CN115197113B - Combretastatin A-4 derivative containing thiourea structure, preparation method and application thereof - Google Patents
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Abstract
The invention belongs to the field of pharmaceutical chemistry, and provides a Combretastatin A-4 derivative with a thiourea structure, a preparation method and application thereof, which are used for preparing antitumor drugs. According to the invention, the thiourea structure modified antitumor drug Combretastatin A-4 is efficiently introduced through simple synthesis steps, so that the Combretastatin A-4 thiourea derivative is obtained, the antitumor spectrum is enlarged, and the antitumor activity is enhanced.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a Combretastatin A-4 derivative with a thiourea structure, a preparation method and application thereof.
Background
Research on the use of natural products as potential anticancer and inhibiting drugs can be traced to 1550 years at least. The structural and active diversity of natural products determines an important source for the discovery of leads, but is not necessarily desirable as a drug directly. Many natural products cannot be directly used as medicines because of low property of action, unreasonable pharmacokinetic property or side effect, but are good lead compounds for creating new medicines.
Combretataceae (Combretataceae) plants are a family of shrubs and trees distributed in tropical and subtropical areas, and have very important medical application value. 25 species of the genus Graptopetalum (Combretum) are known to be used in Africa and India for the treatment of leptospirosis (Combretum sp. Roots), cancer (Combretum latifolium), and the like. Combretastatin A-4 (CA-4) is a series of active ingredients isolated from a shrub in south Africa. The last 70 s of the last century, the national cancer institute has found that this plant has a very high inhibitory effect on murine P388 lymphoblastic leukemia cells. Thus, the synthesis of antitumor CA-4 and its analogues is of increasing interest to researchers. The structural modification of the molecules with known drug effects is an effective method for obtaining drugs with better drug effects and lower toxicity, and is also an important way for developing new drugs.
Disclosure of Invention
The invention aims to solve the technical problem of providing a Combretastatin A-4 derivative with a thiourea structure, a preparation method and application thereof, and introducing thiourea structure modified antitumor drugs Combretastatin A-4 to obtain the Combretastatin A-4 thiourea derivative, expand the antitumor spectrum and enhance the antitumor activity.
In order to solve the technical problems, the embodiment of the invention provides a Combretastatin A-4 derivative with a thiourea structure, which has the following structural formula:
wherein R is a substituent.
Preferably, the substituents include aryl, alkylaryl, haloaryl, etheraryl.
Wherein the Combretastatin A-4 derivative with the thiourea structure is one of the following compounds:
compound E1:
compound E2:
compound E3:
compound E4:
compound E5:
compound E6:
compound E7:
compound E8:
compound E9:
wherein, the synthetic route of the Combretastatin A-4 derivative with the thiourea structure is as follows:
the invention also provides a preparation method of the Combretastatin A-4 derivative with the thiourea structure, which comprises the following steps:
s1, adding 1.22g of arylcarboxylic acid A and 6g of thionyl chloride into a reactor for reflux reaction for about 4 hours, and evaporating the solvent after the reaction is finished to obtain benzoyl chloride B;
s2, 1.20g of KSCN is dissolved by 30mL of anhydrous acetonitrile, benzoyl chloride B prepared in the step S1 is dropwise added, then reflux reaction is carried out for about 4 hours, after the reaction is finished, filtration and reduced pressure concentration are carried out, and benzoyl isocyanate C is obtained;
s3, adding 163mg of p-benzoyl isocyanate C and 315mg of amino CA-4 into a reactor, dissolving with 30mL of anhydrous acetonitrile, carrying out reflux reaction for about 3 hours, concentrating under reduced pressure after the reaction is finished, and recrystallizing with absolute ethanol;
s4, purifying the product by column chromatography to obtain 238mg of Combretastatin A-4 derivative E containing thiourea structure.
The invention also provides application of the Combretastatin A-4 derivative with the thiourea structure in preparing antitumor drugs.
The technical scheme of the invention has the following beneficial effects:
according to the invention, the thiourea structure modified antitumor drug Combretastatin A-4 is efficiently introduced through simple synthesis steps, so that the Combretastatin A-4 thiourea derivative is obtained, the antitumor spectrum is enlarged, and the antitumor activity is enhanced.
Detailed Description
In order to make the technical problems, technical solutions and advantages to be solved by the present invention more apparent, the following detailed description will be made with reference to specific embodiments.
