CN113321594A - Oxidative coupling rearrangement product based on tryptamine skeleton and preparation method and application thereof - Google Patents
Oxidative coupling rearrangement product based on tryptamine skeleton and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses an oxidative coupling rearrangement product based on a tryptamine skeleton and a preparation method and application thereof. The invention realizes the terminal functionalization of the tryptamine derivatives through mild reaction conditions. The preparation method is simple, the reaction condition is mild, the yield is high, the practicability is high, and the relative molecular mass of the synthesized compound is about 300. The skeleton structure is synthesized for the first time, has obvious antitumor activity, and can be used for developing medicaments for treating lung adenocarcinoma, lung cancer and cervical cancer.
Description
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to an oxidative coupling rearrangement product based on a tryptamine skeleton, and a preparation method and application thereof.
Background
Indole alkaloids are one of the largest and most important medicinal categories in alkaloid natural products, and can be applied to treating common diseases such as liver diseases, lung diseases and the like. Because indole derivatives are ubiquitous in various natural products, receptors, proteins and drug molecules, the indole derivatives are indispensable components in organic synthesis and pharmaceutical research, and are always hot research points in the fields of natural product synthesis, new drug research and development and the like. Wherein the tryptamine derivatives have a wide range of biological activities.
According to the invention, a tryptamine skeleton-based oxidative coupling rearrangement product is obtained through an oxidative coupling rearrangement reaction, a tryptamine compound is oxidized by using sodium periodate to obtain a corresponding dicarbonyl compound, then the dicarbonyl compound and an aniline compound are subjected to a coupling rearrangement reaction, and terminal functionalization is carried out on the tryptamine derivative through a mild reaction condition.
Disclosure of Invention
The invention aims to provide an oxidative coupling rearrangement product based on a tryptamine skeleton, and a preparation method and application thereof, wherein the preparation method is simple, the experimental conditions are mild, harsh conditions such as high pressure, strong acid and strong base are not required, and the reaction yield is high (generally over 50%).
In order to achieve the purpose, the invention adopts the following technical scheme:
an oxidative coupling rearrangement product based on tryptamine skeleton has the following structure:
wherein R is1H, Cl or OMe, R2H, Cl or OMe.
The preparation method comprises the following steps: dissolving a raw material B in thionyl chloride, adding trifluoroacetic acid and dimethyl sulfoxide to react for 6-15h at 100 ℃ to obtain the oxidation coupling rearrangement product based on the tryptamine skeleton;
wherein R is1H, Cl or OMe.
R in the raw material B1The preparation of H or OMe comprises the following steps: dissolving sodium periodate in water, and stirring for 1 hour at 0 ℃ to prepare a solution I; mixing the raw material A:wherein R is1Dissolving H or OMe in methanol to obtain solution II; slowly adding the solution I into the solution II, reacting for 15 hours at room temperature, pouring the obtained mixture into water, and extracting for 2-3 times by using dichloromethane; the organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was purified by silica gel Chromatography (CH)2Cl2MeOH ═ 30:1) purification afforded starting material B.
R in the raw material B1The preparation of Cl comprises the following steps: mixing the raw material A:wherein R is1Dissolving Cl in dichloromethane, and adding cuprous chloride and pyridine; the reaction was stirred at room temperature under an oxygen atmosphere, and the resulting mixture was diluted with dichloromethane and washed with water and saturated brine; separating organic layer, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and subjecting the obtained crude product to silica gel Chromatography (CH)2Cl2MeOH ═ 30:1) purification afforded starting material B.
The tryptamine skeleton-based oxidative coupling rearrangement product is applied to the preparation of medicines for treating lung adenocarcinoma, lung cancer and cervical cancer.
The invention has the beneficial effects that:
(1) the method has the advantages of mild reaction conditions, simple operation, controllable product position selection, strong operability, strong practicability, no requirement of harsh conditions such as high pressure, strong acid and strong alkali, short reaction time and high yield of over 50 percent generally.
