CN112898217A - Trifluoromethyl oxazolone-containing compound, preparation method thereof and application thereof in anticancer drugs - Google Patents
Trifluoromethyl oxazolone-containing compound, preparation method thereof and application thereof in anticancer drugs Download PDFInfo
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Abstract
The invention discloses a trifluoromethyl oxazolone-containing compound, a preparation method thereof and application thereof in anticancer drugs, belonging to the field of organic chemistry. The trifluoromethyl oxazolone compound (3) is obtained by reacting 4-substituted-2-trifluoromethyl oxazolone (1) with alpha, beta-unsaturated ketone (2) under the catalysis of thiourea catalyst with high stereoselectivity and high enantioselectivity. The compounds have certain inhibition effect on HepG2 liver cancer cells, MGC-803 stomach cancer cells and PC-9 lung cancer cells. The method has the advantages of mild conditions, short reaction path, simple post-treatment and high selectivity, and two trifluoromethyl oxazolone-containing compounds with chiral centers can be obtained in one step.
Description
Technical Field
The invention belongs to the technical field of asymmetric synthesis in organic chemistry, and particularly relates to a trifluoromethyl oxazolone-containing compound, a preparation method thereof and application thereof in anticancer drugs.
Background
Organic fluorine compounds in agricultural chemicals, diagnostic tools,Biological research, new materials, medicines and the like have important positions. CF (compact flash)3The introduction of groups can change the properties of pKa, lipophilicity, molecular recognition, conformation, metabolic oxidation potential and the like of molecules to a certain extent, thereby influencing the efficacy, selectivity, absorption and metabolism of the molecules. The candidate drug containing the chiral trifluoromethyl group has important medicinal value, and according to statistics, 28 percent of all newly approved drugs approved by the U.S. Food and Drug Administration (FDA) in 2018 contain fluorine atoms or fluoroalkyl groups. More importantly, the 18 fluorine-containing drugs contain 49F atoms in total. Therefore, the introduction of trifluoromethyl into organic chiral molecules has been the focus of attention of chemists.
In 2005, the Ishihara group reported an alpha-CF with a chiral auxiliary3Aldol reaction of imines, alpha-CF3The imine is converted into the corresponding silanol, titanium enol and aldehyde respectively to give good diastereoselective products (Shimada, T.; Yoshioka, M.; Konno, T.; Ishihara, T. org. Lett.2006,8, 1129-1131.). In 2006, the Franck group reported a similar strategy, i.e. using TiCl4TMEDA promotes alpha-CF with chiral auxiliary3Aldol reaction of imines with aldehydes (Franck, X.; Seon-Meniel, B.; Figade re, B.Angew. chem., Int. Ed.2006,45, 5174-5176.). However, alpha-CF3There is no general method for the enolate to participate catalytically in an asymmetric reaction.
Although the above construction of chiral centers containing CF3The strategy of class of compounds has made great progress, but alpha-CF3Nucleophilic reagents of the kind limited to alpha-CF3Imine, alpha-CF3Thioesters and trifluoromethylimines. Thus, a novel alpha-CF was developed3The nucleophilic reagent has important research value when being applied to the organic asymmetric catalytic reaction and needs to be researched.
Disclosure of Invention
The invention aims to provide a trifluoromethyl oxazolone-containing compound, a preparation method thereof and application thereof in anticancer drugs. 4-substituted-2-trifluoromethyl oxazolone (1) and alpha, beta-unsaturated ketone (2) are adopted to react with high stereoselectivity and high enantioselectivity under the catalysis of thiourea catalyst to obtain trifluoromethyl oxazolone compound (3). The compounds have certain inhibition effect on HepG2 liver cancer cells, MGC-803 stomach cancer cells and PC-9 lung cancer cells. The method has the advantages of mild conditions, short reaction path, simple post-treatment and high selectivity, and two trifluoromethyl oxazolone-containing compounds with chiral centers can be obtained in one step.