The invention provides a Combretastatin A-4 derivative with a thiourea structure, which has the following structural formula:
wherein R is a substituent. The substituents include, but are not limited to, one of aryl, alkylaryl, haloaryl, and etheraryl.
The Combretastatin A-4 derivative with the thiourea structure is one of the following compounds:
compound E1:
compound E2:
compound E3:
compound E4:
compound E5:
compound E6:
compound E7:
compound E8:
compound E9:
the synthetic route of the Combretastatin A-4 derivative with the thiourea structure is as follows:
the invention also provides a preparation method of the Combretastatin A-4 derivative with the thiourea structure, which comprises the following steps:
s1, adding 1.22g of arylcarboxylic acid A and 6g of thionyl chloride into a reactor for reflux reaction for about 4 hours, and evaporating the solvent after the reaction is finished to obtain benzoyl chloride B;
s2, 1.20g of KSCN is dissolved by 30mL of anhydrous acetonitrile, benzoyl chloride B prepared in the step S1 is dropwise added, then reflux reaction is carried out for about 4 hours, after the reaction is finished, filtration and reduced pressure concentration are carried out, and benzoyl isocyanate C is obtained;
s3, adding 163mg of p-benzoyl isocyanate C and 315mg of amino CA-4 into a reactor, dissolving with 30mL of anhydrous acetonitrile, carrying out reflux reaction for about 3 hours, concentrating under reduced pressure after the reaction is finished, and recrystallizing with absolute ethanol;
s4, purifying the product by column chromatography to obtain 238mg of Combretastatin A-4 derivative E containing thiourea structure.
The invention also provides application of the Combretastatin A-4 derivative with the thiourea structure in preparing antitumor drugs.
The technical scheme of the invention is further described below in conjunction with several specific embodiments.
Example 1:
1.22g (0.01 mol) of benzoic acid A1 and 6.00g (0.05 mol) of thionyl chloride are put into a reactor for reflux reaction for about 4 hours, and after the reaction is finished, the solvent is evaporated to dryness to obtain benzoyl chloride B1.
1.2g (0.012 mol) of KSCN was dissolved in 30mL of anhydrous acetonitrile, and benzoyl chloride B1 was slowly added dropwise thereto, followed by a reflux reaction for about 4 hours, and after the completion of the reaction, filtration and concentration under reduced pressure were carried out to obtain benzoyl isocyanate C1.
163mg (1 mmol) of p-benzoyl isocyanate C1 and 315mg (1 mmol) of amino CA-4 were added to the reactor, dissolved in 30mL of anhydrous acetonitrile, and reacted for about 3 hours under reflux, after the reaction was completed, concentrated under reduced pressure, and recrystallized from anhydrous ethanol. The product was purified by column chromatography (ethyl acetate: petroleum ether=1:3) to give 238mg of a pale yellow thiourea-containing derivative E1 of Combretastatin a-4 in a yield of about 53%.
Combretastatin A-4 derivative E1 (Z) -1- (5- (3, 4, 5-trimethoxytyryl) -2-methoxyphenyl) -3-phenylthio containing thiourea structure.
1 H NMR(400MHz,CDCl 3 )δ7.57–7.47(m,2H),7.43(dd,J＝6.6,1.9Hz,4H),7.14(s,1H),7.09–7.05(m,2H),6.95(s,1H),6.71(d,J＝44.2Hz,2H),3.90(s,9H),3.81(s,3H). 13 C NMR(100MHz,CDCl 3 )δ178.13,154.26,152.89,141.55,139.19,130.67,130.29,129.79,128.95,126.02,125.21,124.47,121.54,120.54,108.19,106.20,60.65,56.79.ESI-MS：451[M+H] + 。
Example 2:
1.72g (0.01 mol) of 1-naphthoic acid A2 and 6g (0.05 mol) of thionyl chloride are put into a reactor for reflux reaction for about 4 hours, and after the completion, the solvent is evaporated to dryness to obtain 1-naphthoyl chloride B2.
1.2g (0.012 mol) of KSCN was dissolved in 30ml of anhydrous acetonitrile, and then 1-naphthoyl chloride obtained by the above-mentioned reaction was slowly dropped, and the reaction was refluxed for about 4 hours, and after the reaction was completed, the reaction was filtered and concentrated under reduced pressure to obtain 1-naphthoyl isocyanate C2.
