CN111995596A - 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound and application thereof - Google Patents
5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound and application thereof Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D277/24—Radicals substituted by oxygen atoms
Abstract
The invention discloses a 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound and application thereof. The compound has a structural formula shown in (I), and the series of compounds have simple preparation process, show certain antitumor activity, have certain inhibition activity on DNA topoisomerase and have strong cytotoxicity on human breast cancer cells and human colon cancer cells.
Description
Technical Field
The invention relates to a 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound and application thereof.
Background
The stilbenes are a group of natural compounds found in various plants, both wood-based constitutive metabolites and phytoalexins (nat. prod. rep.2012,29,1317-1333), which have the same skeletal Stilbene structure. The common natural stilbenes compounds mainly comprise resveratrol, resveratrol glycoside, piceatannol, pinosylvin, pterostilbene and the like. The stilbenes compounds are reported to have wide biological activity, such as multiple activities in the medical field, such as antioxidation (Life Sciences,1997,61(21):2103-2110), antibiosis (Antibiotics (Basel, Switzerland),2020,9(6)), antiphlogosis (J.Aerosol Med.Pulm.drug Deliv,2017,30, A21-A21), platelet aggregation inhibition (Arch.Pharm.Res,1999,22,401-403), prevention of cell canceration (chem.Med.chem.2017, 12,558-570), and the like; in the agricultural field, the insecticidal composition has activities such as antifungal (J.Nat.Pro d,2014,77(7): 1658-. Stilbene compounds are drawing attention of drug developers as a potential drug lead.
Thiazole compounds are important nitrogen-containing Heterocyclic compounds with wide biological activity, such as antibacterial (Iraqi J Sci,1979,20(1):75), antimicrobial (Heterocyclic Commun,2002,8(5): 433-. Therefore, the thiazole heterocyclic compound is widely applied to the field of medicament creation.
In view of the fact that both Stilbene compounds and thiazole heterocyclic compounds have good biological activity, the invention designs and synthesizes a novel 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound by replacing a benzene ring in a Stilbene skeleton with halophenyl thiazole by using active substructure splicing and biological isostere substitution methods, and aims to find out the new biological activity of the compound.
The research on the structure and the biological activity of the series of 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compounds designed and synthesized by the invention is not reported in documents.
Disclosure of Invention
In order to solve the technical problems in the prior art, the invention aims to provide a 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound, and the 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound provided by the invention has a simple preparation process and shows a certain antitumor activity.
The 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound is characterized in that the structural formula is shown as the formula (I):
in the formula (I), X ═ Cl and Br on a halogenated benzene ring, and H on the benzene ring is mono-substituted, di-substituted or unsubstituted by a substituent R; n is an integer of 0-2, and n represents the number of substituent groups R on a benzene ring; when n is 0, it represents that H on the benzene ring is unsubstituted; when n is 1, it represents that H on the benzene ring is monosubstituted with a substituent R; when n is 2, H on the benzene ring is disubstituted by a substituent R, and the substituents R on different substitution positions are the same or different; the substituent R is C1-C4 alkyl, C1-C3 halogenated alkyl, C1-C3 alkoxy or halogen.
The 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound is characterized in that in the formula (I), a substituent R is methyl, methoxy, tert-butyl, trifluoromethyl, F, Cl or Br.
The 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound is characterized in that in the formula (I), R (n) is o-methyl, m-methyl, p-methyl, o-methoxy, p-tert-butyl, p-methoxy, m-methoxy, p-trifluoromethyl, p-fluorine, o-chlorine, p-chlorine, o-bromine, m-bromine or 2, 4-dichloro, 3,4, 5-trimethoxy.