The invention relates to a trifluoromethyl oxazolone-containing compound, which has a structural formula as follows:
wherein Ar is phenyl, halophenyl, trifluoromethylphenyl, nitrophenyl, C1-C3 alkylphenyl, C1-C3 alkoxyphenyl, thienyl, furyl or naphthyl; r1Is carboxylate, alkylcarbonyl, phenylcarbonyl, phenyl, quinolinyl or phenylalkyl; r2Is C1-C6 alkyl, phenyl or benzyl.
Further, in the above technical scheme, Ar is C6H5、4-CF3C6H5、4-FC6H5、4-ClC6H5、4-BrC6H5、4-NO2C6H5、4-MeC6H5、3-CF3C6H5、3-FC6H5、3-ClC6H5、3-MeOC6H5、3-MeC6H5、2-BrC6H5、2-MeC6H5、3,4-Cl2C6H52-thienyl, 3-thienyl, 2-furyl or 2-naphthyl; r1Is C (O) OEt, C (O) OMe, C (O) C6H5、CH2CH2C6H5、C6H5Or a quinolyl group; r2Is CH3、C2H5、C4H9、C6H5、CH2C6H5Or C6H11。
The invention provides a preparation method of the trifluoromethyl oxazolone-containing compound, and the synthetic route is as follows:
the method comprises the following steps:
reacting 4-substituted-2-trifluoromethyl oxazolone (1) with alpha, beta-unsaturated ketone (2) in an organic solvent in the presence of a thiourea catalyst to obtain a trifluoromethyl oxazolone-containing compound (3).
Further, in the above technical scheme, the thiourea catalyst is selected from C1-C10, and has the following specific structure:
wherein: ar is 3,5- (CF)3)2Ph。
Further, in the above technical solution, the thiourea catalyst is preferably C10.
Further, in the above technical scheme, the molar ratio of the 4-substituted-2-trifluoromethyl oxazolone (1), the α, β -unsaturated ketone (2) and the thiourea catalyst is 1.2-1.5:1.0: 0.05-0.10.
Further, in the above technical solution, the organic solvent is selected from toluene, pentafluorobenzene, chlorobenzene, bromobenzene, trifluoromethylbenzene, xylene, bromotoluene or trimethylbenzene.
Furthermore, in the technical scheme, the reaction temperature is 20-30 ℃, and the reaction time is 1-96 hours.
The invention further provides application of the trifluoromethyl oxazolone-containing compound (3) in anticancer drugs.
Further, in the above technical scheme, the anti-cancer drug is a liver cancer, lung cancer or stomach cancer drug, more preferably a HepG2 liver cancer, PC-9 lung cancer or MGC-803 stomach cancer drug.
The invention has the beneficial effects that:
the invention adopts 4-substituted-2-trifluoromethyl oxazolone (1) and alpha, beta-unsaturated ketone (2) to react under the catalysis of thiourea catalyst to obtain trifluoromethyl oxazolone compound (3). The method has the advantages of mild conditions, short reaction path, simple post-treatment and high selectivity, and two trifluoromethyl oxazolone compounds containing chiral centers are obtained in one step. The compounds can be applied to anti-cancer drugs HepG2 liver cancer, PC-9 lung cancer or MGC-803 stomach cancer drugs.
Detailed Description
The technical solution of the present invention is further described in detail with reference to the following specific examples, but the scope of the present invention is not limited thereto. In all examples, the d.r. values were >20:1, unless otherwise specified.
Instruments and primary chemical reagents
Nuclear magnetic resonance apparatus of the type Bruker AVANCE NEO (switzerland) and Bruker AVANCE III HD600MHZ (switzerland); UltiMate3000 siemer on-the-fly high performance liquid chromatograph (usa).
The raw materials and solvents used in the implementation process of the invention are all purchased from commercial sources.
