliferation activities are equal to or better than that of parent TBA, the TBA has weaker activities of resisting MCF-7, hela and A549, and the eudesmane type sesquiterpene lactone TBA derivative provided by the invention has better activities of resisting cervical cancer cells HeLa, human breast cancer cells MCF-7 and lung cancer cells A549, and can be used for clinically preparing medicaments for treating cervical cancer cells HeLa, human breast cancer cells MCF-7 and lung cancer cells A549.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.

Claims (6)

1. A eudesmane-type sesquiterpene lactone TBA derivative, characterized in that: the structure of the eudesmane type sesquiterpene lactone TBA derivative is as follows:
1a, 2a, 3a, 4a and 5 a.
2. The method for preparing the eudesmane-type sesquiterpene lactone TBA derivative according to claim 1, which is characterized in that: the preparation method of the compound 1a comprises the steps of adding calcium hydride and methanol solution into eudesmane type sesquiterpene lactone TBA for reaction to obtain a mixture, adjusting the pH of the mixture by using 10% hydrochloric acid solution with mass concentration, extracting by using ethyl acetate solution, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, and purifying by column chromatography.
3. The method for preparing the eudesmane-type sesquiterpene lactone TBA derivative according to claim 1, which is characterized in that: the preparation method of the compound 2a is that the eudesmane type sesquiterpene lactone TBA is added with potassium hydroxide and acetone solution for reaction, and the compound is obtained by column chromatography purification.
4. The method for preparing the eudesmane-type sesquiterpene lactone TBA derivative according to claim 1, which is characterized in that: the preparation method of the compound 3a-5a is that alkane type sesquiterpene lactone TBA is added with potassium hydroxide and methanol solution for reaction, and the compound is obtained through column chromatography separation and purification.
5. The application of the eudesmane-type sesquiterpene lactone TBA derivative prepared by the preparation method of the eudesmane-type sesquiterpene lactone TBA derivative according to claim 1 or any one of claims 2-4 in preparing antitumor drugs.
6. The use according to claim 5, wherein: the application is the application of the eudesmane type sesquiterpene lactone TBA derivative in preparing medicaments for resisting breast cancer, cervical cancer and lung cancer.
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