213.2mg (1 mmol) of 1-naphthoyl isocyanate C2 and 315mg (1 mmol) of amino CA-4 are added to the reactor and dissolved in 30ml of anhydrous acetonitrile, the reaction is refluxed for about 3 hours, and after the reaction, the mixture is concentrated under reduced pressure and recrystallized from absolute ethanol. The product was purified by column chromatography (ethyl acetate: petroleum ether=1:3) to give 240mg of the yellow-brown Combretastatin a-4 derivative E2 having a thiourea structure in a yield of about 48%.
Combretastatin A-4 derivative E2 (Z) -1- (5- (3, 4, 5-trimethoxytyryl) -2-methoxyphenyl) -3- (naphthalen-1-yl) thiourea containing thiourea structure.
1 H NMR(400MHz,CDCl 3 )δ7.83(d,J＝10.6Hz,2H),7.43(dt,J＝14.5,11.0Hz,6H),7.07(t,J＝4.2Hz,3H),6.94(d,J＝2.0Hz,2H),6.88(s,1H),3.91(d,J＝9.2Hz,9H),3.81(s,3H). 13 C NMR(100MHz,CDCl 3 )δ179.33,154.26,152.89,141.55,136.74,135.29,130.67,130.29,129.79,129.25,128.95,126.08,125.44(s,1H),125.21,125.02,124.77,124.46,123.44,120.54,116.73,108.19,106.20,60.65,56.80.ESI-MS：501[M+H] + 。
Example 3:
1.36g (0.01 mol) of p-toluic acid A3 and 6g (0.05 mol) of thionyl chloride are put into a reactor for reflux reaction for about 4 hours, and after the completion, the solvent is evaporated to dryness to obtain p-toluoyl chloride B3.
1.2g (0.012 mol) of KSCN was dissolved in 30ml of anhydrous acetonitrile, followed by dropwise addition to the p-toluoyl B3 obtained by the above-mentioned reaction, followed by reflux reaction for about 4 hours, filtration and concentration under reduced pressure to obtain p-toluoyl isocyanate C3.
106.6mg (1 mmol) of p-toluyl isocyanate and 315mg (1 mmol) of amino CA-4 were added to the reactor and dissolved in 30ml of anhydrous acetonitrile, the reaction was refluxed for about 3 hours, and after the reaction was completed, the mixture was concentrated under reduced pressure and recrystallized from absolute ethanol. The product was purified by column chromatography (ethyl acetate: petroleum ether=1:3) to give 236.6mg of the yellow-brown Combretastatin A-4 derivative E3 having a thiourea structure in a yield of about 51%.
Combretastatin A-4 derivative E3 (Z) -1- (5- (3, 4, 5-trimethoxytyryl) -2-methoxyphenyl) -3-p-tolylthiourea containing thiourea structure.
1 H NMR(400MHz,CDCl 3 )δ7.49(s,1H),7.39–7.30(m,3H),7.30–7.15(m,2H),7.00(t,J＝0.6Hz,3H),6.66(d,J＝5.7Hz,2H),3.90(s,9H),3.80(s,3H),2.40(s,3H). 13 C NMR(100MHz,CDCl 3 )δ178.13,154.26,152.89,141.55,137.67,132.71,130.67,130.30,129.79,128.95,126.02,125.21,120.97,120.54,108.19,106.20,60.65,56.78,21.13.ESI-MS：465[M+H] + 。
Example 4:
1.56g (0.01 mol) of p-chlorobenzoic acid A4 and 6g (0.05 mol) of thionyl chloride are put into a reactor for reflux reaction for about 4 hours, and after the completion, the solvent is evaporated to dryness to obtain p-chlorobenzoyl chloride B4.
1.20g (0.012 mol) of KSCN was dissolved in 30ml of anhydrous acetonitrile, followed by dropwise addition to the p-chlorobenzoyl B4 obtained by the above-mentioned reaction, followed by reflux reaction for about 4 hours, filtration after completion of the reaction, and concentration under reduced pressure to obtain p-chlorobenzoyl isocyanate C4.
197.6mg (1 mmol) of p-chlorobenzoyl isocyanate and 315mg (1 mmol) of amino CA-4 were added to the reactor and dissolved in 30ml of anhydrous acetonitrile, and after the reaction was completed, the mixture was concentrated under reduced pressure and recrystallized from absolute ethanol. The product was purified by column chromatography (ethyl acetate: petroleum ether=1:3) to yield 252.2mg of the yellow-brown Combretastatin A-4 derivative E4 having a thiourea structure, in a yield of about 52%.