Example 1:
the synthesis of racemic compound 3 was as follows:
compound 1(0.15mmol,1.5equiv), catalyst (0.01mmol,0.1equiv), 1mL solvent and compound 2(0.1mmol,1.0equiv) were added to a reaction flask and reacted at 25 ℃, thin layer plate (TLC) was used to monitor the reaction, and after the reaction was completed, column chromatography (eluent PE: EA ═ 50:1-10:1) was performed to isolate racemic compound 3.
The catalyst is selected from organic base or inorganic base such as triethylamine, tetramethylguanidine, DBU, sodium hydroxide, etc. The solvent is selected from halogenated alkane, nitrile, ether, benzene and other solvents, the amount of the solvent only influences the reaction rate, and no other influence is caused.
Example 2:
a1a (0.075mmol), Cat. (0.005mmol), 2a (0.05mmol), solvent (0.5mL) unless otherwise noted.bIsolated yield.cThe dr values were obtained by hydrogen spectroscopic analysis of the crude product.dThe ee value was obtained by chiral column HPLC analysis.
In the process of screening reaction conditions, the influence of different chiral catalysts on the reaction is firstly examined (entries 1-10), and C10 is found to be the best chiral catalyst. Subsequently, the influence of various solvents on the reaction was examined (entries 11-18), and pentafluorobenzene was finally determined as the optimum solvent.
Examination of reaction conditions (taking entry 11 as an example), the synthesis procedure of compound 3a is as follows:
1a (0.075mmol,1.5eq), catalyst C10(0.005mmol,0.1eq), 0.5mL pentafluorobenzene and 2a (0.05mmol,1.0eq) were added to a reaction flask and reacted at 25 deg.C, the reaction was monitored by thin layer plate (TLC), and after 1h the column chromatography (eluent PE: EA: 50:1-10:1) was performed to give 3a as a yellow oil, 91% ee, 93% yield.1H NMR(600MHz,CDCl3)δ7.91-7.86(m,2H),7.54-7.50(m,1H),7.43-7.38(m,2H),4.11-3.98(m,2H),3.96(dd,J＝10.5,3.4Hz,1H),3.63(dd,J＝18.1,10.5Hz,1H),3.48(dd,J＝18.1,3.4Hz,1H),1.29(s,9H),1.20(t,J＝7.2Hz,3H).
Example 3:
1a (0.15mmol,1.5eq), catalyst C10(0.01mmol,0.1eq), 1mL pentafluorobenzene and 2b (0.1mmol,1.0eq) were added to a reaction flask and reacted at 25 deg.C, the reaction was monitored by thin layer plate (TLC), and after 1h the reaction was complete, column chromatography (eluent PE: EA ═ 50:1-10:1) was performed to give 3b as a white solid, 87% ee, 87% yield.1H NMR(400MHz,CDCl3)δ8.07(d,J＝8.2Hz,2H),7.76(d,J＝8.2Hz,2H),4.21-4.06(m,2H),4.04(dd,J＝10.3,3.5Hz,1H),3.73(dd,J＝18.3,10.3Hz,1H),3.57(dd,J＝18.3,3.5Hz,1H),1.37(s,9H),1.28(t,J＝7.1Hz,3H).
Example 4:
the reaction was carried out for 1h by replacing the starting material 2a in example 3 with 2c and carrying out the further experimental steps and purification procedures described in example 3 to give 3c as a colourless oil in 81% ee.1H NMR(400MHz,CDCl3)δ8.02-7.95(m,2H),7.19-7.11(m,2H),4.20-4.05(m,2H),4.01(dd,J＝10.4,3.5Hz,1H),3.67(dd,J＝18.1,10.4Hz,1H),3.52(dd,J＝18.1,3.5Hz,1H),1.35(s,9H),1.27(t,J＝7.2Hz,3H).
Example 5:
the starting material 2a from example 3 was replaced with 2d and reacted for 2h, the other experimental steps and purification were carried out according to example 3 to give 3d as a white solid in 91% ee and 81% yield.1H NMR(600MHz,CDCl3)δ7.89(d,J＝8.1Hz,2H),7.46(d,J＝8.1Hz,2H),4.18-4.11(m,1H),4.11-4.04(m,1H),4.01(dd,J＝10.5,3.3Hz,1H),3.66(dd,J＝18.1,10.5Hz,1H),3.51(dd,J＝18.1,3.3Hz,1H),1.36(s,9H),1.27(t,J＝7.2Hz,3H).