The synthesis method of the 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound is characterized by comprising the following steps of:
1) mixing 5-bromo-2- (bromomethyl) -4- (4-halophenyl) thiazole shown as a formula (II) and triethyl phosphite shown as a formula (III) in a molar ratio of 1: 1.2-2.0, then carrying out a reaction under a heating condition, and concentrating and removing redundant triethyl phosphite after TLC monitoring is carried out until the reaction is finished to obtain a concentrated solution;
2) adding a solvent DMF, sodium hydroxide and substituted benzaldehyde shown as a formula (IV) into the concentrated solution obtained in the step 1), reacting at room temperature, monitoring by TLC (thin layer chromatography) until the reaction is finished, and carrying out post-treatment on the reaction solution to obtain a 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound shown as a formula (I);
in the formula (IV), X ═ Cl and Br on a halogenated benzene ring, and H on the benzene ring is mono-substituted, di-substituted or unsubstituted by a substituent R; n is an integer of 0-2, and n represents the number of substituent groups R on a benzene ring; when n is 0, it represents that H on the benzene ring is unsubstituted; when n is 1, it represents that H on the benzene ring is monosubstituted with a substituent R; when n is 2, H on the benzene ring is disubstituted by a substituent R, and the substituents R on different substitution positions are the same or different; the substituent R is C1-C4 alkyl, C1-C3 halogenated alkyl, C1-C3 alkoxy or halogen.
The synthesis method of the 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound is characterized in that the ratio of the 5-bromo-2- (bromomethyl) -4- (4-halophenyl) thiazole shown in the formula (II) to the amount of the substituted benzaldehyde shown in the formula (IV) and the sodium hydroxide is 1: 1.0-3.0: 1.0-5.0.
The synthesis method of the 5-bromo-4- (4-halogenated phenyl) -2- (substituted styryl) thiazole compound is characterized in that the molar ratio of the 5-bromo-2- (bromomethyl) -4- (4-halogenated phenyl) thiazole shown in the formula (II) to a solvent DMF is 1: 2.0-20, and preferably 1: 4.0-10.
The synthesis method of the 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound is characterized in that in the step 1), the heating reaction temperature is 130-140 ℃, the heating reaction time is 1-3 hours, and in the step 2), the reaction time at room temperature is 2-5 hours.
The synthesis method of the 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound is characterized in that in the step 2), the step of post-treating the reaction liquid is as follows: after the reaction is finished, adding a large amount of ice water into the reaction liquid, stirring, extracting with ethyl acetate, desolventizing, and separating the residual liquid by column chromatography to obtain the novel 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound shown in the formula (I). Wherein the mass ratio of the added ice water to the 5-bromo-2- (bromomethyl) -4- (4-halophenyl) thiazole added in the step 1) is 35-50: 1.
The synthesis method of the 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound is characterized in that an eluant used for column chromatographic separation is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1: 5-10.