Combretastatin A-4 derivative E4 (Z) -1- (5- (3, 4, 5-trimethoxytyryl) -2-methoxyphenyl) -3- (4-chlorophenyl) thiourea containing thiourea structure.
1 H NMR(400MHz,CDCl 3 )δ7.44(ddd,J＝42.3,21.2,4.4Hz,42H),7.36–7.35(m,1H),7.33(s,9H),6.99(t,J＝3.0Hz,25H),6.81(d,J＝23.8Hz,17H),3.91(d,J＝19.2Hz,76H),3.78(s,25H). 13 C NMR(100MHz,CDCl 3 )δ178.13,154.26,152.89,141.55,139.93,130.67,130.29,129.79,129.37,128.95,128.20,126.02,125.21,121.95,120.54,108.19,106.20,60.65,56.79.ESI-MS:486[M+H] + 。
Example 5:
1.56g (0.01 mol) of m-chlorobenzoic acid A5 and 6g (0.05 mol) of thionyl chloride are put into a reactor for reflux reaction for about 4 hours, and after the completion, the solvent is evaporated to dryness to obtain m-chlorobenzoyl chloride B5.
1.20g (0.012 mol) of KSCN was dissolved in 30ml of anhydrous acetonitrile, and then the mixture was slowly dropped into the mixture to prepare m-chlorobenzoyl isocyanate B5 by the above-mentioned reaction, followed by reflux reaction for about 4 hours, after the reaction was completed, filtration and concentration under reduced pressure were carried out to obtain p-chlorobenzoyl isocyanate C5.
197.6mg (1 mmol) of m-chlorobenzoyl isocyanate and 315mg (1 mmol) of amino CA-4 were added to the reactor and dissolved in 30ml of anhydrous acetonitrile, and after the reaction was completed, the mixture was concentrated under reduced pressure and recrystallized from absolute ethanol. The product was purified by column chromatography (ethyl acetate: petroleum ether=1:3) to yield 252.2mg of the yellow-brown Combretastatin A-4 derivative E5 having a thiourea structure, in a yield of about 52%.
Combretastatin A-4 derivative E5 (Z) -1- (5- (3, 4, 5-trimethoxytyryl) -2-methoxyphenyl) -3- (3-chlorophenyl) thio containing thiourea structure.
1 H NMR(400MHz,CDCl 3 )δ7.61(s,1H),7.45(s,1H),7.34(s,1H),7.33–7.18(m,3H),7.00(t,J＝3.5Hz,3H),6.77(d,J＝6.6Hz,2H),3.91(d,J＝18.2Hz,9H),3.78(s,3H). 13 C NMR(100MHz,CDCl 3 )δ178.13,154.26,152.89,141.55,140.58,133.11,130.67,130.29,129.79,128.89,126.02,125.21,124.05,120.57,119.66,108.19,106.20,60.65,56.79.ESI-MS：486[M+H] + 。
Example 6:
2.01g (0.01 mol) of m-bromobenzoic acid A6 and 6g (0.05 mol) of thionyl chloride are put into a reactor for reflux reaction for about 4 hours, and after the completion, the solvent is evaporated to dryness to obtain m-bromobenzoyl chloride B6.
1.20g (0.012 mol) of KSCN is dissolved in 30ml of anhydrous acetonitrile, and then the reaction is slowly dripped to prepare m-bromobenzoyl B6 by the step, the reaction is carried out for about 4 hours under reflux, and after the reaction is finished, the filtration and the concentration under reduced pressure are carried out to obtain m-bromobenzoyl isocyanate C6.
242mg (1 mmol) of m-bromobenzoyl isocyanate and 315mg (1 mmol) of amino CA-4 were added to the reactor and dissolved in 30ml of anhydrous acetonitrile, and after the reaction was completed, the mixture was concentrated under reduced pressure and recrystallized from absolute ethanol, followed by reflux reaction for about 3 hours. The product was purified by column chromatography (ethyl acetate: petroleum ether=1:3) to give 301.5mg of a brown-yellow Combretastatin a-4 derivative E6 product containing a thiourea structure in a yield of about 57%.
Combretastatin A-4 derivative E6 (Z) -1- (5- (3, 4, 5-trimethoxytyryl) -2-methoxyphenyl) -3- (3-bromophenyl) thio containing thiourea structure.