(2) The molecular weight of the synthesized oxidation coupling rearrangement product with the tryptamine skeleton structure is small, generally about 300, and the method is expected to be used for preparing related cancer treatment medicines, and simultaneously provides a new solution and scheme for the synthesis of other similar compounds.
Detailed Description
In order to make the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited thereto.
EXAMPLE 1 preparation of Compound 1
(1) Raw material B1Preparation of
6.33g of sodium periodate was dissolved in 150mL of water and stirred at 0 ℃ for 1 hour to prepare a solution I. 1.5g A1Dissolved in 150mL of methanol to obtain solution II. Solution I was slowly added to solution II. After removal of the ice bath, the reaction was stirred at room temperature for 15 hours. The reaction mixture was then poured into 100mL of water and extracted 2 times with 50mL of dichloromethane, respectively. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was purified by silica gel Chromatography (CH)2Cl2Purification with MeOH ═ 30:1) to give compound B1(970mg,58%)。
Physical state: a white solid.
Melting point: 107.5-108.3 ℃.
TLC:Rf=0.23(EtOAc).
1H NMR(500MHz,CDCl3)δ11.56(s,1H),8.74(d,J=10.0Hz,1H),8.50(s,1H),7.91(d,J=8.0Hz,1H),7.57(t,J=7.8Hz,1H),7.17(t,J=7.6Hz,1H),6.13(s,1H),3.66–3.63(m,2H),3.30(t,J=5.6Hz,2H),1.96(s,3H).
13C NMR(126MHz,CDCl3)δ203.68,170.46,159.96,139.86,135.51,131.01,123.38,121.67,121.54,39.59,34.53,23.37.
(2) Preparation of Compound 1
Mixing 117mg of B1Dissolve in 3mL of thionyl chloride and add 91. mu.L of aniline and 37. mu.L of trifluoroacetic acid. The reaction was stirred at 100 ℃ for 8 hours. The resulting mixture was then poured into 30mL of saturated sodium bicarbonate and extracted with 50mL of ethyl acetate. The organic layer was washed with 30mL of water and saturated 30mL of brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was chromatographed on silica gel (CH)2Cl2Purification with MeOH ═ 30:1) afforded compound 1(80mg, 55%).
Physical state: a pale yellow solid.
Melting point: 185.4-186.1 deg.C
TLC:Rf=0.52(CH2Cl2/MeOH=10:1).
1H NMR(500MHz,DMSO-d6)δ8.77–8.70(m,2H),8.57(s,1H),7.98(d,J=8.1Hz,1H),7.87(d,J=7.9Hz,1H),7.68(s,1H),7.45(s,1H),7.17(s,3H),6.82(s,2H),6.67(d,J=6.8Hz,2H),4.33–4.25(m,2H),1.85(s,3H).
13C NMR(126MHz,CDCl3)δ172.03,152.71,149.21,146.71,144.93,129.72,129.17,129.12,126.05,125.47,123.18,122.01,121.13,117.63,38.74,22.98。
EXAMPLE 2 preparation of Compound 2
(1) Raw material B1Preparation of
See example 1.
(2) Preparation of Compound 2
140mg of B1Dissolved in 4mL of thionyl chloride, 135. mu.L of 3-methoxyaniline and 44. mu.L of trifluoroacetic acid were added. The reaction was stirred at 100 ℃ for 7 hours. The resulting mixture was then poured into 30mL of saturated sodium bicarbonate and extracted with 50mL of ethyl acetate. The organic layer was washed with 30mL of water and 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel Chromatography (CH)2Cl2Purification with MeOH ═ 30:1) afforded compound 2(108mg, 56%).
Physical state: green solid.
Melting point: 155.7-156.4 ℃.
TLC:Rf=0.30(CH2Cl2/MeOH=20:1).