The 5-bromo-4- (4-halogenated phenyl) -2- (substituted styryl) thiazole compound is applied to the preparation of antitumor drugs.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound with a novel structure, which has a simple preparation process and shows a certain antitumor activity. The compounds Ia to Il shown in the embodiment of the invention have certain inhibitory activity on Top I (DNA topoisomerase) at a concentration of 50 mu M, wherein the compound Ii has better inhibitory activity on Top I, and the inhibitory activity is '+++'. The shown compound Ig has the strongest cytotoxicity on human breast cancer cells, and the IC thereof50The value is 6.32 +/-0.21 mu M, and Ib and Ie have strong cytotoxicity to human colon cancer cells and IC50The values were 3.32. + -. 0.41. mu.M and 4.15. + -. 0.76. mu.M, respectively.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1 synthesis of compound Ia (X ═ Br, r (n) ═ o-fluoro):
a100 mL three-necked flask was charged with 5-bromo-2- (bromomethyl) -4- (4-bromophenyl) thiazole (4.1g,10mmol), triethyl phosphite (2.5g,15mmol), heated to 140 deg.C for reaction, and the progress of the reaction was checked by TLC, after about 3 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (2.9g,40mmol), o-fluorobenzaldehyde (1.2g,10mmol) and sodium hydroxide (0.4g,10mmol) and reacted at room temperature. And (3) detecting the reaction process by TLC (thin layer chromatography), finishing the reaction for about 4 hours, then pouring the reaction liquid into ice water (135mL), stirring, extracting with ethyl acetate, desolventizing, and separating residual liquid by column chromatography by using a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:5 to obtain 1.39g of yellow solid, namely (E) -5-bromo-4- (4-bromophenyl) -2- (2-fluorophenylvinyl) thiazole, wherein the yield is calculated to be 31.6%. m.p. 140-141 ℃;
1H NMR(500MHz,Chloroform-d)7.89-7.85(m,2H),7.63-7.59(m,2H),7.57(d,J＝8.6Hz,1H),7.50(d,J＝16.5Hz,1H),7.36(d,J＝16.5Hz,1H),7.34(m,1H),7.19(t,J＝7.5Hz,1H),7.15-7.10(m,1H)；13C NMR(125MHz,Chloroform-d)166.3,161.8(d,J＝250.8Hz,C-F),152.1,132.2,131.5,130.6,130.1,128.0,128.9,126.3,124.5,123.4(d,J＝23.5Hz,C-C),122.9,116.3(d,J＝21.4Hz,C-C),103.6,29.7。
example 2 synthesis of compound Ib (X ═ Br, r (n) ═ p-fluoro):
a100 mL three-necked flask was charged with 5-bromo-2- (bromomethyl) -4- (4-bromophenyl) thiazole (4.1g,10mmol), triethyl phosphite (3.3g,20mmol), heated to 130 deg.C for reaction, and the progress of the reaction was checked by TLC, after about 2 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (4.0g,55mmol), p-fluorobenzaldehyde (1.2g,10mmol) and sodium hydroxide (1.3g,32mmol) and reacted at room temperature. And (3) detecting the reaction process by TLC (thin layer chromatography), finishing the reaction for about 4.5h, pouring the reaction liquid into ice water (140mL), stirring, extracting with ethyl acetate, desolventizing, and separating residual liquid by column chromatography by using a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:5 to obtain 1.45g of yellow solid, namely (E) -5-bromo-4- (4-bromophenyl) -2- (4-fluorophenylvinyl) thiazole, wherein the yield is 33.1% by calculation. m.p. 179-181 ℃;
1H NMR(500MHz,Chloroform-d)7.88-7.84(m,2H),7.63-7.59(m,2H),7.56-7.50(m,2H),7.33(d,J＝16.5Hz,1H),7.16(d,J＝16.5Hz,1H),7.14-7.07(m,2H)；13C NMR(125MHz,Chloroform-d)166.2,164.2(d,J＝251.8Hz,C-F),152.0,145.0,137.8,134.1,132.2,131.5,130.1,128.9(d,J＝8.4Hz,C-C),127.5,125.0,122.8,120.7,116.1(d,J＝21.9Hz,C-C)。
example 3 synthesis of compound Id (X ═ Br, r (n) ═ m bromine):