1 H NMR(400MHz,CDCl 3 )δ7.65(s,1H),7.48(d,J＝13.7Hz,2H),7.31(d,J＝9.1Hz,2H),7.15(s,1H),6.99(t,J＝1.2Hz,3H),6.80(d,J＝2.9Hz,2H),3.92(d,J＝14.6Hz,9H),3.78(s,3H). 13 C NMR(100MHz,CDCl 3 )δ178.13,154.26,152.89,141.55,140.91,130.67,130.29,129.79,129.56,128.95,126.02,125.62,125.21,122.81,122.03,120.60,108.19,106.20,60.65,56.79.ESI-MS：530[M+H] + 。
Example 7:
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1.4g (0.01 mol) of p-fluorobenzoic acid A7 and 6g (0.05 mol) of thionyl chloride are put into a reactor for reflux reaction for about 4 hours, and after the completion, the solvent is evaporated to dryness to obtain p-fluorobenzoyl chloride B7.
1.2g (0.012 mol) of KSCN was dissolved in 30ml of anhydrous acetonitrile, followed by dropwise addition to the reaction mixture to give p-fluorobenzoyl B7, followed by reflux reaction for about 4 hours, filtration and concentration under reduced pressure to give p-fluorobenzoyl isocyanate C7.
242mg (1 mmol) of p-fluorobenzoyl isocyanate and 315mg (1 mmol) of amino CA-4 were added to the reactor and dissolved in 30ml of anhydrous acetonitrile, and after the reaction was completed, the mixture was concentrated under reduced pressure and recrystallized from absolute ethanol. The product was purified by column chromatography (ethyl acetate: petroleum ether=1:3) to give 276.1mg of the yellow-brown Combretastatin A-4 derivative E7 in about 59% yield.
Combretastatin A-4 derivative E7 (Z) -1- (5- (3, 4, 5-trimethoxytyryl) -2-methoxyphenyl) -3- (4-fluorophenyl) thiourea containing thiourea structure.
1 H NMR(400MHz,CDCl 3 )δ7.47(s,1H),7.38–7.31(m,3H),7.17–7.10(m,2H),6.99(t,J＝3.5Hz,3H),6.81(d,J＝24.0Hz,2H),3.93(s,3H),3.89(s,6H),3.78(s,3H). 13 C NMR(100MHz,CDCl 3 )δ178.13,159.48,154.26,152.89,141.55,135.60,130.67,130.29,129.79,128.95,126.02,125.21,122.46,120.54,115.34,108.19,106.20,60.65,56.79.ESI-MS：469[M+H] + 。
Example 8:
2.48g (0.01 mol) of paraiodobenzoic acid A8 and 6g (0.05 mol) of thionyl chloride are put into a reactor for reflux reaction for about 4 hours, and after the completion, the solvent is evaporated to dryness to obtain paraiodobenzoyl chloride B8.
1.2g (0.012 mol) of KSCN was dissolved in 30ml of anhydrous acetonitrile, followed by dropwise addition to the reaction mixture to give p-iodobenzoyl B8, followed by reflux reaction for about 4 hours, filtration after completion of the reaction, and concentration under reduced pressure to give p-iodobenzoyl isocyanate C8.
242mg (1 mmol) of p-iodobenzoyl isocyanate and 315mg (1 mmol) of amino CA-4 were added to the reactor and dissolved in 30ml of anhydrous acetonitrile, and after the reaction was completed, the mixture was concentrated under reduced pressure and recrystallized from absolute ethanol, and the reaction was performed under reflux for about 3 hours. The product was purified by column chromatography (ethyl acetate: petroleum ether=1:3) to give 305.3mg of the yellow-brown Combretastatin A-4 derivative E8 having a thiourea structure in a yield of about 53%.
Combretastatin A-4 derivative E8 (Z) -1- (5- (3, 4, 5-trimethoxytyryl) -2-methoxyphenyl) -3- (4-fluorophenyl) thiourea containing thiourea structure.