Example 6:
the starting material 2a from example 3 was replaced by 2e and reacted for 3h, the other experimental steps and purification were carried out according to example 3 to give 3e as a colorless oil in 92% ee and 94% yield.1H NMR(400MHz,CDCl3)δ7.82(d,J＝8.3Hz,2H),7.63(d,J＝8.3Hz,2H),4.20-4.11(m,1H),4.11-4.04(m,1H),4.01(dd,J＝10.4,3.5Hz,1H),3.66(dd,J＝18.2,10.4Hz,1H),3.51(dd,J＝18.2,3.5Hz,1H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 7:
the starting material 2a from example 3 was replaced with 2f and reacted for 3h, and the other experimental procedures and purification were carried out according to example 3 to give white crystals 3f in 85% ee and 90% yield.1H NMR(600MHz,CDCl3)δ8.33(d,J＝8.1Hz,2H),8.12(d,J＝8.1Hz,2H),4.20-4.13(m,1H),4.12-4.05(m,1H),4.02(dd,J＝10.4,3.4Hz,1H),3.75(dd,J＝18.2,10.4Hz,1H),3.59(dd,J＝18.2,3.4Hz,1H),1.36(s,9H),1.28(t,J＝7.1Hz,3H).
Example 8:
the starting material 2a from example 3 was replaced by 2g and reacted for 1h, and the other experimental steps and purification were carried out according to example 3 to give 3g of a pale yellow oil in 94% ee and 82% yield.1H NMR(600MHz,CDCl3)δ7.85(d,J＝7.9Hz,2H),7.27(d,J＝7.9Hz,2H),4.17-4.11(m,1H),4.10-4.04(m,1H),4.02(dd,J＝10.6,3.4Hz,1H),3.66(dd,J＝18.1,10.6Hz,1H),3.53(dd,J＝18.1,3.4Hz,1H),2.42(s,3H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 9:
the starting material 2a from example 3 was replaced by 2h, the reaction was carried out for 2h, the other experimental steps and the purification were carried out according to example 3, and a white solid was obtained in 3h, 84% ee and 74% yield.1H NMR(400MHz,CDCl3)δ8.20(s,1H),8.14(d,J＝7.8Hz,1H),7.86(d,J＝7.8Hz,1H),7.64(t,J＝7.8Hz,1H),4.21-4.05(m,2H),4.05-4.01(m,1H),3.72(dd,J＝18.2,10.4Hz,1H),3.56(dd,J＝18.2,3.4Hz,1H),1.36(s,9H),1.28(t,J＝7.1Hz,3H).
Example 10:
the compound 2a from example 3 was replaced by 2i and reacted for 2h, and the other experimental steps and purification were carried out according to example 3 to give 3i as a colorless oil in 81% ee.1H NMR(400MHz,CDCl3)δ7.76-7.72(m,1H),7.65-7.60(m,1H),7.51-7.43(m,1H),7.33-7.26(m,1H),4.20-4.03(m,2H),4.01(dd,J＝10.4,3.5Hz,1H),3.67(dd,J＝18.2,10.4Hz,1H),3.52(dd,J＝18.2,3.5Hz,1H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 11:
the starting material 2a from example 3 was replaced with 2j and reacted for 2h, the other experimental steps and purification were carried out according to example 3 to give 3j as a white solid in 88% ee and 97% yield.1H NMR(400MHz,CDCl3)δ7.94-7.89(m,1H),7.85-7.80(m,1H),7.59-7.54(m,1H),7.43(t,J＝7.8Hz,1H),4.20-4.04(m,2H),4.01(dd,J＝10.3,3.5Hz,1H),3.67(dd,J＝18.3,10.3Hz,1H),3.52(dd,J＝18.3,3.5Hz,1H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 12:
the starting material 2a from example 3 was changed to 2k and reacted for 2h, and the other experimental steps and purification were carried out according to example 3 to obtain white crystals 3k in 90% ee and 79% yield.1H NMR(600MHz,CDCl3)δ7.56-7.52(m,1H),7.46(s,1H),7.41-7.36(m,1H),7.16-7.12(m,1H),4.18-4.11(m,1H),4.11-4.05(m,1H),4.02(dd,J＝10.5,3.4Hz,1H),3.86(s,3H),3.67(dd,J＝18.1,10.5Hz,1H),3.54(dd,J＝18.1,3.4Hz,1H),1.36(s,9H),1.28(t,J＝7.1Hz,3H).