a100 mL three-necked flask was charged with 5-bromo-2- (bromomethyl) -4- (4-bromophenyl) thiazole (4.1g,10mmol), triethyl phosphite (3.3g,20mmol), heated to 140 deg.C for reaction, and the progress of the reaction was checked by TLC, after about 1 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (4.4g,60mmol), m-bromobenzaldehyde (1.85g,10mmol) and sodium hydroxide (0.4g,10mmol) and reacted at room temperature. And (3) detecting the reaction process by TLC (thin layer chromatography), ending the reaction for about 3 hours, pouring the reaction liquid into ice water (170mL), stirring, extracting with ethyl acetate, desolventizing, and separating the residual liquid by column chromatography by using a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:5 to obtain 3.4g of a yellow solid, namely (E) -5-bromo-4- (4-bromophenyl) -2- (3-bromophenylvinyl) thiazole, wherein the yield is calculated to be 68.7%. m.p. 182-185 ℃;
1H NMR(500MHz,Chloroform-d)7.95-7.93(m,2H),7.68(t,J＝1.5Hz,1H),7.50-7.44(m,4H),7.30-7.27(m,2H),7.22(d,J＝16.0Hz,1H)；13C NMR(125MHz,Chloroform-d)165.6,152.1,137.5,134.6,133.9,133.5,132.1,131.9-131.5,130.5,130.0,129.9,128.6,127.5,125.8,124.5,123.1,122.2,103.6,29.7。
example 4 synthesis of compound Ic (X ═ Br, r (n) ═ p-methoxy):
a100 mL three-necked flask was charged with 5-bromo-2- (bromomethyl) -4- (4-bromophenyl) thiazole (4.1g,10mmol), triethyl phosphite (2.0g,12mmol), heated to 130 deg.C for reaction, and the progress of the reaction was checked by TLC, after about 1 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (3.7g,50mmol), p-methoxybenzaldehyde (2.0g,15mmol) and sodium hydroxide (0.9g,22mmol) and reacted at room temperature. And (3) detecting the reaction process by TLC (thin layer chromatography), finishing the reaction for about 4 hours, then pouring the reaction liquid into ice water (185mL), stirring, extracting with ethyl acetate, desolventizing, and separating the residual liquid by column chromatography by using a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:6 to obtain 2.85g of a yellow solid, namely (E) -5-bromo-4- (4-bromophenyl) -2- (4-methoxystyryl) thiazole, wherein the yield is calculated to be 63.1%. 189-191 ℃ in m.p;
1H NMR(500MHz,Chloroform-d)7.85-7.80(m,2H),7.57(dd,J＝9.0,2.0Hz,2H),7.54-7.50(m,2H),7.43(d,J＝16.0Hz,1H),7.37(s,1H),7.26(d,J＝16.0Hz,1H),6.94(d,J＝8.5Hz,2H),3.86(s,3H)；13C NMR(125MHz,Chloroform-d)167.5,160.4,154.8,134.5,133.4,131.8,128.6,128.4,128.0,122.1,119.3,114.4,112.0,55.4,29.7。
example 5 synthesis of compound Ie (X ═ Br, r (n) ═ 3,4, 5-trimethoxy):
a100 mL three-necked flask was charged with 5-bromo-2- (bromomethyl) -4- (4-bromophenyl) thiazole (4.1g,10mmol), triethyl phosphite (3.3g,20mmol), heated to 135 deg.C for reaction, and TLC checked for reaction progress, after about 1.5 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (4.4g,60mmol), 3,4, 5-trimethoxybenzaldehyde (3.9g,20mmol) and sodium hydroxide (0.8g,20mmol) and reacted at room temperature. And (3) detecting the reaction process by TLC (thin layer chromatography), ending the reaction for about 3 hours, then pouring the reaction liquid into ice water (150mL), stirring, extracting with ethyl acetate, desolventizing, and separating the residual liquid by column chromatography by using a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:6 to obtain 3.0g of a yellow solid, namely (E) -5-bromo-4- (4-bromophenyl) -2- (3,4, 5-trimethoxystyryl) thiazole, wherein the calculated yield is 60.1%. 185-186 ℃ in m.p.;
1H NMR(500MHz,Chloroform-d)7.94(d,J＝8.5Hz,2H),7.45(d,J＝8.5Hz,2H),7.27(d,J＝16.0Hz,1H),7.15(d,J＝16.0Hz,1H),6.75(m,2H),3.92(s,9H)；13C NMR(125MHz,Chloroform-d)166.4,163.7,153.8,153.6,151.9,150.6,139.4,138.7,135.9,135.4,134.5,131.8,131.0,129.9,128.6,123.9,120.4,105.8,105.0,104.4,103.0,61.1,56.3,29.7。
example 6 synthesis of compound If (X ═ Br, r (n) ═ p-tert-butyl):