1 H NMR(400MHz,CDCl 3 )δ7.82–7.68(m,2H),7.48–7.43(m,3H),7.32(s,1H),7.02(t,J＝9.6Hz,3H),6.77(d,J＝9.0Hz,2H),3.92(d,J＝8.4Hz,9H),3.80(s,3H). 13 C NMR(100MHz,CDCl 3 )δ178.13,154.26,152.89,141.55,139.20,137.41,130.67,130.29,129.79,128.95,126.02,125.21,121.51,120.54,108.19,106.20,93.16,60.65,56.79.ESI-MS：577[M+H] + 。
Example 9:
1.52g (0.01 mol) of p-methoxybenzoic acid A9 and 6g (0.05 mol) of thionyl chloride are put into a reactor for reflux reaction for about 4 hours, and after the completion, the solvent is evaporated to dryness to obtain p-methoxybenzoyl chloride B9.
1.2g (0.012 mol) of KSCN was dissolved in 30ml of anhydrous acetonitrile, followed by dropwise addition to the reaction mixture to give p-methoxybenzoyl B9, followed by reflux reaction for about 4 hours, filtration and concentration under reduced pressure to give p-methoxybenzoyl isocyanate C9.
242mg (1 mmol) of p-methoxybenzoyl isocyanate and 315mg (1 mmol) of amino CA-4 were added to the reactor and dissolved in 30ml of anhydrous acetonitrile, and after the reaction was completed, the mixture was concentrated under reduced pressure and recrystallized from absolute ethanol, followed by reflux reaction for about 3 hours. The product was purified by column chromatography (ethyl acetate: petroleum ether=1:3) to give 244.8mg of the brown-yellow thiourea-containing Combretastatin a-4 derivative E9 in about 53% yield.
Combretastatin A-4 derivative E9 (Z) -1- (5- (3, 4, 5-trimethoxytyryl) -2-methoxyphenyl) -3- (4-methoxyphenyl) thiourea containing thiourea structure.
1 H NMR(400MHz,CDCl 3 )δ7.48(s,1H),7.39–7.24(m,2H),7.23(s,1H),7.11–7.00(m,2H),7.00–6.85(m,3H),6.61(s,1H),6.55(s,1H),3.90(t,J＝9.8Hz,12H),3.80(s,3H). 13 C NMR(100MHz,CDCl 3 )δ178.13,154.84,154.26,152.89,141.55 133.03,130.67,130.29,129.79,128.95,126.02,125.21,122.23,120.54,114.13,108.19,106.20,60.65,56.79,56.04.ESI-MS：481[M+H] + 。
The effect of CA-4 and 9 thiourea derivatives thereof on proliferation of three tumor cells of HCT-116 (human colon adenocarcinoma), hepG2 (human liver cancer, A549 (human non-small cell lung adenocarcinoma)) is detected by an MTT method. Three tumor cell lines were subjected to a concentration gradient of 0.01, 0.1, 1, 10, and 100M for 72 hours, and the compound concentration was calculated at a compound inhibition ratio of 50%, and as a result, half inhibition concentration IC was used 50 The (M) value is shown in Table 1.
TABLE 1 half inhibition concentration IC of CA-4 and thiosemicarbazide derivatives thereof in HCT116, hepG2, A549 cells 50 (M)。
The experimental result shows that the synthesized CA-4 thiourea derivative has a certain antitumor activity, and part of the compounds have stronger antitumor activity than CA-4.
While the foregoing is directed to the preferred embodiments of the present invention, it will be appreciated by those skilled in the art that various modifications and adaptations can be made without departing from the principles of the present invention, and such modifications and adaptations are intended to be comprehended within the scope of the present invention.
Claims (3)
1. A Combretastatin A-4 derivative with a thiourea structure is characterized in that,
the Combretastatin A-4 derivative with the thiourea structure is one of the following compounds:
compound E1:
；
compound E2:
；
compound E3:
；
compound E4:
；
compound E5:
；
compound E6:
；
compound E7:
；
compound E8:
；
compound E9:
。
2. the Combretastatin a-4 derivative with a thiourea structure according to claim 1, characterized in that the synthetic route is as follows:
。
3. use of a Combretastatin a-4 derivative with a thiourea structure as claimed in claim 1, characterized in that it is used for preparing antitumor drugs.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210889785.7A CN115197113B (en) | 2022-07-27 | 2022-07-27 | Combretastatin A-4 derivative containing thiourea structure, preparation method and application thereof |
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| Synthesis and biological evaluation as antiangiogenic agents of ureas derived from 3’-aminocombretastatin A-4;Laura Conesa-Milian 等;European Journal of Medicinal Chemistry;第162卷;第781-792页 * |
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