Example 13:
the starting material 2a from example 3 was replaced by 2l and reacted for 2h, the other experimental steps and purification were carried out according to example 3 to give 3l of a white solid in 92% ee and 92% yield.1H NMR(600MHz,CDCl3)δ7.75(m,2H),7.40(d,J＝7.5Hz,1H),7.36(t,J＝7.5Hz,1H),4.19-4.05(m,2H),4.03(dd,J＝10.7,3.3Hz,1H),3.68(dd,J＝18.2,10.7Hz,1H),3.54(dd,J＝18.2,3.3Hz,1H),2.41(s,3H),1.36(s,9H),1.27(t,J＝7.1Hz,3H).
Example 14:
the starting material 2a from example 3 was replaced by 2m and the reaction was carried out for 1h, the other experimental steps and the purification were carried out according to example 3, giving 3m as a colorless oil, 89% ee and 86% yield.1H NMR(400MHz,CDCl3)δ8.05-7.01(m,1H),7.80-7.75(m,1H),7.60-7.55(m,1H),4.20-4.03(m,2H),4.00(dd,J＝10.3,3.5Hz,1H),3.66(dd,J＝18.3,10.3Hz,1H),3.50(dd,J＝18.3,3.5Hz,1H),1.36(s,9H),1.28(t,J＝7.2Hz,3H).
Example 15:
the starting material 2a from example 3 was changed to 2n and reacted for 1h, and the other experimental procedures and purification were carried out according to example 3 to give 3n as a yellow oil in 67% ee and 87% yield.1H NMR(400MHz,CDCl3)δ7.66-7.60(m,1H),7.49-7.44(m,1H),7.42-7.36(m,1H),7.36-7.30(m,1H),4.24-4.06(m,2H),4.00(dd,J＝10.3,3.7Hz,1H),3.62(dd,J＝18.5,10.3Hz,1H),3.51(dd,J＝18.5,3.7Hz,1H),1.36(s,9H),1.30(t,J＝7.2Hz,3H).
Example 16:
the starting material 2a from example 3 was replaced by 2o and reacted for 2h, the other experimental steps and purification were carried out according to example 3 to give 3o as a colorless oil in a yield of 65% ee of 99%.1H NMR(400MHz,CDCl3)δ7.69(d,J＝7.6Hz,1H),7.41(t,J＝7.6Hz,1H),7.33-7.23(m,2H),4.24-4.05(m,2H),4.02(dd,J＝10.5,3.5Hz,1H),3.62(dd,J＝18.1,10.5Hz,1H),3.43(dd,J＝18.1,3.5Hz,1H),2.48(s,3H),1.36(s,9H),1.28(t,J＝7.1Hz,3H).
Example 17:
the starting material 2a from example 3 was replaced with 2p and reacted for 3h, and the other experimental steps and purification were carried out according to example 3 to give 3p as white crystals in 92% ee and 92% yield.1H NMR(600MHz,CDCl3)δ8.49(s,1H),8.02-7.97(m,2H),7.92-7.86(m,2H),7.63(t,J＝7.5Hz,1H),7.58(t,J＝7.5Hz,1H),4.20-4.13(m,1H),4.13-4.06(m,2H),3.85(dd,J＝17.9,10.4Hz,1H),3.71(dd,J＝17.9,3.4Hz,1H),1.38(s,9H),1.28(t,J＝7.2Hz,3H).