a100 mL three-necked flask was charged with 5-bromo-2- (bromomethyl) -4- (4-bromophenyl) thiazole (4.1g,10mmol), triethyl phosphite (2.5g,15mmol), heated to 140 deg.C for reaction, and the progress of the reaction was checked by TLC, after about 2.5 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (7.3g,100mmol), p-tert-butylbenzaldehyde (4.9g,30mmol) and sodium hydroxide (1.6g,40mmol) to react at room temperature. And (3) detecting the reaction process by TLC (thin layer chromatography), finishing the reaction for about 5 hours, then pouring the reaction liquid into ice water (200mL), stirring, extracting with ethyl acetate, desolventizing, and separating residual liquid by column chromatography by using a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:6 to obtain 2.68g of a yellow solid, namely (E) -5-bromo-4- (4-bromophenyl) -2- (4- (tert-butyl) styryl) thiazole, wherein the calculated yield is 56.2%. m.p. 70-73 ℃;
1H NMR(500MHz,Chloroform-d)7.95-7.92(m,2H),7.48(d,J＝8.5Hz,2H),7.47-7.44(m,4H),7.34(d,J＝16.0Hz,1H),7.21(d,J＝16.0Hz,1H),1.35(s,9H)；13C NMR(125MHz,Chloroform-d)166.7,152.8,151.8,135.4,134.5,132.6,131.8,129.9,128.5,127.1,125.9,120.2,102.8,34.8,31.2。
example 7 synthesis of compound Ih (X ═ Cl, r (n) ═ o-fluorine):
a100 mL three-necked flask was charged with 5-bromo-2- (bromomethyl) -4- (4-chlorophenyl) thiazole (3.7g,10mmol), triethyl phosphite (3.3g,20mmol), heated to 130 deg.C for reaction, and the progress of the reaction was checked by TLC, after about 3 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (5.8g,80mmol), o-fluorobenzaldehyde (3.7g,30mmol) and sodium hydroxide (2.0g,50mmol) and reacted at room temperature. And (3) detecting the reaction process by TLC (thin layer chromatography), finishing the reaction for about 5 hours, then pouring the reaction liquid into ice water (120mL), stirring, extracting with ethyl acetate, desolventizing, and separating residual liquid by column chromatography by using a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:8 to obtain 1.7g of yellow solid, namely (E) -5-bromo-4- (4-chlorophenyl) -2- (2-fluorostyryl) thiazole with the yield of 42.4%. m.p. 149-151 ℃;
1H NMR(500MHz,Chloroform-d)7.96-7.91(m,1H),7.89–7.83(m,1H),7.50(d,J＝16.5Hz,1H),7.48–7.39(m,3H),7.34(d,J＝16.5Hz,1H),7.24–7.16(m,2H),6.95(d,J＝7.0Hz,1H)；13C NMR(125MHz,Chloroform-d)166.2,163.2,161.8(d,J＝250.8Hz,C-F),152.0,150.7,134.5,131.7,130.6,129.8,128.5,128.0,127.8,126.3,124.5,123.4(d,J＝23.0Hz,C-C),123.3,116.3(d,J＝21.4Hz,C-C),103.6,100.0,29.7。
example 8 synthesis of compound Ii (X ═ Cl, r (n) ═ m bromine):
a100 mL three-necked flask was charged with 5-bromo-2- (bromomethyl) -4- (4-chlorophenyl) thiazole (3.7g,10mmol), triethyl phosphite (2.5g,15mmol), heated to 135 deg.C for reaction, and the progress of the reaction was checked by TLC, after about 1.5 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (2.9g,40mmol), m-bromobenzaldehyde (3.7g,20mmol) and sodium hydroxide (0.8g,20mmol) and reacted at room temperature. And (3) detecting the reaction process by TLC (thin layer chromatography), ending the reaction for about 3.5h, pouring the reaction liquid into ice water (185mL), stirring, extracting with ethyl acetate, desolventizing, and separating the residual liquid by column chromatography by using a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:8 to obtain 2.2g of yellow solid, namely (E) -5-bromo-4- (4-chlorophenyl) -2- (3-bromostyryl) thiazole, wherein the yield is 47.9%. m.p. 169-171 ℃;
1H NMR(500MHz,Chloroform-d)7.95-7.91(m,2H),7.70(t,J＝1.5Hz,1H),7.50-7.44(m,4H),7.30-7.27(m,2H),7.22(d,J＝16.0Hz,1H)；13C NMR(125MHz,Chloroform-d)165.6,152.1,137.5,134.6,133.9,133.5,132.1,131.9–131.5,130.5,130.0,129.9,128.6,127.5,125.8,124.5,123.1,122.2,103.6,29.7。
example 9 synthesis of the compound Ig (X ═ Cl, r (n) ═ p-trifluoromethyl):