1H NMR(500MHz,CDCl3)δ8.76(s,1H),8.57(s,1H),8.01(d,J=8.1Hz,1H),7.89–7.86(m,1H),7.66–7.62(m,1H),7.36–7.30(m,2H),7.09(t,J=8.1Hz,1H),6.49–6.46(m,1H),6.44–6.41(m,1H),6.36(t,J=2.2Hz,1H),4.51(d,J=6.6Hz,2H),3.69(s,3H),2.03(s,3H).
13C NMR(126MHz,CDCl3)δ171.99,160.55,152.49,148.99,146.69,146.32,129.93,129.80,128.92,126.06,125.59,123.41,122.31,110.35,106.68,103.43,55.29,38.72,22.95。
EXAMPLE 3 preparation of Compound 3
(1) Raw material B1Preparation of
See example 1.
(2) Preparation of Compound 3
Mixing 117mg of B1Dissolved in 3m L thionyl chloride and 128mg 4-chloroaniline and 37. mu.L trifluoroacetic acid were added. The reaction was stirred at 100 ℃ for 10 hours. The resulting mixture was then poured into 30mL of saturated sodium bicarbonate and extracted with 50mL of ethyl acetate. The organic phase was washed with 30mL of water and 30mL of saturated brineLayer, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was chromatographed on silica gel (CH)2Cl2Purification with MeOH ═ 30:1) afforded compound 3(45mg, 28%).
Physical state: a pale green solid.
Melting point: 193.4-194.2 ℃.
TLC:Rf=0.34(CH2Cl2/MeOH=20:1).
1H NMR(500MHz,CDCl3)δ8.86(s,1H),8.58(s,1H),8.02(d,J=8.2Hz,1H),7.80–7.78(m,1H),7.67–7.63(m,1H),7.37–7.33(m,1H),7.19–7.15(m,1H),7.15–7.12(m,2H),6.76–6.73(m,2H),4.51(d,J=6.6Hz,2H),2.03(s,3H).
13C NMR(126MHz,CDCl3)δ172.03,152.52,149.18,146.34,143.58,129.86,129.25,129.09,125.83,125.78,125.71,123.00,122.15,118.61,38.80,22.97。
EXAMPLE 4 preparation of Compound 4
(1) Raw material B1Preparation of
See example 1.
(2) Preparation of Compound 4
Mixing 117mg of B1Dissolved in 3m L thionyl chloride and 143mg of 1-naphthylamine and 37. mu.L of trifluoroacetic acid were added. The reaction was stirred at 100 ℃ for 6 hours. The resulting mixture was then poured into 30mL of saturated sodium bicarbonate and extracted with 50mL of ethyl acetate. The organic layer was washed with 30mL of water and 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel Chromatography (CH)2Cl2Purification with MeOH ═ 30:1) afforded compound 4(55mg, 32%).
Physical state: light grey solid.
Melting point: 217.4-218.6 ℃.
TLC:Rf=0.32(CH2Cl2/MeOH=20:1).
1H NMR(500MHz,DMSO-d6)δ9.16(s,1H),8.80(s,1H),8.75(t,J=6.0Hz,1H),8.51(d,J=8.2Hz,1H),7.99(d,J=8.3Hz,1H),7.93(d,J=7.9Hz,1H),7.67(d,J=8.5Hz,1H),7.65–7.63(m,1H),7.63–7.60(m,1H),7.60–7.57(m,1H),7.46(d,J=8.2Hz,1H),7.35–7.32(m,1H),7.17(t,J=7.8Hz,1H),6.27(d,J=7.4Hz,1H),4.33(s,2H),1.86(s,3H).