Example 18:
the starting material 2a from example 3 was replaced with 2q and reacted for 3h, and the other experimental procedures and purification were carried out according to example 3 to give 3q as a white solid in 91% ee and 85% yield.1H NMR(400MHz,CDCl3)δ8.10(dd,J＝2.9,1.3Hz,1H),7.53(dd,J＝5.1,1.3Hz,1H),7.34(dd,J＝5.1,2.9Hz,1H),4.18-4.10(m,1H),4.10-4.04(m,1H),4.00(dd,J＝10.3,3.6Hz,1H),3.59(dd,J＝17.9,10.3Hz,1H),3.46(dd,J＝17.9,3.6Hz,1H),1.35(s,9H),1.26(t,J＝7.1Hz,3H).
Example 19:
the reaction was carried out for 3h by changing the starting material 2a from example 3 to 2r, and the other experimental steps and purification were carried out in accordance with example 3 to give 3r as a colorless oil in 94% ee and 96% yield.1H NMR(600MHz,CDCl3)δ7.78-7.75(m,1H),7.69-7.66(m,1H),7.17-7.14(m,1H),4.17-4.10(m,1H),4.10-4.04(m,1H),4.01(dd,J＝10.5,3.4Hz,1H),3.62(dd,J＝17.6,10.5Hz,1H),3.50(dd,J＝17.6,3.4Hz,1H),1.36(s,9H),1.26(t,J＝7.3Hz,3H).
Example 20:
the starting material 2a from example 3 was changed to 2s and reacted for 1h, and the other experimental steps and purification were carried out according to example 3 to give 3s as a yellow oil in a yield of 81% ee.1H NMR(600MHz,CDCl3)δ7.60(d,J＝1.7Hz,1H),7.24(d,J＝3.6Hz,1H),6.56(dd,J＝3.6,1.7Hz,1H),4.17-4.04(m,2H),3.98(dd,J＝10.5,3.7Hz,1H),3.52(dd,J＝18.0,10.5Hz,1H),3.42(dd,J＝18.0,3.7Hz,1H),1.36(s,9H),1.26(t,J＝7.1Hz,3H).
Example 21:
the starting material 2a from example 3 was changed to 2t and reacted for 4h, and the other experimental procedures and purification were carried out according to example 3 to give 3t of a white solid in 89% ee and 83% yield.1H NMR(400MHz,CDCl3)δ7.98-7.92(m,2H),7.63-7.56(m,1H),7.52-7.44(m,2H),4.05(dd,J＝10.5,3.5Hz,1H),3.76-3.66(m,4H),3.57(dd,J＝18.3,3.5Hz,1H),1.36(s,9H).
Example 22:
the starting material 2a from example 3 was replaced by 2u and reacted for 60h, and the other experimental procedures and purification were carried out according to example 3 to give 3u as a white solid in 80% ee and 65% yield.1H NMR(600MHz,CDCl3)δ8.07(d,J＝7.7Hz,2H),7.96(d,J＝7.7Hz,2H),7.66-7.56(m,2H),7.51(t,J＝7.7Hz,2H),7.46(t,J＝7.7Hz,2H),5.23(dd,J＝10.4,2.9Hz,1H),4.10(dd,J＝18.5,10.4Hz,1H),3.80(dd,J＝18.5,2.9Hz,1H),1.06(s,9H).
Example 23:
the starting material 2a from example 3 was replaced with 2v and reacted for 96h, and the other experimental procedures and purification were carried out according to example 3 to give a white solid 3v in 94% ee and 90% yield.1H NMR(400MHz,CDCl3)δ7.96-7.91(m,2H),7.61-7.55(m,1H),7.51-7.44(m,2H),7.25-7.20(m,2H),7.19-7.13(m,1H),7.03-7.07(m,2H),3.59-3.48(m,1H),3.23-3.12(m,1H),3.07-2.96(m,1H),2.71-2.61(m,2H),2.02-1.90(m,1H),171-1.59(m,1H),1.34(s,9H).