a100 mL three-necked flask was charged with 5-bromo-2- (bromomethyl) -4- (4-chlorophenyl) thiazole (3.7g,10mmol), triethyl phosphite (2.5g,15mmol), heated to 130 deg.C for reaction, and the progress of the reaction was checked by TLC, after about 1 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (4.4g,60mmol), p-trifluoromethylbenzaldehyde (3.5g,20mmol) and sodium hydroxide (0.8g,20mmol) and reacted at room temperature. And (3) detecting the reaction process by TLC (thin layer chromatography), finishing the reaction for about 3 hours, then pouring the reaction liquid into ice water (165mL), stirring, extracting with ethyl acetate, desolventizing, and separating the residual liquid by column chromatography by using a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:8 to obtain 2.3g of yellow solid, namely (E) -5-bromo-4- (4-chlorophenyl) -2- (4- (trifluoromethyl) styryl) thiazole with the yield of 51.4%. m.p. 121-123 ℃;
1H NMR(500MHz,Chloroform-d)7.95-7.91(m,2H),7.68-7.61(m,4H),7.48-7.43(m,2H),7.39(d,J＝16.5Hz,1H),7.30(d,J＝16.0Hz,1H)；13C NMR(125MHz,Chloroform-d)165.4,152.2,138.8,134.7,133.4,131.6,130.8(q,J＝32.5Hz,C-CF3),129.9,128.6,127.3,125.9(q,J＝3.8Hz,C-C),125.0(d,J＝270.0Hz,CF3),123.1,103.9。
example 10 synthesis of compound Ij (X ═ Cl, r (n) ═ m-methoxy):
a100 mL three-necked flask was charged with 5-bromo-2- (bromomethyl) -4- (4-chlorophenyl) thiazole (3.7g,10mmol), triethyl phosphite (3.0g,18mmol), heated to 140 deg.C for reaction, and the progress of the reaction was checked by TLC, after about 2.5 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (5.1g,70mmol), m-methoxybenzaldehyde (4.1g,30mmol) and sodium hydroxide (1.6g,40mmol) and reacted at room temperature. Detecting the reaction process by TLC (thin layer chromatography), wherein the reaction is finished for about 4.5h, then pouring the reaction solution into ice water (165mL), stirring, extracting with ethyl acetate, desolventizing, and separating the residual liquid by column chromatography with a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:10 to obtain 1.66g of yellow solid, namely (E) -5-bromo-4- (4-chlorophenyl) -2- (3-methoxystyryl) thiazole, wherein the yield is 40.9%, and the m.p. is 103-105 ℃;
1H NMR(500MHz,Chloroform-d)7.94-7.91(m,2H),7.47-7.43(m,2H),7.35-7.30(m,1H),7.34(d,J＝16.5Hz,1H),7.24(d,J＝16.5Hz,1H),7.14(d,J＝7.5Hz,1H),7.08-7.07(m,1H),6.92(ddd,J＝8.0,2.5,0.5Hz,1H),3.86(s,3H)；13C NMR(125MHz,Chloroform-d)166.4,160.0,152.0,136.8,135.4,134.6,131.8,130.0,128.6,121.3,120.0,115.3,112.1,103.2,55.4。
example 11 synthesis of compound Ik (X ═ Cl, r (n) ═ 3,4, 5-trimethoxy):
a100 mL three-necked flask was charged with 5-bromo-2- (bromomethyl) -4- (4-chlorophenyl) thiazole (3.7g,10mmol), triethyl phosphite (3.0g,18mmol), heated to 140 deg.C for reaction, and the progress of the reaction was checked by TLC, after about 1 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (4.4g,60mmol), 3,4, 5-trimethoxybenzaldehyde (4.9g,25mmol) and sodium hydroxide (2.0g,50mmol) and reacted at room temperature. Detecting the reaction process by TLC (thin layer chromatography), wherein the reaction is finished for about 5 hours, then pouring the reaction liquid into ice water (170mL), stirring, extracting with ethyl acetate, desolventizing, and separating the residual liquid by column chromatography with a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:10 to obtain 1.9g of yellow solid, namely (E) -5-bromo-4- (4-chlorophenyl) -2- (3,4, 5-trimethoxy styryl) thiazole, wherein the yield is 40.6%, and m.p. is 162-164 ℃;