13C NMR(126MHz,DMSO-d6)δ171.28,153.19,149.01,145.77,142.06,134.74,129.90,129.60,128.70,126.89,126.52,126.21,126.07,125.81,124.93,124.46,123.71,122.90,121.18,112.38,38.06,22.80。
EXAMPLE 5 preparation of Compound 5
(1) Raw material B2Preparation of
Solution I was prepared by dissolving 2.56g of sodium periodate in 60mL of water and then stirring at 0 ℃ for 1 hour. 697mg of A2Dissolve in 60mL of methanol to obtain solution II. The solution was slowly added to solution II. After removal of the ice bath, the reaction was stirred at room temperature for 12 hours. The resulting mixture was then poured into 50mL of water and then extracted with 80mL of dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting crude product was purified by silica gel Chromatography (CH)2Cl2Purification with MeOH ═ 30:1) to give compound B2(405mg,51%)。
Physical state: a pale yellow solid.
Melting point: 137.7-138.3 ℃.
TLC:Rf=0.49(CH2Cl2/MeOH=20:1).
1H NMR(500MHz,CDCl3)δ11.18(s,1H),8.61(d,J=9.2Hz,1H),8.39(s,1H),7.34(d,J=2.5Hz,1H),7.11–7.07(m,1H),6.28(s,1H),3.80(s,3H),3.61(q,J=5.6Hz,2H),3.24(t,J=5.6Hz,2H),1.94(s,3H).
13C NMR(126MHz,CDCl3)δ203.36,170.46,159.53,154.99,133.23,123.23,122.78,120.80,115.63,55.80,39.69,34.58,23.34.
(2) Preparation of Compound 5
Mixing 132mg of B2Dissolve in 3mL of thionyl chloride and add 112. mu.L of methoxyaniline and 37. mu.L of trifluoroacetic acid. The reaction was stirred at 100 ℃ for 9 hours. The resulting mixture was then poured into 30mL of saturated sodium bicarbonate and extracted with 50mL of ethyl acetate. The organic layer was washed with 30mL of water and 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel Chromatography (CH)2Cl2Purification with MeOH ═ 30:1) afforded compound 5(82mg, 47%).
Physical state: grey solid.
Melting point: 173.5-174.3 ℃.
TLC:Rf=0.34(CH2Cl2/MeOH=20:1)。
1H NMR(500MHz,CDCl3)δ8.69(s,1H),8.49(s,1H),7.92(d,J=9.2Hz,1H),7.29(dd,J=9.2,2.8Hz,1H),7.10(d,J=8.1Hz,1H),7.07(d,J=4.1Hz,1H),7.06–7.04(m,1H),6.47–6.44(m,1H),6.40–6.37(m,1H),6.36(t,J=2.2Hz,1H),4.51(d,J=6.5Hz,2H),3.71(s,3H),3.59(s,3H),2.01(s,3H).
13C NMR(126MHz,DMSO-d6)δ170.67,160.64,157.29,149.79,146.79,144.67,142.98,131.26,130.36,125.15,124.94,121.63,109.06,105.62,103.20,102.40,55.74,55.37,38.12,22.90。
EXAMPLE 6 preparation of Compound 6
(1) Raw material B2Preparation of
See example 5.
(2) Preparation of Compound 6
Mixing 132mg of B2Dissolved in 3mL of thionyl chloride solution, 128mg of 4-chloroaniline and 37. mu.L of trifluoroacetic acid were added. The reaction was stirred at 100 ℃ for 10 hours. The resulting mixture was then poured into 30mL of saturated sodium bicarbonate and extracted with 50mL of ethyl acetate. The organic layer was washed with 30mL of water and 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel Chromatography (CH)2Cl230% MeOH: 1) purification yielded compound 6(80mg, 45%).
Physical state: brown solid.
Melting point: 209.3-210.4 ℃.
TLC:Rf=0.36(CH2Cl2/MeOH=20:1).
1H NMR(500MHz,CDCl3)δ8.78(s,1H),8.47(s,1H),7.93(d,J=9.2Hz,1H),7.30(dd,J=9.2,2.8Hz,1H),7.16–7.13(m,2H),7.00(s,1H),6.97(d,J=2.8Hz,1H),6.73–6.70(m,2H),4.50(d,J=6.6Hz,2H),3.60(s,3H),2.01(s,3H).