Example 24:
the starting material 2a from example 3 was changed to 2w and reacted for 96h, and the other experimental steps and purification were carried out according to example 3 to give 3w as a yellow oil in 85% ee and 79% yield. 1H NMR (600MHz, CDCl3) δ 8.09-8.02(m,1H),8.00-7.94(m,2H),7.91-783(m,1H),7.76-7.69(m,1H),7.65-7.57(m,1H),7.56-7.48(m,2H),7.48-7.38(m,3H),4.81(dd, J ═ 10.4,2.5Hz,1H),4.47(dd, J ═ 18.5,10.4Hz,1H),3.87(dd, J ═ 18.5,2.5Hz,1H),0.74(s,9H).
Example 25:
the starting material 2a from example 3 was changed to 2x and reacted for 96h, and the other experimental steps and purification were carried out according to example 3 to give the compound 3x as a colorless oil in 86% ee and 67% yield. 1H NMR (400MHz, CDCl 3). delta.7.95-7.88 (m,2H),7.60-7.53(m,1H),7.49-7.41(m,2H),7.25-7.13(m,5H),4.65-4.59(m,1H),3.86-3.70(m,2H),0.97(s,9H).
Example 26
Determining toxicity of high optical purity compound 3h on HepG2 hepatocarcinoma cell, MGC-803 gastric cancer cell and PC-9 lung cancer cell by MTT method, and calculating half Inhibitory Concentration (IC) of each compound50)。
The determination method comprises the following specific steps:
maintenance of the tumor cell line in RPMI1640 containing 10% fetal bovine serum and 2mM glutamine by mass, promoted the cells to 5% CO by volume2Grown at 37 ℃ in a humidified incubator. 40uL cells were seeded (10000 cells/well) in growth medium in Corning black clear bottom 384-well plates at 37 ℃ with 5% CO by volume2Cultured overnight in the medium. A compound of the invention diluted serially in 100% DMSO by mass was added to the cells using Echo555 sonication dosing (Cacous total dose). The plates were incubated for an additional 2 hours and after gentle mixing of the media, 40uL of lysis buffer was added to each well. Greiner black high binding 384 well plates were covered with capture antibody and then blocked with 3% BAS by mass. The blocking solution was then removed and the 15uL lysate was transferred to Greiner black high binding 384 well plates and incubated for 2 hours. After gentle mixing and washing of the plates with PBS, 20uL of detection antibody was added and incubated for 2 hours. After gently mixing and washing the plates with PBS, 20uL of QuantaBlu fluorescent peroxidase substrate was added and incubated for 1 hour. 20uL of QuantaBlu stop solution was added to the plates and fluorescence was read using an Envision microplate detector with an excitation wavelength of 352nm and an emission wavelength of 460 nm. The data obtained for each compound was entered into an appropriate software package to perform curve fitting analysis. IC was determined based on this data and by calculating the concentration of compound required to obtain 50% effect50The value of (c).
IC of H22 liver cancer cell in 3H50The values are respectively 50.17,>100 and 70.06.
The above experimental results show that: 3h respectively has certain inhibiting effect on HepG2 liver cancer cells, MGC-803 stomach cancer cells and PC-9 lung cancer cells, so according to the general approach of drug development (firstly carrying out conventional anti-tumor in vitro screening and then carrying out targeted research), the compound can be used for preparing new anti-tumor drugs by salifying with acid acceptable for human bodies or mixing with medicinal carriers.
The foregoing embodiments have described the general principles, principal features and advantages of the invention. It will be understood by those skilled in the art that the present invention is not limited to the embodiments described above, which are merely illustrative of the principles of the present invention, and that various changes and modifications may be made without departing from the scope of the principles of the present invention, and the invention is intended to be covered by the appended claims.