1H NMR(500MHz,Chloroform-d)7.92(d,J＝8.5Hz,2H),7.44(d,J＝8.5Hz,2H),7.27(d,J＝16.0Hz,1H),7.17(d,J＝16.0Hz,1H),6.75(m,2H),3.92(s,9H)；13C NMR(125MHz,Chloroform-d)166.4,163.7,153.8,153.6,151.9,150.6,139.4,138.7,135.9,135.4,134.5,131.8,131.0,129.9,128.6,123.9,120.4,105.8,105.0,104.4,103.0,61.1,56.3,29.7。
example 12 synthesis of compound Il (X ═ Cl, r (n) ═ p-tert-butyl):
a100 mL three-necked flask was charged with 5-bromo-2- (bromomethyl) -4- (4-chlorophenyl) thiazole (3.7g,10mmol), triethyl phosphite (3.3g,20mmol), heated to 135 deg.C for reaction, and the progress of the reaction was checked by TLC, after about 1.5 h. Concentrating to remove redundant triethyl phosphite to obtain concentrated solution; to the resulting concentrated solution were added DMF (2.9g,40mmol), p-tert-butylbenzaldehyde (3.2g,20mmol) and sodium hydroxide (0.8g,20mmol) to react at room temperature. Detecting the reaction process by TLC (thin layer chromatography), wherein the reaction is finished for about 3 hours, then pouring the reaction liquid into ice water (185mL), stirring, extracting with ethyl acetate, desolventizing, and separating the residual liquid by column chromatography with a mixed liquid of ethyl acetate and petroleum ether in a volume ratio of 1:8 to obtain 2.2g of a yellow solid, namely (E) -5-bromo-4- (4-chlorophenyl) -2- (4- (tert-butyl) styryl) thiazole, wherein the yield is 50.8%, and the m.p. is 77-79 ℃;
1H NMR(500MHz,Chloroform-d)7.95-7.91(m,2H),7.49(d,J＝8.5Hz,2H),7.47-7.41(m,4H),7.34(d,J＝16.0Hz,1H),7.23(d,J＝16.0Hz,1H),1.36(s,9H)；13C NMR(125MHz,Chloroform-d)166.7,152.8,151.8,135.4,134.5,132.6,131.8,129.9,128.5,127.1,125.9,120.2,102.8,34.8,31.2。
example 13Top1 inhibition activity assay:
the novel 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compounds prepared in examples 1 to 12 were labeled as test compounds and subjected to a Top1 (topoisomerase 1) inhibition activity test at a test concentration of 50 μ M.
(1) Experimental principle and preparation method of topoisomerase 1(Top1)
The enzyme used for the experiment is topoisomerase I (Top I), and the experimental reagent is the 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound prepared in the example 1-12 (whether the topoisomerase I is inhibited or not is tested). If the compound has anti-tumor activity, a band in which supercoils can appear is particularly shown on an electrophoretogram.
The experimental DNA was pBR 322.
The preparation method is as follows, and the reaction system volume of the following three preparations is 20. mu.L.
1. Blank DNA sample: mu.L pBR322 (0.5. mu.g/. mu.L) + 19. mu.L BSA
Sample 1: mu.L test compound + 1. mu.L pBR322 (0.5. mu.g/uL) + 1. mu.L Top1 (1. mu.L) + 16. mu.LBSA
Sample 2: mu.L CPT + 1. mu.L pBR322 (0.5. mu.g/. mu.L) + 1. mu.L Top1 (1. mu.L) + 16. mu.L BSA
2. After the samples were prepared, they were incubated at 37 ℃ for half an hour, respectively. After incubation, 4. mu.L of 6 XLoading Buffer was added and mixed, and the mixture was applied to a sample well of 0.8% agarose gel and electrophoresed at 4.6V/cm for 1.5 hours.
3. After the electrophoresis was completed, the agarose gel was stained in an aqueous solution of 1 Xgel red for 0.5 hour, and photographed.
Note: CPT: positive control drug BSA: bovine serum albumin
The test results are shown in Table 1.
TABLE 1 screening test results for anti-cancer Activity of Compounds Ia-Il
Note a: TOP I (topoisomerase I) DNA Loose assay inhibitory Activity CPT (positive control drug having inhibitory activity against TOP I) was used as a control group. The data obtained are quantified relative to CPT 50. mu.M as follows: + + + + +, indicating an activity of 80% or more; + + + + represents between 40% and 79%; + means between 10% and 39%; +, less than 10% activity.