13C NMR(126MHz,DMSO-d6)δ170.79,157.47,149.86,144.68,144.51,142.62,131.38,129.35,125.21,125.07,123.43,121.75,117.71,102.93,100.00,55.76,38.07,22.85。
EXAMPLE 7 preparation of Compound 7
(1) Raw material B3Preparation of
1.61g A3Dissolved in dichloromethane, 67mg of cuprous chloride and 3.8mL of pyridine were added. The reaction was stirred at room temperature for 15 hours. The reaction mixture was then poured into 80mL of water and extracted with 150mL of dichloromethane. The organic layer was washed with 80mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel Chromatography (CH)2Cl2Purification with MeOH ═ 30:1) to give compound B3(985mg,54%)。
Physical state: yellow solid.
Melting point: 145.2-146.1 ℃.
TLC:Rf=0.25(EtOAc).
1H NMR(500MHz,CDCl3)δ11.42(s,1H),8.73(d,J=9.0Hz,1H),8.48(s,1H),7.86(d,J=2.4Hz,1H),7.53–7.50(m,1H),6.06(s,1H),3.64(q,J=5.9Hz,2H),3.28(t,J=5.7Hz,2H),1.97(s,3H).
13C NMR(126MHz,CDCl3)δ202.69,170.50,159.83,138.32,135.18,130.57,128.43,123.17,122.70,39.70,34.47,23.33.
(2) Preparation of Compound 7
161mg of B3Dissolve in 3mL of thionyl chloride solution and add 109. mu.L of aniline and 44. mu.L of trifluoroacetic acid. The reaction was stirred at 100 ℃ for 14 hours. The resulting mixture was then poured into 30mL of saturated sodium bicarbonate and extracted with 50mL of ethyl acetate. The organic layer was washed with 30mL of water and 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel Chromatography (CH)2Cl2Purification with MeOH ═ 30:1) afforded compound 7(94mg, 48%).
Physical state: a pale yellow solid.
Melting point: 119.3-200.1 ℃.
TLC:Rf=0.39(CH2Cl2/MeOH=20:1).
1H NMR(500MHz,DMSO-d6)δ8.76(s,1H),8.75(s,1H),8.51(t,J=5.8Hz,1H),8.00(d,J=8.9Hz,1H),7.94(d,J=2.3Hz,1H),7.72–7.68(m,1H),7.21(t,J=7.9Hz,2H),6.86(t,J=7.3Hz,1H),6.70(d,J=7.7Hz,2H),4.24(d,J=5.9Hz,2H),1.84(s,3H).
13C NMR(126MHz,DMSO-d6)δ170.62,152.99,147.35,145.29,143.44,132.04,130.83,130.06,129.72,125.09,124.90,123.39,120.74,116.74,38.12,22.91。
EXAMPLE 8 preparation of Compound 8
(1) Raw material B3Preparation of
See example 7.
(2) Preparation of Compound 8
Mixing 134mg of B3Dissolved in 3mL of thionyl chloride and 127mg of 4-chloroaniline and 37. mu.L of trifluoroacetic acid were added. The reaction was stirred at 100 ℃ for 6 hours. The resulting mixture was then poured into 30mL of saturated sodium bicarbonate and extracted with 50mL of ethyl acetate. The organic layer was washed with 30mL of water and 30mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel Chromatography (CH)2Cl2Purification with MeOH ═ 30:1) afforded compound 8(90mg, 50%).
Physical state: yellow solid.
Melting point: 226.7-227.4 ℃.
TLC:Rf=0.42(CH2Cl2/MeOH=20:1).
1H NMR(500MHz,CDCl3)δ8.81(s,1H),8.64(s,1H),7.97(d,J=9.0Hz,1H),7.75(d,J=2.3Hz,1H),7.58(dd,J=8.9,2.3Hz,1H),7.18–7.15(m,2H),6.73–6.71(m,2H),6.68(t,J=6.1Hz,1H),4.51(d,J=6.6Hz,2H),2.01(s,3H).