Claims (10)
1. A trifluoromethyl oxazolone-containing compound is characterized in that the structural formula is as follows:
wherein Ar is phenyl, halophenyl, trifluoromethylphenyl, nitrophenyl, C1-C3 alkylphenyl, C1-C3 alkoxyphenyl, thienyl, furyl or naphthyl; r1Is carboxylate, alkylcarbonyl, phenylcarbonyl, phenyl, quinolinyl or phenylalkyl; r2Is C1-C6 alkyl, phenyl or benzyl.
2. The trifluoromethyl oxazolone-containing compound according to claim 1, characterized in that: ar is C6H5、4-CF3C6H5、4-FC6H5、4-ClC6H5、4-BrC6H5、4-NO2C6H5、4-MeC6H5、3-CF3C6H5、3-FC6H5、3-ClC6H5、3-MeOC6H5、3-MeC6H5、2-BrC6H5、2-MeC6H5、3,4-Cl2C6H52-thienyl, 3-thienyl, 2-furyl or 2-naphthyl; r1Is C (O) OEt, C (O) OMe, C (O) C6H5、CH2CH2C6H5、C6H5Or a quinolyl group; r2Is CH3、C2H5、C4H9、C6H5、CH2C6H5Or C6H11。
3. The process for preparing trifluoromethyl oxazolone-containing compounds as claimed in claim 1 or 2, characterized in that the synthetic route is as follows:
the method comprises the following steps:
reacting 4-substituted-2-trifluoromethyl oxazolone (1) with alpha, beta-unsaturated ketone (2) in an organic solvent in the presence of a thiourea catalyst to obtain a trifluoromethyl oxazolone-containing compound (3).
4. The method for preparing trifluoromethyl oxazolone-containing compounds according to claim 3, characterized in that: the thiourea catalyst is selected from
Wherein Ar is 3,5- (CF)3)2Ph。
5. The method for producing a trifluoromethyl-oxazolone-containing compound according to claim 3 or 4, characterized in that: the molar ratio of the 4-substituted-2-trifluoromethyl oxazolone (1), the alpha, beta-unsaturated ketone (2) and the thiourea catalyst is 1.2-1.5:1.0: 0.05-0.10.
6. The method for preparing trifluoromethyl oxazolone-containing compounds according to claim 3, characterized in that: the organic solvent is selected from toluene, pentafluorobenzene, chlorobenzene, bromobenzene, trifluoromethylbenzene, xylene, bromotoluene or trimethylbenzene.
7. The method for preparing trifluoromethyl oxazolone-containing compounds according to claim 3, characterized in that: the reaction temperature is 20-30 ℃, and the reaction time is 1-96 hours.
8. The use of trifluoromethyl oxazolone-containing compounds as claimed in claim 1 in anticancer drugs.
9. The use of trifluoromethyl oxazolone-containing compounds according to claim 8 in anticancer drugs, characterized in that: the anticancer drug is HepG2 liver cancer, PC-9 lung cancer or MGC-803 stomach cancer drug.
10. The use of trifluoromethyl oxazolone-containing compounds according to claim 9 in anticancer drugs, characterized in that: the trifluoromethyl oxazolone compound is
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| CN107652255A (en) * | 2017-11-03 | 2018-02-02 | 宁夏大学 | 2 (5H) furanone derivatives of a kind of chirality and its preparation method and the application in anti-cervical cancer and medicines resistant to liver cancer is prepared |
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| CN107652255A (en) * | 2017-11-03 | 2018-02-02 | 宁夏大学 | 2 (5H) furanone derivatives of a kind of chirality and its preparation method and the application in anti-cervical cancer and medicines resistant to liver cancer is prepared |
Non-Patent Citations (2)
| Title |
|---|
| HAO JIANG 等: "Acyl Phosphonates: Good Hydrogen Bond Acceptors and", 《JACS》 * |
| SHAO-YUN ZHANG 等: "Organocatalytic regioselective asymmetric Michael addition of azlactones to o-hydroxy chalcone derivatives", 《ORGANIC & BIOMOLECULAR CHEMISTRY》 * |
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