As is clear from the experimental results shown in Table 1, the compounds Ia to Il shown in the examples of the present invention all have certain inhibitory activity against Top I (DNA topoisomerase) at a concentration of 50. mu.M, wherein the compound Ii has a good inhibitory activity against Top I, and the inhibitory activity is "+++".
Example 14 cytotoxicity assay:
the novel 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compounds prepared in examples 1 to 12 were labeled as test compounds and subjected to cytotoxicity test by MTT method.
The experimental method comprises the following steps: the cells used for the experiment were human breast cancer cells (MCF-7) and human colon cancer cells (HCT116), and the experimental agent was 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound prepared in examples 1 to 12. The experimental principle of the MTT method is that the activity of enzymes in mitochondria is utilized, specific tetrazolium salts can be converted, and then the light absorption value is detected by an enzyme-linked immunosorbent assay, so that the number of living cells can be indirectly reflected.
The experimental steps are as follows:
1. collecting cells in logarithmic phase, and adjusting the cell density to be 5 multiplied by 10^4 cells/mL;
2. the cells were seeded at 100. mu.L/well in 96-well plates at 37 ℃ in 5% CO2Culturing for 24 hours under the condition;
3. old medium was removed from 96-well plates and different concentrations (100. mu.M, 10. mu.M, 1. mu.M, 0.1. mu.M) were added0.01. mu.M) of drug-containing medium, 100. mu.L/well, at 37 ℃ with 5% CO2Culturing for 72 hours under the condition;
4. mu.L of 2.5mg/mL MTT solution was added to each well and 5% CO at 37 ℃2Culturing for 4 hours under the condition;
5. remove the well solution and add 100 μ L DMSO per well;
6. placing the 96-well plate in an enzyme labeling instrument, and detecting the light absorption value at 570nm/490 nm;
7. calculating the inhibition rate of the compound on cells, wherein the formula is as follows: inhibition rate ═ 1- (A)Experiment of-ABlank space)]/(AControl of-ABlank space) And calculating the half inhibitory concentration IC from the inhibition ratio50The value is obtained.
The test results are shown in Table 2.
TABLE 2 cytotoxicity test results of Compounds Ia to Il
The results in Table 2 show that the compound Ig of the present invention, as shown in the examples, is the most cytotoxic to human breast cancer cells and has an IC50The values are 6.32 + -0.21. mu.M, Ib and Ie have good cytotoxicity on human colon cancer cells, IC thereof50The values were 3.32. + -. 0.41. mu.M and 4.15. + -. 0.76. mu.M, respectively.
The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (6)
1. A5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound is characterized in that the structural formula is shown as the formula (I):
in the formula (I), X ═ Cl and Br on a halogenated benzene ring, and H on the benzene ring is mono-substituted, di-substituted or unsubstituted by a substituent R; n is an integer of 0-2, and n represents the number of substituent groups R on a benzene ring; when n is 0, it represents that H on the benzene ring is unsubstituted; when n is 1, it represents that H on the benzene ring is monosubstituted with a substituent R; when n is 2, H on the benzene ring is disubstituted by a substituent R, and the substituents R on different substitution positions are the same or different; the substituent R is C1-C4 alkyl, C1-C3 halogenated alkyl, C1-C3 alkoxy or halogen.
2. The 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound according to claim 1, wherein in the formula (I), the substituent R is methyl, methoxy, tert-butyl, trifluoromethyl, F, Cl or Br.
3. The 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound according to claim 1, wherein R (n) in the formula (I) is o-methyl, m-methyl, p-methyl, o-methoxy, p-tert-butyl, p-methoxy, m-methoxy, p-trifluoromethyl, p-fluoro, o-chloro, p-chloro, o-bromo, m-bromo, or 2, 4-dichloro, 3,4, 5-trimethoxy.
4. Use of the 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compound according to claim 1 for the preparation of an antitumor agent.
5. The use of 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compounds according to claim 4 for the preparation of antitumor agents for the inhibition of DNA topoisomerase.
6. The use of 5-bromo-4- (4-halophenyl) -2- (substituted styryl) thiazole compounds according to claim 4 for the preparation of antitumor agents for the prevention and treatment of human breast cancer cells and human colon cancer cells.
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