13C NMR(126MHz,DMSO-d6)δ170.66,152.94,147.22,144.33,142.99,132.02,131.19,130.25,129.50,125.63,124.97,123.99,123.15,117.93,38.07,22.89。
And (3) biological activity test:
human lung cancer cell line PC-9 cells were used as the test cell line (cells purchased from cell resource center of Shanghai Life sciences institute of Chinese academy of sciences).
Application example: inhibition of human lung cancer cell line PC-9 cell proliferation and survival
Materials: human lung cancer cell line PC-9; the tested drugs are: 10 μm; the cell culture method comprises the following steps: taking out PC-9 cells frozen in liquid nitrogen, thawing in 37 deg.C warm water, transferring cell suspension into 1.5mL centrifuge tube, placing in centrifuge, and separating at 2000rpmRemoving supernatant for 10min, adding 1mL of RPMI 1640 complete culture solution, gently blowing and beating uniformly, adding the cell suspension into a culture dish, supplementing 2mL of RPMI 1640 complete culture solution, and placing the culture dish in 5% CO2And cultured in an incubator at 37 ℃. Cytotoxicity experiments: PC-9 cells were cultured at 8X 103Inoculating the cells/well into a 96-well culture plate, culturing for 20h, sucking and removing the old culture medium, adding a compound with the concentration of 10 mu m in each well, additionally arranging a solvent control group and a blank control group, incubating in an incubator for 72h, carefully sucking and removing the culture medium, washing with PBS for 3 times, adding 90 mu L of 1640 culture medium without serum and phenol red and 10 mu L of MTT solution (5mg/mL) into each well, continuing to incubate for 5h, terminating the culture, carefully sucking and removing the culture solution in the 96-well plate, adding 150 mu L of DMSO solution into each well, and shaking for 10min in a dark place to fully dissolve the purple crystal; the absorbance (A) of each well was measured at a wavelength of 570nm with a multifunctional microplate reader, and the survival rate of the cells was calculated as follows: cell viability ═ 100% (test group a value/blank control group a value).
The activity parameters of the products obtained in examples 1 to 8 are shown in Table 1: survival was at a concentration of 10 μ M compound.
TABLE 1 antitumor Activity of the Compounds obtained in examples 1-8
The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (6)
2. A process for preparing the oxidatively coupled rearrangement product of claim 1, wherein: dissolving a raw material B in thionyl chloride, adding trifluoroacetic acid and dimethyl sulfoxide to react for 6-15h at 100 ℃ to obtain the oxidation coupling rearrangement product based on the tryptamine skeleton;
wherein R is1H, Cl or OMe.
3. The method of claim 2, wherein: r in the raw material B1The preparation of H or OMe comprises the following steps: dissolving sodium periodate in water, and stirring for 1 hour at 0 ℃ to prepare a solution I; dissolving the raw material A in methanol to prepare a solution II; slowly adding the solution I into the solution II, reacting for 15 hours at room temperature, pouring the obtained mixture into water, and extracting for 2-3 times by using dichloromethane; separating the organic layer, drying over anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the crude product by silica gel chromatography to obtain starting material B; the structural general formula of the raw material A isWherein R is1H or OMe.
4. The method of claim 2, wherein: r in the raw material B1The preparation of Cl comprises the following steps: dissolving a raw material A in dichloromethane, and adding cuprous chloride and pyridine; the reaction was stirred at room temperature under an oxygen atmosphere, and the resulting mixture was diluted with dichloromethane and washed with water and saturated brine; separating the organic layer, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and purifying the obtained crude product with silica gel chromatography to obtain raw material B;
5. The method according to claim 3 or 4, characterized in that: the eluent in the silica gel chromatography is CH2Cl2/MeOH=30:1。
6. Use of the oxidative coupling rearrangement product of claim 1 in the preparation of a medicament for the treatment of lung adenocarcinoma, lung cancer and cervical cancer.
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